650
Views
1
CrossRef citations to date
0
Altmetric
Review

The role of phosphoinositide 3-kinases in immune-inflammatory responses: potential therapeutic targets for abdominal aortic aneurysm

, , &
Pages 2339-2364 | Received 30 Mar 2021, Accepted 23 Jun 2022, Published online: 06 Jul 2022

References

  • Li G, Qin L, Wang L, et al. Inhibition of the mTOR pathway in abdominal aortic aneurysm: implications of smooth muscle cell contractile phenotype, inflammation, and aneurysm expansion. Am J Physiol Heart Circ Physiol. 2017;312(6):H1110–H1119.
  • Luebke T, Brunkwall J. Risk-adjusted meta-analysis of 30-day mortality of endovascular versus open repair for ruptured abdominal aortic aneurysms. Ann Vasc Surg. 2015;29(4):845–863.
  • Daugherty A, Cassis L. Mechanisms of abdominal aortic aneurysm formation. Curr Atheroscler Rep. 2002;4(3):222–227.
  • Zhang S, Du X, Chen Y-Q, et al. Potential medication treatment according to pathological mechanisms in abdominal aortic aneurysm. J Cardiovasc Pharmacol. 2018;71(1):46–57.
  • Yan Y, Fan J, Bai S-L, et al. Zinc prevents abdominal aortic aneurysm formation by induction of a20-mediated suppression of NF-κB pathway. PloS one. 2016;11(2):e0148536.
  • Rateri D, Howatt DA, Moorleghen JJ, et al. Prolonged infusion of angiotensin II in apoE(-/-) mice promotes macrophage recruitment with continued expansion of abdominal aortic aneurysm. Am J Pathol. 2011;179(3):1542–1548.
  • Wang J, Lindholt JS, Sukhova GK, et al. IgE actions on CD 4 + T cells, mast cells, and macrophages participate in the pathogenesis of experimental abdominal aortic aneurysms. EMBO Mol Med. 2014;6(7):952–969.
  • Forester N, Cruickshank SM, Scott DJA, et al. Increased natural killer cell activity in patients with an abdominal aortic aneurysm. Br J Surg. 2006;93(1):46–54.
  • Eliason J, Hannawa KK, Ailawadi G, et al. Neutrophil depletion inhibits experimental abdominal aortic aneurysm formation. Circulation. 2005;112(2):232–240.
  • Longo G, Xiong W, Greiner TC, et al. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest. 2002;110(5):625–632.
  • Longo G, Buda SJ, Fiotta N, et al. MMP-12 has a role in abdominal aortic aneurysms in mice. Surgery. 2005;137(4):457–462.
  • Rizzo R, McCarthy WJ, Dixit SN, et al. Collagen types and matrix protein content in human abdominal aortic aneurysms. J Vasc Surg. 1989;10(4):365–373.
  • Keeling W, Armstrong PA, Stone PA, et al. An overview of matrix metalloproteinases in the pathogenesis and treatment of abdominal aortic aneurysms. Vasc Endovascular Surg. 2005;39(6):457–464.
  • Culav E, Clark C, Merrilees M. Connective tissues: matrix composition and its relevance to physical therapy. Phys Ther. 1999;79(3):308–319.
  • Yamaguchi T, Yokokawa M, Suzuki M, et al. The effect of immunosuppression on aortic dilatation in a rat aneurysm model. Surg Today. 2000;30(12):1093–1099.
  • Liu Y, Liao J, Zhao M, et al. Increased expression of TLR2 in CD4 + T cells from SLE patients enhances immune reactivity and promotes IL-17 expression through histone modifications. Eur J Immunol. 2015;45(9):2683–2693.
  • Jagadesham V, Scott D, Carding S. Abdominal aortic aneurysms: an autoimmune disease? Trends Mol Med. 2008;14(12):522–529.
  • Nunes-Santos C, Uzel G, Rosenzweig S. PI3K pathway defects leading to immunodeficiency and immune dysregulation. J Allergy Clin Immunol. 2019;143(5):1676–1687.
  • Elmenier F, Lasheen D, Abouzid K. Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer. Eur J Med Chem. 2019;183:111718.
  • Duronio V. The life of a cell: apoptosis regulation by the PI3K/PKB pathway. Biochem J. 2008;415(3):333–344.
  • Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606–619.
  • Basu A, Lambring C. Akt isoforms: a family affair in breast cancer. Cancers (Basel). 2021;13(14):3445.
  • Giacinti C, Giordano A. RB and cell cycle progression. Oncogene. 2006;25(38):5220–5227.
  • Chen K, Jiao X, Di Rocco A, et al. Endogenous cyclin D1 promotes the rate of onset and magnitude of mitogenic signaling via Akt1 Ser473 phosphorylation. Cell Rep. 2020;32(11):108151.
  • Abukhdeir A, Park B. P21 and p27: roles in carcinogenesis and drug resistance. Expert Rev Mol Med. 2008;10:e19.
  • Li Y, Dowbenko D, Lasky L. AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. J Biol Chem. 2002;277(13):11352–11361.
  • Héron-Milhavet L, Franckhauser C, Rana V, et al. Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding. Mol Cell Biol. 2006;26(22):8267–8280.
  • Yang X, Feng Y, Liu Y, et al. Fuzheng Jiedu Xiaoji formulation inhibits hepatocellular carcinoma progression in patients by targeting the AKT/CyclinD1/p21/p27 pathway. Phytomedicine. 2021;87:153575.
  • Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9(6):400–414.
  • Mayo L, Donner D. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A. 2001;98(20):11598–11603.
  • Linton M, Moslehi J, Babaev V. Akt signaling in macrophage polarization, survival, and atherosclerosis. Int J Mol Sci. 2019;20(11):2703.
  • Gardai S, Hildeman DA, Frankel SK, et al. Phosphorylation of bax ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem. 2004;279(20):21085–21095.
  • Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96(6):857–868.
  • Maurer U, Charvet C, Wagman AS, et al. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006;21(6):749–760.
  • Sellge G, Kufer T. PRR-signaling pathways: learning from microbial tactics. Semin Immunol. 2015;27(2):75–84.
  • Hontelez S, Sanecka A, Netea MG, et al. Molecular view on PRR cross-talk in antifungal immunity. Cell Microbiol. 2012;14(4):467–474.
  • Pryshchep O, Ma-Krupa W, Younge BR, et al. Vessel-specific toll-like receptor profiles in human medium and large arteries. Circulation. 2008;118(12):1276–1284.
  • Richards M, Black AS, Bonnet DJ, et al. The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic low density lipoprotein receptor knockout mice. Innate Immun. 2013;19(1):20–29.
