1,354
Views
35
CrossRef citations to date
0
Altmetric
Review Articles

Serpina3n: Potential drug and challenges, mini review

&
Pages 368-378 | Received 14 Aug 2019, Accepted 11 Nov 2019, Published online: 02 Dec 2019

References

  • Forsyth S, Horvath A, Coughlin P. A review and comparison of the murine alpha1-antitrypsin and alpha1-antichymotrypsin multigene clusters with the human clade A serpins. Genomics. 2003;81(3):336–345.
  • Horvath AJ, Forsyth SL, Coughlin PB. Expression patterns of murine antichymotrypsin-like genes reflect evolutionary divergence at the Serpina3 locus. J Mol Evol. 2004;59(4):488–497.
  • Bodmer JL, Schnebli HP. Plasma proteinase inhibitors. Schweiz Med Wochenschr. 1984;114(40):1359–1363.
  • Chandra T, Stackhouse R, Kidd VJ. Sequence homology between human alpha 1-antichymotrypsin, alpha 1-antitrypsin, and antithrombin III. Biochemistry. 1983;22(22):5055–5061.
  • Heit C, Jackson BC, McAndrews M, et al. Update of the human and mouse SERPIN gene superfamily. Hum Genomics. 2013;7(1):22.
  • Hsu I, Parkinson LG, Shen Y, et al. Serpina3n accelerates tissue repair in a diabetic mouse model of delayed wound healing. Cell Death Dis. 2014;5(10):e1458.
  • Horvath AJ, Irving JA, Rossjohn J, et al. The murine orthologue of human antichymotrypsin: a structural paradigm for clade A3 serpins. J Biol Chem. 2005;280(52):43168–43178.
  • Sipione S, Simmen KC, Lord SJ, et al. Identification of a novel human granzyme B inhibitor secreted by cultured sertoli cells. J Immunol. 2006;177(8):5051–5058.
  • Gettins PG. Serpin structure, mechanism, and function. Chem Rev. 2002;102(12):4751–4804.
  • Ang LS, Boivin WA, Williams SJ, et al. Serpina3n attenuates granzyme B-mediated decorin cleavage and rupture in a murine model of aortic aneurysm. Cell Death Dis. 2011;2(9):e209.
  • Hoffmann DC, Textoris C, Oehme F, et al. Pivotal role for alpha1-antichymotrypsin in skin repair. J Biol Chem. 2011;286(33):28889–28901.
  • Haile Y, Carmine-Simmen K, Olechowski C, et al. Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo. J Neuroinflammation. 2015;12(1):157.
  • Vicuna L, Strochlic DE, Latremoliere A, et al. The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. Nat Med. 2015;21(5):518–523.
  • Tjondrokoesoemo A, Schips T, Kanisicak O, et al. Genetic overexpression of Serpina3n attenuates muscular dystrophy in mice. Hum Mol Genet. 2016;25(6):1192–1202.
  • Coronado MJ, Brandt JE, Kim E, et al. Testosterone and interleukin-1beta increase cardiac remodeling during coxsackievirus B3 myocarditis via serpin A 3n. Am J Physiol Heart Circ Physiol. 2012;302(8):H1726–36.
  • Ishida M, Kawao N, Okada K, et al. Serpina3n, dominantly expressed in female osteoblasts, suppresses the phenotypes of differentiated osteoblasts in mice. Endocrinology. 2018;159(11):3775–3790.
  • Zamanian JL, Xu L, Foo LC, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32(18):6391–6410.
  • Patterson SD, Bell K, Shaw DC. The equine major plasma serpin multigene family: partial characterization including sequence of the reactive-site regions. Biochem Genet. 1991;29(9–10):477–499.
  • Potempa J, Korzus E, Travis J. The serpin superfamily of proteinase inhibitors: structure, function, and regulation. J Biol Chem. 1994;269(23):15957–15960.
  • Irving JA, Pike RN, Lesk AM, et al. Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function. Genome Res. 2000;10(12):1845–1864.
  • Silverman GA, Bird PI, Carrell RW, et al. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem. 2001;276(36):33293–33296.
  • Selawry HP, Cameron DF. Sertoli cell-enriched fractions in successful islet cell transplantation. Cell Transplant. 1993;2(2):123–129.
