{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:20:36Z","timestamp":1761862836531,"version":"3.37.0"},"reference-count":38,"publisher":"The Endocrine Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,8,1]]},"abstract":"<jats:p>Angiotensin II plays a key role in the development of cardiac hypertrophy. The contribution of the angiotensin II type 1 receptor (AT1) in angiotensin II-induced cardiac hypertrophy is well established, but the role of AT2 signaling remains controversial. Previously, we have shown that natriuretic peptide receptor\/guanylyl cyclase-A (GCA) signaling protects the heart from hypertrophy at least in part by inhibiting AT1-mediated pro-hypertrophic signaling. Here, we investigated the role of AT2 in cardiac hypertrophy observed in mice lacking GCA. Real-time RT-PCR and immunoblotting approaches indicated that the cardiac AT2 gene was overexpressed in GCA-deficient mice. Mice lacking AT2 alone did not exhibit an abnormal cardiac phenotype. In contrast, GCA-deficiency-induced increases in heart to body weight ratio, cardiomyocyte cross-sectional area, and collagen accumulation as evidenced by van Gieson staining were attenuated when AT2 was absent. Furthermore, the up-regulated cardiac expression of hypertrophy-related genes in GCA-null animals was also suppressed. Pharmacological blockade of AT2 with PD123319 similarly attenuated cardiac hypertrophy in GCA-deficient mice. In addition, whereas the AT1 antagonist olmesartan attenuated cardiac hypertrophy in GCA-deficient mice, this treatment was without effect on cardiac hypertrophy in GCA\/AT2-double null mice, notwithstanding its potent antihypertensive effect in these animals. These results suggest that the interplay of AT2 and AT1 may be important in the development of cardiac hypertrophy. Collectively, our findings support the assertion that GCA inhibits AT2-mediated pro-hypertrophic signaling in heart and offer new insights into endogenous cardioprotective mechanisms during disease pathogenesis.<\/jats:p>","DOI":"10.1210\/en.2008-1353","type":"journal-article","created":{"date-parts":[[2009,4,17]],"date-time":"2009-04-17T00:46:33Z","timestamp":1239929193000},"page":"3759-3765","source":"Crossref","is-referenced-by-count":12,"title":["Guanylyl Cyclase-A Inhibits Angiotensin II Type 2 Receptor-Mediated Pro-Hypertrophic Signaling in the Heart"],"prefix":"10.1210","volume":"150","author":[{"given":"Yuhao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Medicine and Clinical Science (Y.L., K.K., X.R., M.H., Y.A., M.N., H.K., K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiko","family":"Saito","sequence":"first","affiliation":[{"name":"First Department of Internal Medicine (Y.S.), Nara Medical University, Nara 634, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichiro","family":"Kuwahara","sequence":"first","affiliation":[{"name":"Department of Medicine and Clinical Science (Y.L., K.K., X.R., M.H., Y.A., M.N., H.K., K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianglu","family":"Rong","sequence":"first","affiliation":[{"name":"Department of Medicine and Clinical Science (Y.L., K.K., X.R., M.H., Y.A., M.N., H.K., K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ichiro","family":"Kishimoto","sequence":"first","affiliation":[{"name":"National Cardiovascular Center Research Institute (I.K.), Osaka 565-8565, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaki","family":"Harada","sequence":"first","affiliation":[{"name":"Department of Medicine and Clinical Science (Y.L., K.K., X.R., M.H., Y.A., M.N., H.K., K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichiro","family":"Adachi","sequence":"first","affiliation":[{"name":"Department of Medicine and Clinical Science (Y.L., K.K., X.R., M.H., Y.A., M.N., H.K., K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michio","family":"Nakanishi","sequence":"first","affiliation":[{"name":"Department of Medicine and Clinical Science (Y.L., K.K., X.R., M.H., Y.A., M.N., H.K., K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideyuki","family":"Kinoshita","sequence":"first","affiliation":[{"name":"Department of Medicine and Clinical Science (Y.L., K.K., X.R., M.H., Y.A., M.N., H.K., K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masatsugu","family":"Horiuchi","sequence":"first","affiliation":[{"name":"Department of Molecular Cardiovascular Biology and Pharmacology (M.H.), Ehime University Graduate School of Medicine, Ehime 791-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Murray","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy (M.M.), The University of Sydney, Sydney, New South