  • Yang Y, Ma Z, Yang G, et al. Alginate oligosaccharide indirectly affects toll-like receptor signaling via the inhibition of microRNA-29b in aneurysm patients after endovascular aortic repair. Drug Des Devel Ther. 2017;11:2565–2579.
  • Shang T, Ran F, Qiao Q, et al. Tanshinone IIA attenuates elastase-induced AAA in rats via inhibition of myd88-dependent TLR-4 signaling. VASA Z Gefasskrankheiten. 2014;43(1):39–46.
  • Pirianov G, Torsney E, Howe F, et al. Rosiglitazone negatively regulates c-Jun N-terminal kinase and toll-like receptor 4 proinflammatory signalling during initiation of experimental aortic aneurysms. Atherosclerosis. 2012;225(1):69–75.
  • Balistreri C. Genetic contribution in sporadic thoracic aortic aneurysm? Emerging evidence of genetic variants related to TLR-4-mediated signaling pathway as risk determinants. Vascul Pharmacol. 2015;74:1–10.
  • Lai C, Wang K-C, Lee F-T, et al. Toll-like receptor 4 is essential in the development of abdominal aortic aneurysm. PloS one. 2016;11(1):e0146565.
  • Qin Z, Bagley J, Sukhova G, et al. Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3. J Mol Cell Cardiol. 2015;87:160–170.
  • Fukao T, Tanabe M, Terauchi Y, et al. PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat Immunol. 2002;3(9):875–881.
  • Zhang X, Li N, Shao H, et al. Methane limit LPS-induced NF-κB/MAPKs signal in macrophages and suppress immune response in mice by enhancing PI3K/AKT/GSK-3β-mediated IL-10 expression. Sci Rep. 2016;6(1):29359.
  • Hazeki K, Kinoshita S, Matsumura T, et al. Opposite effects of wortmannin and 2-(4-morpholinyl)-8-phenyl-1(4 H)-benzopyran-4-one hydrochloride on toll-like receptor-mediated nitric oxide production: negative regulation of nuclear Factor-κB by phosphoinositide 3-kinase. Mol Pharmacol. 2006;69(5):1717–1724.
  • Fukao T, Koyasu S. PI3K and negative regulation of TLR signaling. Trends Immunol. 2003;24(7):358–363.
  • (Baltimore, Md.: 1950), Utsugi M, Dobashi K, Ono A, et al. PI3K p110beta positively regulates lipopolysaccharide-induced IL-12 production in human macrophages and dendritic cells and JNK1 plays a novel role. J Iimmunol. 2009;182(9):5225–5231.
  • Liu Q, Shan P, Li H. Gambogic acid prevents angiotensin II‑induced abdominal aortic aneurysm through inflammatory and oxidative stress dependent targeting the PI3K/Akt/mTOR and NF‑κB signaling pathways. Mol Med Rep. 2019;19(2):1396–1402.
  • Ma X, Yao H, Yang Y, et al. miR-195 suppresses abdominal aortic aneurysm through the TNF-α/NF-κB and VEGF/PI3K/Akt pathway. Int J Mol Med. 2018;41(4):2350–2358.
  • Huggins C, Pearce S, Peri F, et al. A novel small molecule TLR4 antagonist (IAXO-102) negatively regulates non-hematopoietic toll like receptor 4 signalling and inhibits aortic aneurysms development. Atherosclerosis. 2015;242(2):563–570.
  • Owens A, Rateri DL, Howatt DA, et al. MyD88 deficiency attenuates angiotensin II-induced abdominal aortic aneurysm formation independent of signaling through toll-like receptors 2 and 4. Arterioscler Thromb Vasc Biol. 2011;31(12):2813–2819.
  • Nagarsheth N, Wicha M, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017;17(9):559–572.
  • Marchese A. Endocytic trafficking of chemokine receptors. Curr Opin Cell Biol. 2014;27:72–77.
  • van der Vorst E, Döring Y, Weber C. Chemokines. Arterioscler Thromb Vasc Biol. 2015;35(11):e52–6.
  • Michineau S, Franck G, Wagner-Ballon O, et al. Chemokine (C-X-C motif) receptor 4 blockade by AMD3100 inhibits experimental abdominal aortic aneurysm expansion through anti-inflammatory effects. Arterioscler Thromb Vasc Biol. 2014;34(8):1747–1755.
  • Tanios F, Pelisek J, Lutz B, et al. CXCR4: a potential marker for inflammatory activity in abdominal aortic aneurysm wall. Eur J Vasc Endovasc Surg. 2015;50(6):745–753.
  • Mo X, Sun H. The anti-inflammatory effect of the CXCR4 antagonist-N15P peptide and its modulation on inflammation-associated mediators in LPS-induced PBMC. Inflammation. 2015;38(3):1374–1383.
  • Zhang H, Wang P, Zhang X, et al. SDF1/CXCR4 axis facilitates the angiogenesis via activating the PI3K/AKT pathway in degenerated discs. Mol Med Rep. 2020;22(5):4163–4172.
  • Long M, Li -H-H, Pen X-Z, et al. Expression of chemokine receptor-4 in bone marrow mesenchymal stem cells on experimental rat abdominal aortic aneurysms and the migration of bone marrow mesenchymal stem cells with stromal-derived factor-1. Kaohsiung J Med Sci. 2014;30(5):224–228.
  • van den Borne P, Quax PHA, Hoefer IE, et al. The multifaceted functions of CXCL10 in cardiovascular disease. Biomed Res Int. 2014;2014:893106.
  • Gallo A, Saad A, Ali R, et al. Circulating interferon-γ-inducible Cys-X-Cys chemokine receptor 3 ligands are elevated in humans with aortic aneurysms and Cys-X-Cys chemokine receptor 3 is necessary for aneurysm formation in mice. J Thorac Cardiovasc Surg. 2012;143(3):704–710.
  • Smit M, Verdijk P, van der Raaij-helmer EMH, et al. CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- and phospholipase C-dependent pathway and not via activation of MEK/p44/p42 MAPK nor Akt/PI-3 kinase. Blood. 2003;102(6):1959–1965.
  • Barbi J, Cummings HE, Lu B, et al. PI3Kgamma (PI3Kgamma) is essential for efficient induction of CXCR3 on activated T cells. Blood. 2008;112(8):3048–3051.
  • Liu R, Huang J, Ge Y, et al. Inhibition of phosphatidylinositol 3-kinase γ by IPI-549 attenuates abdominal aortic aneurysm formation in mice. Eur J Vasc Endovasc Surg. 2020;60(2):254–263.
  • Anzai A, Shimoda M, Endo J, et al. Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture. Circ Res. 2015;116(4):612–623.
  • Kim N, Woo D-C, Joo SJ, et al. Reduction in renal ischemia-reperfusion injury in mice by a phosphoinositide 3-kinase p110gamma-specific inhibitor. Transplantation. 2015;99(10):2070–2076.