  • Korbutt GS, Elliott JF, Rajotte RV. Cotransplantation of allogeneic islets with allogeneic testicular cell aggregates allows long-term graft survival without systemic immunosuppression. Diabetes. 1997;46(2):317–322.
  • Suarez-Pinzon W, Korbutt GS, Power R, et al. Testicular sertoli cells protect islet beta-cells from autoimmune destruction in NOD mice by a transforming growth factor-beta1-dependent mechanism. Diabetes. 2000;49(11):1810–1818.
  • Takeda Y, Gotoh M, Dono K, et al. Protection of islet allografts transplanted together with Fas ligand expressing testicular allografts. Diabetologia. 1998;41(3):315–321.
  • Janciauskiene S. Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles. Biochim Biophys Acta. 2001;1535(3):221–235.
  • Licastro F, Campbell IL, Kincaid C, et al. A role for apoE in regulating the levels of alpha-1-antichymotrypsin in the aging mouse brain and in Alzheimer's disease. Am J Pathol. 1999;155(3):869–875.
  • Licastro F, Candore G, Lio D, et al. Innate immunity and inflammation in ageing: a key for understanding age-related diseases. Immun Ageing. 2005;2(1):8.
  • Sardi F, Fassina L, Venturini L, et al. Alzheimer's disease, autoimmunity and inflammation. The good, the bad and the ugly. Autoimmun Rev. 2011;11(2):149–153.
  • Zhou J, Cheng Y, Tang L, et al. Up-regulation of SERPINA3 correlates with high mortality of melanoma patients and increased migration and invasion of cancer cells. Oncotarget. 2017;8(12):18712–18725.
  • Li Y, Dong X, Cai J, et al. SERPINA3 induced by astroglia/microglia co-culture facilitates glioblastoma stem-like cell invasion. Oncol Lett. 2018;15(1):285–291.
  • Law RH, Zhang Q, McGowan S, et al. An overview of the serpin superfamily. Genome Biol. 2006;7(5):216.
  • Huntington JA. Serpin structure, function and dysfunction. J Thromb Haemost. 2011;9(Suppl 1):26–34.
  • Bots M, Medema JP. Serpins in T cell immunity. J Leukoc Biol. 2008;84(5):1238–1247.
  • Kaiserman D, Bird PI. Control of granzymes by serpins. Cell Death Differ. 2010;17(4):586–595.
  • Davies MJ, Lomas DA. The molecular aetiology of the serpinopathies. Int J Biochem Cell Biol. 2008;40(6–7):1273–1286.
  • Laursen I, Lykkesfeldt AE. Purification and characterization of an alpha 1-antichymotrypsin-like 66 kDa protein from the human breast cancer cell line, MCF-7. Biochim Biophys Acta. 1992;1121(1–2):119–129.
  • Higashiyama M, Doi O, Yokouchi H, et al. Alpha-1-antichymotrypsin expression in lung adenocarcinoma and its possible association with tumor progression. Cancer. 1995;76(8):1368–1376.
  • Clemmensen SN, Jacobsen LC, Rorvig S, et al. Alpha-1-antitrypsin is produced by human neutrophil granulocytes and their precursors and liberated during granule exocytosis. Eur J Haematol. 2011;86(6):517–530.
  • Gooptu B, Hazes B, Chang WS, et al. Inactive conformation of the serpin alpha(1)-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease. Proc Natl Acad Sci U S A. 2000;97(1):67–72.
  • Saunders DN, Tindall EA, Shearer RF, et al. A novel SERPINA1 mutation causing serum alpha(1)-antitrypsin deficiency. PLoS One. 2012;7(12):e51762.
  • Rabieian R, Boshtam M, Zareei M, et al. Plasminogen Activator Inhibitor Type-1 as a Regulator of Fibrosis. J Cell Biochem. 2018;119(1):17–27.
  • Andreasen PA, Riccio A, Welinder KG, et al. Plasminogen activator inhibitor type-1: reactive center and amino-terminal heterogeneity determined by protein and cDNA sequencing. Febs Lett. 1986;209(2):213–218.
  • Reilly CF, Fujita T, Mayer EJ, et al. Both circulating and clot-bound plasminogen activator inhibitor-1 inhibit endogenous fibrinolysis in the rat. Arterioscler Thromb. 1991;11(5):1276–1286.
  • Ghosh AK, Vaughan DE. PAI-1 in tissue fibrosis. J Cell Physiol. 2012;227(2):493–507.
