A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-β cascades with restored caveolin-1 expression

REFERENCES

• Farber HW, Loscalzo J: Pulmonary arterial hypertension. N Engl J Med. 2004;351:1655–1665.
   PubMed Web of Science ®Google Scholar
• Mathew R: Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol. 2014;306:H15–H25.
   PubMed Web of Science ®Google Scholar
• Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA 3rd, Soubrier F, Trembath RC, Chung WK: Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S32–S42.
   PubMed Web of Science ®Google Scholar
• Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R: Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43–S54.
   PubMed Web of Science ®Google Scholar
• Austin ED, Ma L, LeDuc C, Berman Rosenzweig E, Borczuk A, Phillips JA, 3rd,Palomero T, Sumazin P, Kim HR, Talati MH, West J, Loyd JE, Chung WK: Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet. 2012;5:336–343.
   PubMed Web of Science ®Google Scholar
• Chidlow JH, Jr., Sessa WC: Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. Cardiovasc Res. 2010;86:219–225.
   PubMed Web of Science ®Google Scholar
• Roth RA, Reindel JF: Lung vascular injury from monocrotaline pyrrole, a putative hepatic metabolite. Adv Exp Med Biol. 1991;283:477–487.
   PubMedGoogle Scholar
• Wilson DW, Segall HJ, Pan LC, Lame MW, Estep JE, Morin D: Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol. 1992;22:307–325.
   PubMed Web of Science ®Google Scholar
• Huang J, Wolk JH, Gewitz MH, Mathew R: Progressive endothelial cell damage in an inflammatory model of pulmonary hypertension. Exp Lung Res. 2010;36:57–66.
   PubMed Web of Science ®Google Scholar
• Kasahara Y, Kiyatake K, Tatsumi K, Sugito K, Kakusaka I, Yamagata S,Ohmori S, Kitada M, Kuriyama T: Bioactivation of monocrotaline by P-450 3A in rat liver. J Cardiovasc Pharmacol. 1997;30:124–129.
   PubMed Web of Science ®Google Scholar
• Mathew R, Huang J, Shah M, Patel K, Gewitz M, Sehgal PB: Disruption of endothelial-cell caveolin-1alpha/raft scaffolding during development of monocrotaline-induced pulmonary hypertension. Circulation. 2004;110:1499–1506.
   PubMed Web of Science ®Google Scholar
• Eickelberg O, Pansky A, Mussmann R, Bihl M, Tamm M, Hildebrand P,Perruchoud AP, Roth M: Transforming growth factor-beta1 induces interleukin-6 expression via activating protein-1 consisting of JunD homodimers in primary human lung fibroblasts. J Biol Chem. 1999;274:12933–12938.
   PubMed Web of Science ®Google Scholar
• Wang H, Wang AX, Barrett EJ: Caveolin-1 is required for vascular endothelial insulin uptake. Am J Physiol Endocrinol Metab. 2011;300:E134–E144.
   Web of Science ®Google Scholar
• Yoshimatsu Y, Watabe T: Roles of TGF-beta signals in endothelial-mesenchymal transition during cardiac fibrosis. Int J Inflam. 2011;2011:724080.
   PubMedGoogle Scholar
• Li Z, Wermuth PJ, Benn BS, Lisanti MP, Jimenez SA: Caveolin-1 deficiency induces spontaneous endothelial-to-mesenchymal transition in murine pulmonary endothelial cells in vitro. Am J Pathol. 2013;182:325–331.
   PubMed Web of Science ®Google Scholar
• Heeneman S, Sluimer JC, Daemen MJ: Angiotensin-converting enzyme and vascular remodeling. Circ Res. 2007;101:441–454.
   PubMed Web of Science ®Google Scholar
• Koka V, Huang XR, Chung AC, Wang W, Truong LD, Lan HY: Angiotensin II upregulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am J Pathol. 2008;172:1174–1183.
   PubMed Web of Science ®Google Scholar
• Imai Y, Kuba K, Ohto-Nakanishi T, Penninger JM: Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis. Circ J. 2010;74:405–410.
   PubMed Web of Science ®Google Scholar
• Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ: A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275:33238–33243.
   PubMed Web of Science ®Google Scholar
• Kuba K, Imai Y, Penninger JM: Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases. Circ J. 2013;77:301–308.
   PubMed Web of Science ®Google Scholar
• Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B,Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM: Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–116.
   PubMed Web of Science ®Google Scholar
• Yamazato Y, Ferreira AJ, Hong KH, Sriramula S, Francis J, Yamazato M,Yuan L, Bradford CN, Shenoy V, Oh SP, Katovich MJ, Raizada MK: Prevention of pulmonary hypertension by Angiotensin-converting enzyme 2 gene transfer. Hypertension. 2009;54:365–371.
   PubMed Web of Science ®Google Scholar
• Shenoy V, Ferreira AJ, Qi Y, Fraga-Silva RA, Diez-Freire C, Dooies A,Jun JY, Sriramula S, Mariappan N, Pourang D, Venugopal CS, Francis J, Reudelhuber T, Santos RA, Patel JM, Raizada MK, Katovich MJ: The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med. 2010;182:1065–1072.
   PubMed Web of Science ®Google Scholar
• Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I,Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T: Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA. 2003;100:8258–8263.
   PubMed Web of Science ®Google Scholar
• Hernández Prada JA, Ferreira AJ, Katovich MJ, Shenoy V, Qi Y, Santos RA,Castellano RK, Lampkins AJ, Gubala V, Ostrov DA, Raizada MK: Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension. 2008;51: 1312–1317.