  • Nie H, Wang H-X, Tian C, et al. Chemokine (C-X-C motif) receptor 2 blockade by SB265610 inhibited angiotensin II-induced abdominal aortic aneurysm in apo E mice. Heart Vessels. 2019;34(5):875–882.
  • (London, England: 1979), Daugherty A, Rateri D, Charo I, et al. Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE-/- mice. Clin Sci. 2010;118(11):681–689.
  • MacTaggart J, Xiong W, Knispel R, et al. Deletion of CCR2 but not CCR5 or CXCR3 inhibits aortic aneurysm formation. Surgery. 2007;142(2):284–288.
  • Zhang J, Chen H, Liu L, et al. Chemokine (C-C motif) receptor 2 mediates mast cell migration to abdominal aortic aneurysm lesions in mice. Cardiovasc Res. 2012;96(3):543–551.
  • Li R, Paul A, Ko KWS, et al. Interleukin-7 induces recruitment of monocytes/macrophages to endothelium. Eur Heart J. 2012;33(24):3114–3123.
  • Klopf J, Brostjan C, Eilenberg W, et al. Neutrophil extracellular traps and their implications in cardiovascular and inflammatory disease. Int J Mol Sci. 2021;22(2):559.
  • (London England: 1979), Fougerat A, Gayral S, Malet N, et al. Phosphoinositide 3-kinases and their role in inflammation: potential clinical targets in atherosclerosis? Clin Sci. 2009;116(11):791–804.
  • Michel J, Martin-Ventura J-L, Egido J, et al. Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans. Cardiovasc Res. 2011;90(1):18–27.
  • Hannigan M, Zhan L, Li Z, et al. Neutrophils lacking phosphoinositide 3-kinase γ show loss of directionality during N -formyl-Met-Leu-Phe-induced chemotaxis. Proc Natl Acad Sci U S A. 2002;99(6):3603–3608.
  • Sasaki T, Sasaki J, Watanabe K, et al. Non-invasive visualization of the lipid product of class I PI3K in transgenic mouse models. Biochem Soc Trans. 2007;35(2):215–218.
  • Sapey E, Greenwood H, Walton G, et al. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood. 2014;123(2):239–248.
  • Manning B, Cantley L. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261–1274.
  • Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35.
  • Gordon S, Martinez F. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32(5):593–604.
  • Liu X, Shi Y, Birnbaum MJ, et al. Quantitative analysis of anti-apoptotic function of Akt in Akt1 and Akt2 double knock-out mouse embryonic fibroblast cells under normal and stressed conditions. J Biol Chem. 2006;281(42):31380–31388.
  • Mantovani A, Sica A, Sozzani S, et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–686.
  • (Baltimore, Md.: 1950), Dale M, Xiong W, Carson JS, et al. Elastin-derived peptides promote abdominal aortic aneurysm formation by modulating M1/M2 macrophage polarization. J Iimmunol. 2016;196(11):4536–4543.
  • Pope N, Salmon M, Davis JP, et al. D-series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization. FASEB J. 2016;30(12):4192–4201.
  • Rao J, Brown BN, Weinbaum JS, et al. Distinct macrophage phenotype and collagen organization within the intraluminal thrombus of abdominal aortic aneurysm. J Vasc Surg. 2015;62(3):585–593.
  • Raffort J, Lareyre F, Clément M, et al. Monocytes and macrophages in abdominal aortic aneurysm. Nat Rev Cardiol. 2017;14(8):457–471.
  • (Baltimore, Md.: 1950), Stout R, Jiang C, Matta B, et al. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Iimmunol. 2005;175(1):342–349.
  • Covarrubias A, Aksoylar H, Horng T. Control of macrophage metabolism and activation by mTOR and Akt signaling. Semin Immunol. 2015; 27(4):286–296.
  • Troutman T, Bazan J, Pasare C, (GeorgetownTex.). Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K. Cell Cycle. 2012;11(19):3559–3567.
  • Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005;9(1):59–71.
  • Aksoy E, Vanden Berghe W, Detienne S, et al. Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-kappa B activation and IFN-beta synthesis downstream of toll-like receptor 3 and 4. Eur J Immunol. 2005;35(7):2200–2209.
  • Guha M, Mackman N. The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem. 2002;277(35):32124–32132.
  • Covarrubias A, Aksoylar HI, Yu J, et al. Akt-mTORC1 signaling regulates acly to integrate metabolic input to control of macrophage activation. eLife. 2016;5.
  • Luo L, Wall AA, Yeo JC, et al. Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling. Nat Commun. 2014;5(1):4407.
  • (Baltimore, Md.: 1950), Luyendyk J, Schabbauer GA, Tencati M, et al. Genetic analysis of the role of the PI3K-Akt pathway in lipopolysaccharide-induced cytokine and tissue factor gene expression in monocytes/macrophages. J Iimmunol. 2008;180(6):4218–4226.
  • (Baltimore, Md.: 1950)Díaz-Guerra M, Castrillo A, Martín-Sanz, P, et al. Negative regulation by phosphatidylinositol 3-kinase of inducible nitric oxide synthase expression in macrophages. J Iimmunol 1999;162(10):6184–6190.
  • Weichhart T, Säemann M. The multiple facets of mTOR in immunity. Trends Immunol. 2009;30(5):218–226.
  • Fung-Leung W. Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signaling and function. Cell Signal. 2011;23(4):603–608.
  • Franke T, Yang S-I, Chan TO, et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell. 1995;81(5):727–736.
  • Jean S, Kiger A. Classes of phosphoinositide 3-kinases at a glance. J Cell Sci. 2014;127(5):923–928.
  • (Baltimore, Md.: 1950), Beharka A, Crowther JE, McCormack FX, et al. Pulmonary surfactant protein A activates a phosphatidylinositol 3-kinase/calcium signal transduction pathway in human macrophages: participation in the up-regulation of mannose receptor activity. J Iimmunol. 2005;175(4):2227–2236.
  • Locatelli S, Careddu G, Serio S, et al. Targeting cancer cells and tumor microenvironment in preclinical and clinical models of Hodgkin lymphoma using the dual PI3Kδ/γ inhibitor RP6530. Clin Cancer Res off J Am Assoc Cancer Res. 2019;25(3):1098–1112.
  • Su Z, Zhang P, Yu Y, et al. HMGB1 facilitated macrophage reprogramming towards a proinflammatory M1-like phenotype in experimental autoimmune myocarditis development. Sci Rep. 2016;6(1):21884.
  • Lee P, Yang C-H, Kao M-C, et al. Phosphoinositide 3-kinase β, phosphoinositide 3-kinase δ, and phosphoinositide 3-kinase γ mediate the anti-inflammatory effects of magnesium sulfate. J Surg Res. 2015;197(2):390–397.