  • Gatto M, Iaccarino L, Ghirardello A, et al. Serpins, immunity and autoimmunity: old molecules, new functions. Clinic Rev Allerg Immunol. 2013;45(2):267–280.
  • Taphoorn MJ, Stupp R, Coens C, et al. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol. 2005;6(12):937–944.
  • Izuhara K, Ohta S, Kanaji S, et al. Recent progress in understanding the diversity of the human ov-serpin/clade B serpin family. Cell Mol Life Sci. 2008;65(16):2541–2553.
  • Khan MS, Singh P, Azhar A, et al. Serpin inhibition mechanism: a delicate balance between native metastable state and polymerization. J Amino Acids. 2011;2011:1.
  • Tsuruta JK, Eddy EM, O’Brien DA. Insulin-like growth factor-II/cation-independent mannose 6-phosphate receptor mediates paracrine interactions during spermatogonial development. Biol Reprod. 2000;63(4):1006–1013.
  • Bird CH, Sutton VR, Sun J, et al. Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol Cell Biol. 1998;18(11):6387–6398.
  • Hendel A, Hiebert PR, Boivin WA, et al. Granzymes in age-related cardiovascular and pulmonary diseases. Cell Death Differ. 2010;17(4):596–606.
  • Turner CT, Lim D, Granville DJ. Granzyme B in skin inflammation and disease. Matrix Biol. 2019;75–76:126–140. Jan
  • Fabricius D, Trzaska T, Fecher T, et al. Differential expression of serpins may selectively licence distinct granzyme B functions including antigen cross-presentation. Mol Immunol. 2017;87:325–326.
  • Hirst CE, Buzza MS, Bird CH, et al. The intracellular granzyme B inhibitor, proteinase inhibitor 9, is up-regulated during accessory cell maturation and effector cell degranulation, and its overexpression enhances CTL potency. J Immunol. 2003;170(2):805–815.
  • Motyka B, Korbutt G, Pinkoski MJ, et al. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell. 2000;103(3):491–500.
  • Pinkoski MJ, Hobman M, Heibein JA, et al. Entry and trafficking of granzyme B in target cells during granzyme B-perforin-mediated apoptosis. Blood. 1998;92(3):1044–1054.
  • Shi L, Kraut RP, Aebersold R, et al. A natural killer cell granule protein that induces DNA fragmentation and apoptosis. J Exp Med. 1992;175(2):553–566.
  • Caputo A, James MN, Powers JC, et al. Conversion of the substrate specificity of mouse proteinase granzyme B. Nat Struct Mol Biol. 1994;1(6):364–367.
  • Heusel JW, Wesselschmidt RL, Shresta S, et al. Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell. 1994;76(6):977–987.
  • Darmon AJ, Nicholson DW, Bleackley RC. Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature. 1995;377(6548):446–448.
  • Nakajima H, Park HL, Henkart PA. Synergistic roles of granzymes A and B in mediating target cell death by rat basophilic leukemia mast cell tumors also expressing cytolysin/perforin. J Exp Med. 1995;181(3):1037–1046.
  • Sun J, Ooms L, Bird CH, et al. A new family of 10 murine ovalbumin serpins includes two homologs of proteinase inhibitor 8 and two homologs of the granzyme B inhibitor (proteinase inhibitor 9). J Biol Chem. 1997;272(24):15434–15441.
  • Sun J, Whisstock JC, Harriott P, et al. Importance of the P4' residue in human granzyme B inhibitors and substrates revealed by scanning mutagenesis of the proteinase inhibitor 9 reactive center loop. J Biol Chem. 2001;276(18):15177–15184.
  • Cao X, Cai SF, Fehniger TA, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity. 2007;27(4):635–646.
  • Paydarnia N, Khoshtinat Nikkhoi S, Fakhravar A, et al. Synergistic effect of granzyme B-azurin fusion protein on breast cancer cells. Mol Biol Rep. 2019;46(3):3129–3140.
  • Amoury M, Kolberg K, Pham AT, et al. Granzyme B-based cytolytic fusion protein targeting EpCAM specifically kills triple negative breast cancer cells in vitro and inhibits tumor growth in a subcutaneous mouse tumor model. Cancer Lett. 2016;372(2):201–209.
  • Mikolajczyk SD, Marks LS, Partin AW, et al. Free prostate-specific antigen in serum is becoming more complex. Urology. 2002;59(6):797–802.