   PubMed Web of Science ®Google Scholar
• Ferreira AJ, Shenoy V, Yamazato Y, Sriramula S, Francis J, Yuan L,Castellano RK, Ostrov DA, Oh SP, Katovich MJ, Raizada MK: Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179:1048–1054.
   PubMed Web of Science ®Google Scholar
• Shenoy V, Gjymishka A, Jarajapu YP, Qi Y, Afzal A, Rigatto K,Ferreira AJ, Fraga-Silva RA, Kearns P, Douglas JY, Agarwal D, Mubarak KK, Bradford C, Kennedy WR, Jun JY, Rathinasabapathy A, Bruce E, Gupta D, Cardounel AJ, Mocco J, Patel JM, Francis J, Grant MB, Katovich MJ, Raizada MK: Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. Am J Respir Crit Care Med. 2013;187:648–657.
   PubMed Web of Science ®Google Scholar
• Andersen CU, Markvardsen LH, Hilberg O, Simonsen U: Pulmonary apelin levels and effects in rats with hypoxic pulmonary hypertension. Respir Med. 2009;103:1663–1671.
   PubMed Web of Science ®Google Scholar
• Meyrick B, Hislop A, Reid L: Pulmonary arteries of the normal rat: the thick walled oblique muscle segment. J Anat. 1978;125:209–221.
   PubMed Web of Science ®Google Scholar
• Furuya Y, Satoh T, Kuwana M: Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. Int J Rheumatol. 2010;2010:720305.
   PubMedGoogle Scholar
• Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T,Kubo M, Yamashita A, Okabe M, Takeda K, Akira S, Matsumoto S, Toyonaga A, Sata M, Yoshimura A: CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med. 2001;193:471–481.
   PubMed Web of Science ®Google Scholar
• Takaguri A, Shirai H, Kimura K, Hinoki A, Eguchi K, Carlile-Klusacek M,Yang B, Rizzo V, Eguchi S: Caveolin-1 negatively regulates a metalloprotease-dependent epidermal growth factor receptor transactivation by angiotensin II. J Mol Cell Cardiol. 2011;50:545–551.
   PubMed Web of Science ®Google Scholar
• Zhao YY, Zhao YD, Mirza MK, Huang JH, Potula HH, Vogel SM,Brovkovych V, Yuan JX, Wharton J, Malik AB: Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest. 2009;119:2009–2018.
   PubMed Web of Science ®Google Scholar
• Wang XM, Zhang Y, Kim HP, Zhou Z, Feghali-Bostwick CA, Liu F,Ifedigbo E, Xu X, Oury TD, Kaminski N, Choi AM: Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med. 2006;203:2895–2906.
   PubMed Web of Science ®Google Scholar
• Cohen AW, Park DS, Woodman SE, Williams TM, Chandra M, Shirani J,Pereira de Souza A, Kitsis RN, Russell RG, Weiss LM, Tang B, Jelicks LA, Factor SM, Shtutin V, Tanowitz HB, Lisanti MP: Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiac fibroblasts. Am J Physiol Cell Physiol. 2003;284:C457–C474.
   PubMed Web of Science ®Google Scholar
• Ou ZJ, Wei W, Huang DD, Luo W, Luo D, Wang ZP,Zhang X, Ou JS: L-arginine restores endothelial nitric oxide synthase-coupled activity and attenuates monocrotaline-induced pulmonary artery hypertension in rats. Am J Physiol Endocrinol Metab. 2010;298:E1131–E1139.
   Google Scholar
• Mount PF, Kemp BE, Power DA: Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol. 2007;42:271–279.
   PubMed Web of Science ®Google Scholar
• Dias-Peixoto MF, Santos RA, Gomes ER, Alves MN, Almeida PW, Greco L: Molecular mechanisms involved in the angiotensin-(1-7)/Mas signaling pathway in cardiomyocytes. Hypertension. 2008;52:542–548.
   PubMed Web of Science ®Google Scholar
• Haber PK, Ye M, Wysocki J, Maier C, Haque SK, Batlle D: Angiotensin-converting enzyme 2-independent action of presumed angiotensin-converting enzyme 2 activators: studies in vivo, ex vivo, and in vitro. Hypertension. 2014;63: 774–782.
   PubMed Web of Science ®Google Scholar
• Zhong J, Basu R, Guo D, Chow FL, Byrns S, Schuster M,Loibner H, Wang XH, Penninger JM, Kassiri Z, Oudit GY: Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Circulation. 2010;122:717–728.
   PubMed Web of Science ®Google Scholar
• Li X, Molina-Molina M, Abdul-Hafez A, Uhal V, Xaubet A, Uhal BD: Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis. Am J Physiol Lung Cell Mol Physiol. 2008;295:L178–185.
   PubMed Web of Science ®Google Scholar
• Wong DW, Oudit GY, Reich H, Kassiri Z, Zhou J, Liu QC,Backx PH, Penninger JM, Herzenberg AM, Scholey JW: Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury. Am J Pathol. 2007;171:438–451.
   PubMed Web of Science ®Google Scholar
• Reich HN, Oudit GY, Penninger JM, Scholey JW, Herzenberg AM: Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease. Kidney Int. 2008;74:1610–1616.
   PubMed Web of Science ®Google Scholar
• Nadarajah R, Milagres R, Dilauro M, Gutsol A, Xiao F, Zimpelmann J,Kennedy C, Wysocki J, Batlle D, Burns KD: Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice. Kidney Int. 2012;82:292–303.
   PubMed Web of Science ®Google Scholar