  • Wang T, Su N-Y, Shih P-C, et al. Anti-inflammation effects of naloxone involve phosphoinositide 3-kinase delta and gamma. J Surg Res. 2014;192(2):599–606.
  • Jan W, Kao M-C, Yang C-H, et al. Phosphoinositide 3-kinase is involved in mediating the anti-inflammation effects of vasopressin. Inflammation. 2017;40(2):435–441.
  • Lee J, Nauseef WM, Moeenrezakhanlou A, et al. Monocyte p110alpha phosphatidylinositol 3-kinase regulates phagocytosis, the phagocyte oxidase and cytokine production. J Leukoc Biol. 2007;81(6):1548–1561.
  • Guillermet-Guibert J, Bjorklof K, Salpekar A, et al. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci U S A. 2008;105(24):8292–8297.
  • Bourdonnay E, Serezani CH, Aronoff DM, et al. Regulation of alveolar macrophage p40phox: hierarchy of activating kinases and their inhibition by PGE 2. J Leukoc Biol. 2012;92(1):219–231.
  • Li D, Sun H. TEP1, encoded by a candidate tumor suppressor locus is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997;57(11):2124–2129.
  • Myers M, Stolarov JP, Eng C, et al. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A. 1997;94(17):9052–9057.
  • Yehia L, Ngeow J, Eng C. PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest. 2019;129(2):452–464.
  • Funamoto S, Meili R, Lee S, et al. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell. 2002;109(5):611–623.
  • (Baltimore, Md.: 1950), Sahin E, Haubenwallner S, Kuttke M, et al. Macrophage PTEN regulates expression and secretion of arginase I modulating innate and adaptive immune responses. J Immunol. 2014;193(4):1717–1727.
  • Park M, Sheng R, Silkov A, et al. SH2 domains serve as lipid-binding modules for pTyr-signaling proteins. Mol Cell. 2016;62(1):7–20.
  • Sly L, Ho V, Antignano F, et al. The role of SHIP in macrophages. Front Biosci. 2007;12(8–12):2836–2848.
  • Peng K, Gu J-F, Su S-L, et al. Salvia miltiorrhiza stems and leaves total phenolic acids combination with tanshinone protect against DSS-induced ulcerative colitis through inhibiting TLR4/PI3K/AKT/mTOR signaling pathway in mice. J Ethnopharmacol. 2021;264:113052.
  • Huang J, Ding Y, Huang D-S, et al. RNA interference targeting p110β reduces tumor necrosis factor-alpha production in cellular response to wear particles in vitro and osteolysis in vivo. Inflammation. 2013;36(5):1041–1054.
  • Molnarfi N, Brandt KJ, Gruaz L, et al. Differential regulation of cytokine production by PI3Kdelta in human monocytes upon acute and chronic inflammatory conditions. Mol Immunol. 2008;45(12):3419–3427.
  • Takeda A, Maher TJ, Zhang Y, et al. Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nat Commun. 2019;10(1):4364.
  • Luo L, Wall AA, Tong SJ, et al. TLR crosstalk activates LRP1 to recruit Rab8a and PI3Kγ for suppression of inflammatory responses. Cell Rep. 2018;24(11):3033–3044.
  • Dale M, Ruhlman M, Baxter B. Inflammatory cell phenotypes in AAAs: their role and potential as targets for therapy. Arterioscler Thromb Vasc Biol. 2015;35(8):1746–1755.
  • Abbas A, Murphy K, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383(6603):787–793.
  • discussion 154-8: Mosmann T, Li L, Hengartner H, et al. Differentiation and functions of T cell subsets. Ciba Found Symp. 1997;204:148–154.
  • (Hoboken N.J.), Saadoun D, Garrido M, Comarmond C, et al. Th1 and Th17 cytokines drive inflammation in Takayasu arteritis. Arthritis Rheumatol. 2015;67(5):1353–1360.
  • Wang L, Gao S, Xu W, et al. Allergic asthma accelerates atherosclerosis dependent on Th2 and Th17 in apolipoprotein E deficient mice. J Mol Cell Cardiol. 2014;72:20–27.
  • Yu W, Du H, Fu Q, et al. The influence of Th1/Th2 and CD4+ regulatory t cells of mesenteric lymph nodes on systemic lipopolysaccharide. POL J PATHOL. 2014;65(2):125–129.
  • Shimizu K, Shichiri M, Libby P, et al. Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas. J Clin Invest. 2004;114(2):300–308.
  • Schönbeck U, Sukhova GK, Gerdes N, et al. T(H)2 predominant immune responses prevail in human abdominal aortic aneurysm. Am J Pathol. 2002;161(2):499–506.
  • Galle C, Schandené L, Stordeur P, et al. Predominance of type 1 CD4+ T cells in human abdominal aortic aneurysm. Clin Exp Immunol. 2005;142(3):519–527.
  • Téo F, de Oliveira RTD, Villarejos L, et al. Characterization of CD4 + T cell subsets in patients with abdominal aortic aneurysms. Mediators Inflamm. 2018;2018:6967310.
  • Huang L, Wang M, Yan Y, et al. OX40L induces helper T cell differentiation during cell immunity of asthma through PI3K/AKT and P38 MAPK signaling pathway. J Transl Med. 2018;16(1):74.
  • (Baltimore, Md.: 1950), Kuroda E, Antignano F, Ho VW, et al. SHIP represses Th2 skewing by inhibiting IL-4 production from basophils. J Iimmunol. 2011;186(1):323–332.
  • (Baltimore, Md.: 1950), Okkenhaug K, Patton DT, Bilancio A, et al. The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Iimmunol. 2006;177(8):5122–5128.
  • Ailawadi G, Moehle CW, Pei H, et al. Smooth muscle phenotypic modulation is an early event in aortic aneurysms. J Thorac Cardiovasc Surg. 2009;138(6):1392–1399.
  • Rombouts K, van Merrienboer TAR, Ket JCF, et al. The role of vascular smooth muscle cells in the development of aortic aneurysms and dissections. Eur J Clin Invest. 2021;52(4):e13697.
  • Gurung R, Choong AM, Woo CC, et al. Genetic and epigenetic mechanisms underlying vascular smooth muscle cell phenotypic modulation in abdominal aortic aneurysm. Int J Mol Sci. 2020;21(17):6334.
  • Lu H, Du W, Ren L, et al. Vascular smooth muscle cells in aortic aneurysm: from genetics to mechanisms. J Am Heart Assoc. 2021;10(24):e023601.
  • Spin J, Maegdefessel L, Tsao P. Vascular smooth muscle cell phenotypic plasticity: focus on chromatin remodelling. Cardiovasc Res. 2012;95(2):147–155.