  • Stephan C, Jung K, Schnorr D, et al. Re: a prospective study to evaluate the role of complexed prostate specific antigen and free/total prostate specific antigen ratio for the diagnosis of prostate cancer. I.D.C. Mitchell, B.L. Croal, A. Dickie, N.P. Cohen and I. Ross. J Urol. 2001;165:1549–1553. J Urol. 2002 Jan;167(1):259-60.
  • Karashima S, Kataoka H, Itoh H, et al. Prognostic significance of alpha-1-antitrypsin in early stage of colorectal carcinomas. Int J Cancer. 1990;45(2):244–250.
  • Hurlimann J, van Melle G. Prognostic value of serum proteins synthesized by breast carcinoma cells. Am J Clin Pathol. 1991;95(6):835–843.
  • Zelvyte I, Wallmark A, Piitulainen E, et al. Increased plasma levels of serine proteinase inhibitors in lung cancer patients. Anticancer Res. 2004;24(1):241–247.
  • Tahara E, Ito H, Taniyama K, et al. Alpha 1-antitrypsin, alpha 1-antichymotrypsin, and alpha 2-macroglobulin in human gastric carcinomas: a retrospective immunohistochemical study. Hum Pathol. 1984;15(10):957–964.
  • Dano K, Andreasen PA, Grondahl-Hansen J, et al. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266.
  • Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev. 1993;73(1):161–195.
  • Chen D, Song M, Mohamad O, et al. Inhibition of Na+/K+-ATPase induces hybrid cell death and enhanced sensitivity to chemotherapy in human glioblastoma cells. BMC Cancer. 2014;14(1):716.
  • Baker C, Belbin O, Kalsheker N, et al. SERPINA3 (aka alpha-1-antichymotrypsin). Front Biosci. 2007;12(8–12):2821–2835.
  • Balch CM, Soong SJ. Predicting outcomes in metastatic melanoma. J Clin Oncol. 2008;26(2):168–169.
  • Eggermont AM, Spatz A, Robert C. Cutaneous melanoma. Lancet. 2014;383(9919):816–827.
  • Turnier JL, Brunner HI, Bennett M, et al. Discovery of SERPINA3 as a candidate urinary biomarker of lupus nephritis activity. Rheumatology (Oxford). 2019;58(2):321–330.
  • O'Riordan E, Orlova TN, Mei JJ, et al. Bioinformatic analysis of the urine proteome of acute allograft rejection. J Am Soc Nephrol. 2004;15(12):3240–3248.
  • O'Riordan E, Orlova TN, Podust VN, et al. Characterization of urinary peptide biomarkers of acute rejection in renal allografts. Am J Transplant. 2007;7(4):930–940.
  • Ziegler ME, Chen T, LeBlanc JF, et al. Apolipoprotein A1 and C-terminal fragment of alpha-1 antichymotrypsin are candidate plasma biomarkers associated with acute renal allograft rejection. Transplantation. 2011;92(4):388–395.
  • Porcellini E, Davis EJ, Chiappelli M, et al. Elevated plasma levels of alpha-1-anti-chymotrypsin in age-related cognitive decline and Alzheimer's disease: a potential therapeutic target. Curr Pharm Des . 2008;14(26):2659–2664.
  • Sergi D, Campbell FM, Grant C, et al. SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice. Genes Nutr. 2018;13(1):28.
  • Dalby MJ, Aviello G, Ross AW, et al. Diet induced obesity is independent of metabolic endotoxemia and TLR4 signalling, but markedly increases hypothalamic expression of the acute phase protein, SerpinA3N. Sci Rep. 2018;8(1):15648.
  • Gueugneau M, d'Hose D, Barbe C, et al. Increased Serpina3n release into circulation during glucocorticoid-mediated muscle atrophy. J Cachexia Sarcopenia Muscle. 2018;9(5):929–946.
  • Kniesel U, Wolburg H. Tight junctions of the blood-brain barrier. Cell Mol Neurobiol. 2000;20(1):57–76.
  • Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol. 2005;26(9):485–495.
  • Pittock SJ, Lucchinetti CF. The pathology of MS: new insights and potential clinical applications. Neurologist. 2007;13(2):45–56.
  • Lu JQ, Fan Y, Mitha AP, et al. Association of alpha-synuclein immunoreactivity with inflammatory activity in multiple sclerosis lesions. J Neuropathol Exp Neurol. 2009;68(2):179–189.