Wales 2006, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuwa","family":"Nakao","sequence":"first","affiliation":[{"name":"Department of Medicine and Clinical Science (Y.L., K.K., X.R., M.H., Y.A., M.N., H.K., K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2009,4,16]]},"reference":[{"key":"2020071612370888700_R1","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1097\/01.hjh.0000165625.79933.9a","article-title":"Left ventricular hypertrophy as a predictor of cardiovascular risk","volume":"23","author":"Gosse","year":"2005","journal-title":"J Hypertens Suppl"},{"key":"2020071612370888700_R2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1097\/00041552-199601000-00003","article-title":"The natriuretic peptide family.","volume":"5","author":"Nakao","year":"1996","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"2020071612370888700_R3","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1161\/01.HYP.35.1.19","article-title":"Inhibitory regulation of hypertrophy by endogenous atrial natriuretic peptide in cultured cardiac myocytes.","volume":"35","author":"Horio","year":"2000","journal-title":"Hypertension"},{"key":"2020071612370888700_R4","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1139\/y01-052","article-title":"Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart.","volume":"79","author":"Ogawa","year":"2001","journal-title":"Can J Physiol Pharmacol"},{"key":"2020071612370888700_R5","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/378065a0","article-title":"Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide.","volume":"378","author":"Lopez","year":"1995","journal-title":"Nature"},{"key":"2020071612370888700_R6","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1161\/01.CIR.0000029923.57048.61","article-title":"Guanylyl cyclase A inhibits angiotensin II type 1a receptor-mediated cardiac remodeling, an endogenous protective mechanism in the heart.","volume":"106","author":"Li","year":"2002","journal-title":"Circulation"},{"key":"2020071612370888700_R7","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1210\/en.2003-0816","article-title":"Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A.","volume":"145","author":"Li","year":"2004","journal-title":"Endocrinology"},{"key":"2020071612370888700_R8","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1161\/01.HYP.0000173420.31354.ef","article-title":"Role of natriuretic peptide receptor GC-A in myocardial infarction evaluated using genetically engineered mice.","volume":"46","author":"Nakanishi","year":"2005","journal-title":"Hypertension"},{"key":"2020071612370888700_R9","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.tem.2004.09.003","article-title":"The role of the AT1 angiotensin receptor in cardiac hypertrophy: angiotensin II receptor or stretch sensor?","volume":"15","author":"Hunyady","year":"2004","journal-title":"Trends Endocrinol Metab"},{"key":"2020071612370888700_R10","doi-asserted-by":"crossref","first-page":"H2337","DOI":"10.1152\/ajpheart.2001.281.6.H2337","article-title":"Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide","volume":"281","author":"Berry","year":"2001","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2020071612370888700_R11","first-page":"H844","article-title":"Distribution and function of cardiac angiotensin AT1- and AT2-receptor subtypes in hypertrophied rat hearts","volume":"267","author":"Lopez","year":"1994","journal-title":"Am J Physiol"},{"key":"2020071612370888700_R12","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1161\/01.RES.73.3.439","article-title":"Rat angiotensin II (type 1A) receptor mRNA regulation and subtype expression in myocardial growth and hypertrophy.","volume":"73","author":"Suzuki","year":"1993","journal-title":"Circ Res"},{"key":"2020071612370888700_R13","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1161\/01.RES.83.10.1035","article-title":"Angiotensin II type 2 receptor is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its expression.","volume":"83","author":"Tsutsumi","year":"1998","journal-title":"Circ Res"},{"key":"2020071612370888700_R14","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1161\/01.HYP.36.5.845","article-title":"Angiotensin II type 2 receptors stimulate collagen synthesis in cultured vascular smooth muscle cells.","volume":"36","author":"Mifune","year":"2000","journal-title":"Hypertension"},{"key":"2020071612370888700_R15","doi-asserted-by":"crossref","first-page":"R25","DOI":"10.1172\/JCI10037","article-title":"Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload","volume":"106","author":"Senbonmatsu","year":"2000","journal-title":"J