  • Petsophonsakul P, Furmanik M, Forsythe R, et al. Role of vascular smooth muscle cell phenotypic switching and calcification in aortic aneurysm formation. Arterioscler Thromb Vasc Biol. 2019;39(7):1351–1368.
  • Basatemur G, Jørgensen HF, Clarke MCH, et al. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol. 2019;16(12):727–744.
  • Sorokin V, Vickneson K, Kofidis T, et al. Role of vascular smooth muscle cell plasticity and interactions in vessel wall inflammation. Front Immunol. 2020;11:599415.
  • Alencar G, Owsiany KM, Karnewar S, et al. Stem cell pluripotency genes Klf4 and oct4 regulate complex SMC phenotypic changes critical in late-stage atherosclerotic lesion pathogenesis. Circulation. 2020;142(21):2045–2059.
  • Shankman L, Gomez D, Cherepanova OA, et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med. 2015;21(6):628–637.
  • Sun Y, Zheng B, Zhang X-H, et al. PPAR-γ agonist stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination. Biochem Biophys Res Commun. 2014;443(2):382–388.
  • Tang Y, Huang Q, Liu C, et al. p22phox promotes Ang-II-induced vascular smooth muscle cell phenotypic switch by regulating KLF4 expression. Biochem Biophys Res Commun. 2019;514(1):280–286.
  • Garg A, Devereaux PJ, Hill A, et al. Oral curcumin in elective abdominal aortic aneurysm repair: a multicentre randomized controlled trial. CMAJ = Journal de l’Association Medicale Canadienne. 2018;190(43):E1273–E1280.
  • Hao Q, Chen X, Wang X, et al. Curcumin attenuates angiotensin II-induced abdominal aortic aneurysm by inhibition of inflammatory response and ERK signaling pathways. Evid Based Complement Alternat Med. 2014;2014:270930.
  • Xiong J, Liu H, Chen J, et al. Curcumin nicotinate suppresses abdominal aortic aneurysm pyroptosis via lncRNA PVT1/miR-26a/KLF4 axis through regulating the PI3K/AKT signaling pathway. Toxicol Res (Camb). 2021;10(3):651–661.
  • Kansakar U, Jankauskas SS, Gambardella J, et al. Targeting the phenotypic switch of vascular smooth muscle cells to tackle atherosclerosis. Atherosclerosis. 2021;324:117–120.
  • Zhang H, Jiang L, Guo Z, et al. PPARβ/δ, a novel regulator for vascular smooth muscle cells phenotypic modulation and vascular remodeling after subarachnoid hemorrhage in rats. Sci Rep. 2017;7(1):45234.
  • Yang X, Gong Y, Tang Y, et al. Spry1 and Spry4 differentially regulate human aortic smooth muscle cell phenotype via Akt/FoxO/myocardin signaling. PloS one. 2013;8(3):e58746.
  • Liu Z, Wang Z, Yanagisawa H, et al. Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin. Dev Cell. 2005;9(2):261–270.
  • López-Candales A, Holmes DR, Liao S, et al. Decreased vascular smooth muscle cell density in medial degeneration of human abdominal aortic aneurysms. Am J Pathol. 1997;150(3):993–1007.
  • Henderson E, Geng Y-J, Sukhova GK, et al. Death of smooth muscle cells and expression of mediators of apoptosis by T lymphocytes in human abdominal aortic aneurysms. Circulation. 1999;99(1):96–104.
  • Wang Q, Shu C, Su J, et al. A crosstalk triggered by hypoxia and maintained by MCP-1/miR-98/IL-6/p38 regulatory loop between human aortic smooth muscle cells and macrophages leads to aortic smooth muscle cells apoptosis via Stat1 activation. Int J Clin Exp Pathol. 2015;8(3):2670–2679.
  • Yamanouchi D, Morgan S, Kato K, et al. Effects of caspase inhibitor on angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2010;30(4):702–707.
  • Morgan S, Yamanouchi D, Harberg C, et al. Elevated protein kinase C-δ contributes to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling. Arterioscler Thromb Vasc Biol. 2012;32(10):2493–2502.
  • Xue M, Li G, Li D, et al. Up-regulated MCPIP1 in abdominal aortic aneurysm is associated with vascular smooth muscle cell apoptosis and MMPs production. Biosci Rep. 2019;39(11).
  • (London, England: 1979), Emeto T, Moxon J, Au M, et al. Oxidative stress and abdominal aortic aneurysm: potential treatment targets. Clin Sci. 2016;130(5):301–315.
  • Sawada H, Hao H, Naito Y, et al. Aortic iron overload with oxidative stress and inflammation in human and murine abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 2015;35(6):1507–1514.
  • Kaneko H, Anzai T, Morisawa M, et al. Resveratrol prevents the development of abdominal aortic aneurysm through attenuation of inflammation, oxidative stress, and neovascularization. Atherosclerosis. 2011;217(2):350–357.
  • Thomas M, Gavrila D, McCormick ML, et al. Deletion of p47 phox attenuates angiotensin II–Induced abdominal aortic aneurysm formation in apolipoprotein E–Deficient mice. Circulation. 2006;114(5):404–413.
  • Maiellaro-Rafferty K, Weiss D, Joseph G, et al. Catalase overexpression in aortic smooth muscle prevents pathological mechanical changes underlying abdominal aortic aneurysm formation. Am J Physiol Heart Circ Physiol. 2011;301(2):H355–62.
  • Parastatidis I, Weiss D, Joseph G, et al. Overexpression of catalase in vascular smooth muscle cells prevents the formation of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2013;33(10):2389–2396.
  • Tsai Y, Yeh H, Chao C, et al. Superoxide dismutase 2 (SOD2) in vascular calcification: a focus on vascular smooth muscle cells, calcification pathogenesis. And Therapeutic Strategies. Oxidative Medicine and Cellular Longevity. 2021;2021:6675548.
  • Zhang F, Ren X, Zhao M, et al. Angiotensin-(1-7) abrogates angiotensin II-induced proliferation, migration and inflammation in VSMCs through inactivation of ROS-mediated PI3K/Akt and MAPK/ERK signaling pathways. Sci Rep. 2016;6(1):34621.
  • Almajdoob S, Hossain E, Anand-Srivastava MB. Resveratrol attenuates hyperproliferation of vascular smooth muscle cells from spontaneously hypertensive rats: role of ROS and ROS-mediated cell signaling. Vascul Pharmacol. 2018;101:48–56.
  • (London, England: 1979), Navas-Madroñal M, Rodriguez C, Kassan M, et al. Enhanced endoplasmic reticulum and mitochondrial stress in abdominal aortic aneurysm. Clin Sci. 2019;133(13):1421–1438.