  • Neumann H, Medana IM, Bauer J, et al. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 2002;25(6):313–319.
  • Chaitanya GV, Kolli M, Babu PP. Granzyme-b mediated cell death in the spinal cord-injured rat model. Neuropathology. 2009;29(3):270–279.
  • Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol. 2002;20(1):323–370.
  • Bien CG, Vincent A, Barnett MH, et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain. 2012;135(5):1622–1638.
  • Diotti RA, Nakanishi A, Clementi N, et al. JC polyomavirus (JCV) and monoclonal antibodies: friends or potential foes? Clin Dev Immunol. 2013;2013:1.
  • Havla J, Kleiter I, Kumpfel T. Bridging, switching or drug holidays - how to treat a patient who stops natalizumab? Ther Clin Risk Manag. 2013;9:361–369.
  • Wuthrich C, Popescu BF, Gheuens S, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis: a postmortem study. J Neuropathol Exp Neurol. 2013;72(11):1043–1051.
  • Tegeder I, Costigan M, Griffin RS, et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006;12(11):1269–1277.
  • Persson AK, Gebauer M, Jordan S, et al. Correlational analysis for identifying genes whose regulation contributes to chronic neuropathic pain. Mol Pain. 2009;5:7.
  • Costigan M, Belfer I, Griffin RS, et al. Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain. 2010;133(9):2519–2527.
  • Sorge RE, Trang T, Dorfman R, et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med. 2012;18(4):595–599.
  • D'Andrea MR. Evidence linking neuronal cell death to autoimmunity in Alzheimer's disease. Brain Res. 2003;982(1):19–30.
  • Strous RD, Shoenfeld Y. To smell the immune system: olfaction, autoimmunity and brain involvement. Autoimmun Rev. 2006;6(1):54–60.
  • Zukor K, Belin S, Wang C, et al. Short hairpin RNA against PTEN enhances regenerative growth of corticospinal tract axons after spinal cord injury. J Neurosci. 2013;33(39):15350–15361.
  • Williams RR, Henao M, Pearse DD, et al. Permissive Schwann cell graft/spinal cord interfaces for axon regeneration. Cell Transplant. 2015;24(1):115–131.
  • Bush TG, Puvanachandra N, Horner CH, et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron. 1999;23(2):297–308. Jun
  • Faulkner JR, Herrmann JE, Woo MJ, et al. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 2004;24(9):2143–2155.
  • Wanner IB, Anderson MA, Song B, et al. Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci. 2013;33(31):12870–12886.
  • Dringen R, Gutterer JM, Hirrlinger J. Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem. 2000;267(16):4912–4916.
  • Slemmer JE, Shacka JJ, Sweeney MI, et al. Antioxidants and free radical scavengers for the treatment of stroke, traumatic brain injury and aging. CMC. 2008;15(4):404–414.
  • Benarroch E. Endocannabinoids in basal ganglia circuits: implications for Parkinson disease. Neurology. 2007;69(3):306–309.
  • Adhami F, Yu D, Yin W, et al. Deleterious effects of plasminogen activators in neonatal cerebral hypoxia-ischemia. Am J Pathol. 2008;172(6):1704–1716.
  • Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119(1):7–35.
  • Valiente M, Obenauf AC, Jin X, et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014;156(5):1002–1016.
  • Yepes M, Sandkvist M, Wong MK, et al. Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood. 2000;96(2):569–576.
  • Chia WJ, Dawe GS, Ong WY. Expression and localization of the iron-siderophore binding protein lipocalin 2 in the normal rat brain and after kainate-induced excitotoxicity. Neurochem Int. 2011;59(5):591–599.
  • Fukada Y, Yasui K, Kitayama M, et al. Gene expression analysis of the murine model of amyotrophic lateral sclerosis: studies of the Leu126delTT mutation in SOD1. Brain Res. 2007;1160:1–10.
  • Wang L, Jiang S, Xiao L, et al. Inhibition of granzyme B activity blocks inflammation induced by lipopolysaccharide through regulation of endoplasmic reticulum stress signaling in NK92 cells. Mol Med Rep. 2018;18(1):580–586.
  • Satta J, Laurila A, Paakko P, et al. Chronic inflammation and elastin degradation in abdominal aortic aneurysm disease: an immunohistochemical and electron microscopic study. Eur J Vasc Endovasc Surg. 1998;15(4):313–319. Apr
  • Ailawadi G, Eliason JL, Upchurch GR. Jr. Current concepts in the pathogenesis of abdominal aortic aneurysm. J Vasc Surg. 2003;38(3):584–588. Sep
  • Theocharis AD, Karamanos NK. Decreased biglycan expression and differential decorin localization in human abdominal aortic aneurysms. Atherosclerosis. 2002;165(2):221–230.
  • Boivin WA, Shackleford M, Vanden Hoek A, et al. Granzyme B cleaves decorin, biglycan and soluble betaglycan, releasing active transforming growth factor-beta1. PLoS One. 2012;7(3):e33163.
  • Afonina IS, Cullen SP, Martin SJ. Cytotoxic and non-cytotoxic roles of the CTL/NK protease granzyme B. Immunol Rev. 2010;235(1):105–116.
  • Ewen CL, Kane KP, Bleackley RC. A quarter century of granzymes. Cell Death Differ. 2012;19(1):28–35. Jan
  • Susanto O, Trapani JA, Brasacchio D. Controversies in granzyme biology. Tissue Antigens. 2012;80(6):477–487.
  • Hiebert PR, Wu D, Granville DJ. Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice. Cell Death Differ. 2013;20(10):1404–1414.
  • Burr AR, Molkentin JD. Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy. Cell Death Differ. 2015;22(9):1402–1412.
  • Hollinger K, Selsby JT. The physiological response of protease inhibition in dystrophic muscle. Acta Physiol. 2013;208(3):234–244.
  • Mantle D, Preedy VR. Adverse and beneficial functions of proteolytic enzymes in skeletal muscle. An overview. Adv Drug React Toxicol Rev. 2002;21(1–2):31–49.
  • Li H, Mittal A, Makonchuk DY, et al. Matrix metalloproteinase-9 inhibition ameliorates pathogenesis and improves skeletal muscle regeneration in muscular dystrophy. Hum Mol Genet. 2009;18(14):2584–2598.
  • Morris CA, Selsby JT, Morris LD, et al. Bowman-Birk inhibitor attenuates dystrophic pathology in mdx mice. J Appl Physiol (1985). 2010;109(5):1492–1499.
  • Regitz-Zagrosek V, Oertelt-Prigione S, Seeland U, et al. Sex and gender differences in myocardial hypertrophy and heart failure. Circ J. 2010;74(7):1265–1273.
  • Kania G, Blyszczuk P, Eriksson U. Mechanisms of cardiac fibrosis in inflammatory heart disease. Trends Cardiovasc Med. 2009;19(8):247–252.
  • Gjesdal O, Bluemke DA, Lima JA. Cardiac remodeling at the population level–risk factors, screening, and outcomes. Nat Rev Cardiol. 2011;8(12):673–685.
  • Nikolic I, Liu D, Bell JA, et al. Treatment with an estrogen receptor-beta-selective agonist is cardioprotective. J Mol Cell Cardiol. 2007;42(4):769–780.
  • Barth AS, Kuner R, Buness A, et al. Identification of a common gene expression signature in dilated cardiomyopathy across independent microarray studies. J Am Coll Cardiol. 2006;48(8):1610–1617. Oct 17
  • Asakura M, Kitakaze M. Global gene expression profiling in the failing myocardium. Circ J. 2009;73(9):1568–1576.
  • Ucer S, Iyer S, Kim HN, et al. The effects of aging and sex steroid deficiency on the murine skeleton are independent and mechanistically distinct. J Bone Miner Res. 2017;32(3):560–574.
  • Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 1999;13(10):1211–1233.
  • Roger VL, Go AS, Lloyd-Jones DM, et al. Executive summary: heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125(1):188–197.
  • Marcet-Palacios M, Ewen C, Pittman E, et al. Design and characterization of a novel human Granzyme B inhibitor. Protein Eng Des Sel. 2015;28(1):9–17.
  • Gardill BR, Schmidt K, Muller YA. NewBG: A surrogate corticosteroid-binding globulin with an unprecedentedly high ligand release efficacy. J Struct Biol. 2019;207(2):169–182.
  • Schmidt K, Gardill BR, Kern A, et al. Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein. Proc Natl Acad Sci USA. 2018;115(22):5744–5749.

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.