  • Mizushima N, Levine B, Cuervo AM, et al. Autophagy fights disease through cellular self-digestion. Nature. 2008;451(7182):1069–1075.
  • Ren J, Zhang Y. Targeting autophagy in aging and aging-related cardiovascular diseases. Trends Pharmacol Sci. 2018;39(12):1064–1076.
  • Shirakabe A, Ikeda Y, Sciarretta S, et al. Aging and autophagy in the heart. Circ Res. 2016;118(10):1563–1576.
  • Phadwal K, Feng D, Zhu D, et al. Autophagy as a novel therapeutic target in vascular calcification. Pharmacol Ther. 2020;206:107430.
  • Lu H, Sun J, Liang W, et al. Cyclodextrin prevents abdominal aortic aneurysm via activation of vascular smooth muscle cell transcription factor EB. Circulation. 2020;142(5):483–498.
  • Clément M, Chappell J, Raffort J, et al. Vascular smooth muscle cell plasticity and autophagy in dissecting aortic aneurysms. Arterioscler Thromb Vasc Biol. 2019;39(6):1149–1159.
  • Widmer R, Lerman A. Endothelial dysfunction and cardiovascular disease. Glob Cardiol Sci Pract. 2014;2014(3):291–308.
  • Murad F. Shattuck lecture. nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med. 2006;355(19):2003–2011.
  • Furchgott R. The 1996 Albert Lasker medical research awards. the discovery of endothelium-derived relaxing factor and its importance in the identification of nitric oxide. JAMA. 1996;276(14):1186–1188.
  • DeRoo E, Stranz A, Yang H, et al. Endothelial dysfunction in the pathogenesis of abdominal aortic aneurysm. Biomolecules. 2022;12(4):509.
  • Sung S, Wu T-C, Chen J-S, et al. Reduced number and impaired function of circulating endothelial progenitor cells in patients with abdominal aortic aneurysm. Int J Cardiol. 2013;168(2):1070–1077.
  • Lee R, Bellamkonda K, Jones A, et al. Flow mediated dilatation and progression of abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2017;53(6):820–829.
  • Lee R, Jarchi D, Perera R, et al. Applied machine learning for the prediction of growth of abdominal aortic aneurysm in humans. EJVES Short Rep. 2018;39:24–28.
  • Sun J, Deng H, Zhou Z, et al. Endothelium as a potential target for treatment of abdominal aortic aneurysm. Oxid Med Cell Longev. 2018;2018:6306542.
  • Ahmed R, Ghoorah K, Kunadian V. Abdominal aortic aneurysms and risk factors for adverse events. Cardiol Rev. 2016;24(2):88–93.
  • Barua R, Ambrose JA, Srivastava S, et al. Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells. Circulation. 2003;107(18):2342–2347.
  • Baxter B, Terrin M, Dalman R. Medical management of small abdominal aortic aneurysms. Circulation. 2008;117(14):1883–1889.
  • (Dallas, Tex.: 1979), Gao L, Siu KL, Chalupsky K, et al. Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation: treatment with folic acid. Hypertension. 2012;59(1):158–166.
  • Li Q, Youn JY, Siu KL, et al. Knockout of dihydrofolate reductase in mice induces hypertension and abdominal aortic aneurysm via mitochondrial dysfunction. Redox Biol. 2019;24:101185.
  • Siu K, Li Q, Zhang Y, et al. NOX isoforms in the development of abdominal aortic aneurysm. Redox Biol. 2017;11:118–125.
  • Huang K, Wang Y, Siu KL, et al. Targeting feed-forward signaling of TGFβ/NOX4/DHFR/eNOS uncoupling/TGFβ axis with anti-TGFβ and folic acid attenuates formation of aortic aneurysms: novel mechanisms and therapeutics. Redox Biol. 2021;38:101757.
  • Zhou Z, Xie X-L, Zhou S-F, et al. Mechanism of reversal of high glucose-induced endothelial nitric oxide synthase uncoupling by tanshinone IIA in human endothelial cell line EA.hy926. Eur J Pharmacol. 2012;697(1–3):97–105.
  • McCormick M, Gavrila D, Weintraub N. Role of oxidative stress in the pathogenesis of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2007;27(3):461–469.
  • Li X, Huang S, Zhuo B, et al. κComparison of three species of rhubarb in inhibiting vascular endothelial injury via regulation of PI3K/AKT/NF-B signaling pathway. Oxid Med Cell Longev. 2022;2022:8979329.
  • Hu C, Zhang X, Teng T, et al. Cellular senescence in cardiovascular diseases: a systematic review. Aging Dis. 2022;13(1):103–128.
  • Wilcox J, Waksman R, King SB, et al. The role of the adventitia in the arterial response to angioplasty: the effect of intravascular radiation. Int J Radiat Oncol Biol Phys. 1996;36(4):789–796.
  • Shi Y, O’Brien JE, Fard A, et al. Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation. 1996;94(7):1655–1664.
  • Scott N, Cipolla GD, Ross CE, et al. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation. 1996;93(12):2178–2187.
  • Maiellaro K, Taylor W. The role of the adventitia in vascular inflammation. Cardiovasc Res. 2007;75(4):640–648.
  • Gao J, Guo W. Mechanisms of abdominal aortic aneurysm progression: a review. Vasc Med. 2022;27(1):88–96.
  • Feng E, Wang J, Wang X, et al. Inhibition of HMGB1 might enhance the protective effect of taxifolin in cardiomyocytes via PI3K/AKT signaling pathway. Iran J Pharm Res. 2021;20(2):316–332.
  • Bumdelger B, Otani M, Karasaki K, et al. Disruption of osteoprotegerin has complex effects on medial destruction and adventitial fibrosis during mouse abdominal aortic aneurysm formation. PloS one. 2020;15(7):e0235553.
  • van Keulen C, van de Akker E, Pals G, et al. The role of type III collagen in the development of familial abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 1999;18(1):65–70.
  • van Keulen C, van den Akker E, van den Berg FG, et al. The role of type III collagen in family members of patients with abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2000;20(4):379–385.
  • Haurani M, Pagano P. Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: bellwether for vascular disease? Cardiovasc Res. 2007;75(4):679–689.
  • Chiang M, Chen I-M, Hsu -F-F, et al. Gal-1 (Galectin-1) upregulation contributes to abdominal aortic aneurysm progression by enhancing vascular inflammation. Arterioscler Thromb Vasc Biol. 2021;41(1):331–345.
  • Hermenean A, Oatis D, Herman H, et al. Galectin 1-A key player between tissue repair and fibrosis. Int J Mol Sci. 2022;23(10):5548.
  • Romaniuk M, Croci D, Lapponi M, et al. Binding of galectin-1 to αIIbβ₃ integrin triggers “outside-in” signals, stimulates platelet activation. And Controls Primary Hemostasis. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2012;26(7):2788–2798.
  • Tsuruda T, Kato J, Hatakeyama K, et al. Adrenomedullin in mast cells of abdominal aortic aneurysm. Cardiovasc Res. 2006;70(1):158–164.
  • Tsuruda T, Kato J, Hatakeyama K, et al. Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm. Circ Res. 2008;102(11):1368–1377.
  • Veerappan A, Reid AC, Estephan R, et al. Mast cell renin and a local renin-angiotensin system in the airway: role in bronchoconstriction. Proc Natl Acad Sci U S A. 2008;105(4):1315–1320.
  • Miyazaki M, Takai S, Jin D, et al. Pathological roles of angiotensin II produced by mast cell chymase and the effects of chymase inhibition in animal models. Pharmacol Ther. 2006;112(3):668–676.
  • Owen CA, Campbell EJ. Angiotensin II generation at the cell surface of activated neutrophils: novel cathepsin G-mediated catalytic activity that is resistant to inhibition. J Immunol. 1998;160(3):1436–1443.
  • Swedenborg J, Mäyränpää MI, Kovanen PT. Mast cells: important players in the orchestrated pathogenesis of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2011;31(4):734–740.
  • Kovanen PT. Mast cells: multipotent local effector cells in atherothrombosis. Immunol Rev. 2007;217(1):105–122.
  • Leskinen MJ, Heikkila H, Speer M, et al. Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-kappaB-mediated survival signaling. Exp Cell Res. 2006;312(8):1289–1298.
  • Wang Z, Guo J, Han X, et al. Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE(-/-) mice. Cell Biosci. 2019;9(1):68.
  • Wang J, Zhou Y, Wu S, et al. Astragaloside IV attenuated 3,4-benzopyrene-induced abdominal aortic aneurysm by ameliorating macrophage-mediated inflammation. Front Pharmacol. 2018;9:496.
  • Takahara Y, Tokunou T, Ichiki T. Suppression of abdominal aortic aneurysm formation in mice by teneligliptin, a dipeptidyl peptidase-4 inhibitor. J Atheroscler Thromb. 2018;25(8):698–708.
  • Satta J, Läärä E, Juvonen T. Intraluminal thrombus predicts rupture of an abdominal aortic aneurysm. J Vasc Surg. 1996;23(4):737–739.
  • Parr A, McCann M, Bradshaw B, et al. Thrombus volume is associated with cardiovascular events and aneurysm growth in patients who have abdominal aortic aneurysms. J Vasc Surg. 2011;53(1):28–35.
  • Sagan A, Mrowiecki W, Mikolajczyk T, et al. Local inflammation is associated with aortic thrombus formation in abdominal aortic aneurysms. relationship to clinical risk factors. Thromb Haemost. 2012;108(5):812–823.
  • Vorp D, Lee PC, Wang DHJ, et al. Association of intraluminal thrombus in abdominal aortic aneurysm with local hypoxia and wall weakening. J Vasc Surg. 2001;34(2):291–299.
  • Swedenborg J, Eriksson P. The intraluminal thrombus as a source of proteolytic activity. Ann N Y Acad Sci. 2006;1085(1):133–138.
  • Kazi M, Thyberg J, Religa P, et al. Influence of intraluminal thrombus on structural and cellular composition of abdominal aortic aneurysm wall. J Vasc Surg. 2003;38(6):1283–1292.
  • Dai J, Louedec L, Philippe M, et al. Effect of blocking platelet activation with AZD6140 on development of abdominal aortic aneurysm in a rat aneurysmal model. J Vasc Surg. 2009;49(3):719–727.
  • Min S, Abrams C. Regulation of platelet plug formation by phosphoinositide metabolism. Blood. 2013;122(8):1358–1365.
  • Watanabe N, Nakajima H, Suzuki H, et al. Functional phenotype of phosphoinositide 3-kinase p85alpha-null platelets characterized by an impaired response to GP VI stimulation. Blood. 2003;102(2):541–548.
  • Kim S, Mangin P, Dangelmaier C, et al. Role of phosphoinositide 3-kinase beta in glycoprotein VI-mediated Akt activation in platelets. J Biol Chem. 2009;284(49):33763–33772.
  • Gilio K, Munnix ICA, Mangin P, et al. Non-redundant roles of phosphoinositide 3-kinase isoforms alpha and beta in glycoprotein VI-induced platelet signaling and thrombus formation. J Biol Chem. 2009;284(49):33750–33762.
  • Laurent P, Hechler B, Solinhac R, et al. Impact of PI3Kα (phosphoinositide 3-kinase alpha) inhibition on hemostasis and thrombosis. Arterioscler Thromb Vasc Biol. 2018;38(9):2041–2053.
  • Senis Y, Atkinson BT, Pearce AC, et al. Role of the p110delta PI 3-kinase in integrin and ITAM receptor signalling in platelets. Platelets. 2005;16(3–4):191–202.
  • Hirsch E, Bosco O, Tropel P, et al. Resistance to thromboembolism in PI3Kgamma-deficient mice. FASEB J. 2001;15(11):2019–2021.
  • Lian L, Wang Y, Draznin J, et al. The relative role of PLCbeta and PI3Kgamma in platelet activation. Blood. 2005;106(1):110–117.
  • Jackson S, Schoenwaelder SM, Goncalves I, et al. PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med. 2005;11(5):507–514.
  • Ohlsson C, Langenskiöld M, Smidfelt K, et al. Low progesterone and low estradiol levels associate with abdominal aortic aneurysms in men. J Clin Endocrinol Metab. 2022;107(4):e1413–e1425.
  • Schiff R, Massarweh SA, Shou J, et al. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res. 2004;10(1 Pt 2):331s–6s.
  • Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–529.
  • Thangavel C, Dean JL, Ertel A, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. 2011;18(3):45–333.
  • du Rusquec P, Blonz C, Frenel JS, et al. Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer. Ther Adv Med Oncol. 2020;12:1758835920940939.
  • Brandão M, Caparica R, Eiger D, et al. Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors. Ann Oncol. 2019;30(Suppl_10):x27–x42.
  • Zhao X, Huang L, Yin Y, et al. Estrogen induces endothelial progenitor cells proliferation and migration by estrogen receptors and PI3K-dependent pathways. Microvasc Res. 2008;75(1):45–52.
  • Zhang T, Liang X, Shi L, et al. Estrogen receptor and PI3K/Akt signaling pathway involvement in S-(-)equol-induced activation of Nrf2/ARE in endothelial cells. PLoS One. 2013;8(11):e79075.
  • Hohmann N, Xia N, Steinkamp-Fenske K, et al. Estrogen receptor signaling and the PI3K/Akt pathway are involved in betulinic acid-induced eNOS activation. Molecules. 2016;21(8):973.
  • Yuan Z, Heng Z, Lu Y, et al. The protective effect of metformin on abdominal aortic aneurysm: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2021;12:721213.
  • Shah A, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people. The Lancet Diabetes & Endocrinology. 2015;3(2):105–113.
  • Golledge J, Krishna S, and Wang Y. Mouse models for abdominal aortic aneurysm. Br J Pharmacol. 2022;179(5):792–810.
  • Ni X, Zhang Y-R, Jia L-X, et al. Inhibition of notch1-mediated inflammation by intermedin protects against abdominal aortic aneurysm via PI3K/Akt signaling pathway. Aging (Albany NY). 2021;13(4):5164–5184.
  • Daugherty A, Manning M, Cassis L. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest. 2000;105(11):1605–1612.
  • Saraff K, Babamusta F, Cassis LA, et al. Aortic dissection precedes formation of aneurysms and atherosclerosis in angiotensin II-infused, apolipoprotein E-deficient mice. arteriosclerosis, thrombosis. And Vascular Biology. 2003;23(9):1621–1626.
  • Thompson R, Curci JA, Ennis TL, et al. Pathophysiology of abdominal aortic aneurysms: insights from the elastase-induced model in mice with different genetic backgrounds. Ann N Y Acad Sci. 2006;1085(1):59–73.
  • Busch A, Holm A, Wagner N, et al. Extra- and intraluminal elastase induce morphologically distinct abdominal aortic aneurysms in mice and thus represent specific subtypes of human disease. J Vasc Res. 2016;53(1–2):49–57.
  • Lu G, Su G, Davis JP, et al. A novel chronic advanced stage abdominal aortic aneurysm murine model. J Vasc Surg. 2017;66(1):232–242.e4.
  • Phillips E, Yrineo AA, Schroeder HD, et al. Morphological and biomechanical differences in the elastase and AngII apoE −/− rodent models of abdominal aortic aneurysms. Biomed Res Int. 2015;2015:413189.
  • Wang Y, Krishna S, Golledge J. The calcium chloride-induced rodent model of abdominal aortic aneurysm. Atherosclerosis. 2013;226(1):29–39.
  • Chen H, Wang F, Gao P, et al. Age-associated sirtuin 1 reduction in vascular smooth muscle links vascular senescence and inflammation to abdominal aortic aneurysm. Circ Res. 2016;119(10):1076–1088.
  • Liu C, Wang Y, Liao M, et al. Allergic lung inflammation aggravates angiotensin II-induced abdominal aortic aneurysms in mice. Arterioscler Thromb Vasc Biol. 2016;36(1):69–77.
  • Li G, Qin L, Wang L, et al. Inhibition of the mTOR pathway in abdominal aortic aneurysm: implications of smooth muscle cell contractile phenotype, inflammation, and aneurysm expansion. Am J Physiol Heart Circ Physiol. 2017;312(6):H1110–H1119.
  • Yu J, Liu R, Huang J, et al. Inhibition of phosphatidylinositol 3-kinease suppresses formation and progression of experimental abdominal aortic aneurysms. Sci Rep. 2017;7(1):15208.
  • Escudero P, Navarro A, Ferrando C, et al. Combined treatment with bexarotene and rosuvastatin reduces angiotensin-II-induced abdominal aortic aneurysm in apoE −/− mice and angiogenesis. Br J Pharmacol. 2015;172(12):2946–2960.
  • Zhang S, Kan X, Li Y, et al. Deficiency of γδT cells protects against abdominal aortic aneurysms by regulating phosphoinositide 3-kinase/AKT signaling. J Vasc Surg. 2018;67(3):899–908.e1.
  • Rabkin S. The effect of nicotine and tobacco on aortic matrix metalloproteinases in the production of aortic aneurysm. Curr Vasc Pharmacol. 2016;14(6):514–522.
  • Yu M, Chen C, Cao Y, et al. Inhibitory effects of doxycycline on the onset and progression of abdominal aortic aneurysm and its related mechanisms. Eur J Pharmacol. 2017;811:101–109.
  • (Georgetown, Tex.), Tian Y, Li X, Bai C, et al. MiR-17-5p promotes the endothelialization of endothelial progenitor cells to facilitate the vascular repair of aneurysm by regulating PTEN-mediated PI3K/AKT/VEGFA pathway. Cell Cycle. 2020;19(24):3608–3621.
  • Zhou Y, Wang M, Zhang J, et al. MicroRNA-29a-3p regulates abdominal aortic aneurysm development and progression via direct interaction with PTEN. J Cell Physiol. 2020;235(12):9414–9423.
  • Li K, Cui M-Z, Zhang K-W, et al. Effect of miR-21 on rat thoracic aortic aneurysm model by regulating the expressions of MMP-2 and MMP-9. Eur Rev Med Pharmacol Sci. 2020;24(2):878–884.
  • Maegdefessel L, Azuma J, Toh R, et al. MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci Transl Med. 2012;4(122):122ra22.
  • Zhao L, Huang J, Zhu Y, et al. miR-33-5p knockdown attenuates abdominal aortic aneurysm progression via promoting target adenosine triphosphate-binding cassette transporter A1 expression and activating the PI3K/Akt signaling pathway. Perfusion2019;35(1):57–65.
  • Chen S, Chen H, Yu C, et al. Long noncoding RNA myocardial infarction associated transcript promotes the development of thoracic aortic by targeting microRNA-145 via the PI3K/Akt signaling pathway. J Cell Biochem. 2019;120(9):14405–14413.
  • Ma X, Yao H, Yang Y, et al. miR-195 suppresses abdominal aortic aneurysm through the TNF-alpha/NF-kappaB and VEGF/PI3K/Akt pathway. Int J Mol Med. 2018;41(4):2350–2358.
  • J P, He X, Zhang L, et al. MicroRNA‑26a protects vascular smooth muscle cells against H2O2‑induced injury through activation of the PTEN/AKT/mTOR pathway. Int J Mol Med. 2018;42(3):1367–1378.
  • Licholai S, Szczeklik W, Sanak M. miR-29c-3p is an effective biomarker of abdominal aortic aneurysm in patients undergoing elective surgery. MicroRNA (Shariqah United Arab Emir). 2016;5(2):124–131.
  • Shen G, Sun Q, Yao Y, et al. Role of ADAM9 and miR-126 in the development of abdominal aortic aneurysm. Atherosclerosis. 2020;297:47–54.
  • Li B, Wang Z, Chen R, et al. Up regulation of isoleucyl-tRNA synthetase promotes vascular smooth muscle cells dysfunction via p38 MAPK/PI3K signaling pathways. Life Sci. 2019;224:51–57.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.