Clin Invest"},{"key":"2020071612370888700_R16","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1161\/01.CIR.104.3.346","article-title":"Angiotensin type 2 receptor is essential for ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension.","volume":"104","author":"Ichihara","year":"2001","journal-title":"Circulation"},{"key":"2020071612370888700_R17","doi-asserted-by":"crossref","first-page":"H2179","DOI":"10.1152\/ajpheart.00361.2003","article-title":"Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice","volume":"285","author":"Yan","year":"2003","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2020071612370888700_R18","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1161\/01.HYP.0000193504.51489.cf","article-title":"The angiotensin II type 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin II type 1 receptor-mediated hypertrophy.","volume":"46","author":"D'Amore","year":"2005","journal-title":"Hypertension"},{"key":"2020071612370888700_R19","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1161\/01.HYP.0000062881.36813.7A","article-title":"Long-acting Ca2+ blockers prevent myocardial remodeling induced by chronic NO inhibition in rats.","volume":"41","author":"Sanada","year":"2003","journal-title":"Hypertension"},{"key":"2020071612370888700_R20","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1681\/ASN.V1351162","article-title":"Angiotensin III activates nuclear transcription factor-\u03baB in cultured mesangial cells mainly via AT2 receptors: studies with AT1 receptor-knockout mice.","volume":"13","author":"Lorenzo","year":"2002","journal-title":"J Am Soc Nephrol"},{"key":"2020071612370888700_R21","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1161\/01.CIR.102.14.1684","article-title":"Inhibitory effect of angiotensin II type 2 receptor on coronary arterial remodeling after aortic banding in mice.","volume":"102","author":"Akishita","year":"2000","journal-title":"Circulation"},{"key":"2020071612370888700_R22","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0008-6363(95)00121-2","article-title":"Mechanical and neuroendocrine regulation of the endocrine heart.","volume":"31","author":"Bold","year":"1996","journal-title":"Cardiovasc Res"},{"key":"2020071612370888700_R23","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1172\/JCI1885","article-title":"Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects.","volume":"101","author":"Masaki","year":"1998","journal-title":"J Clin Invest"},{"key":"2020071612370888700_R24","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/S1050-1738(01)00136-0","article-title":"Dual effects of angiotensin II type 2 receptor on cardiovascular hypertrophy.","volume":"11","author":"Inagami","year":"2001","journal-title":"Trends Cardiovasc Med"},{"key":"2020071612370888700_R25","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1006\/jmcc.2000.1198","article-title":"Effect of pressure overload on angiotensin receptor expression in the rat heart during early postnatal life.","volume":"32","author":"Olivie\u0301ro","year":"2000","journal-title":"J Mol Cell Cardiol"},{"key":"2020071612370888700_R26","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.cardiores.2004.04.030","article-title":"TGF-\u03b21 and angiotensin networking in cardiac remodeling.","volume":"63","author":"Rosenkranz","year":"2004","journal-title":"Cardiovasc Res"},{"key":"2020071612370888700_R27","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1172\/JCI0214190","article-title":"TGF-\u03b21 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II.","volume":"109","author":"Schultz Jel","year":"2002","journal-title":"J Clin Invest"},{"key":"2020071612370888700_R28","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1159\/000159245","article-title":"Subendothelial proteoglycan synthesis and transforming growth factor \u03b2 distribution correlate with susceptibility to atherosclerosis.","volume":"34","author":"Scott","year":"1997","journal-title":"J Vasc Res"},{"key":"2020071612370888700_R29","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.yjmcc.2004.08.004","article-title":"Angiotensin AT2 receptor contributes to cardiovascular remodelling of aged rats during chronic AT1 receptor blockade.","volume":"37","author":"Jones","year":"2004","journal-title":"J Mol Cell Cardiol"},{"key":"2020071612370888700_R30","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1161\/01.HYP.0000176744.15592.7d","article-title":"Combined angiotensin II type 1 and type 2 receptor blockade on vascular remodeling and matrix metalloproteinases in resistance arteries.","volume":"46","author":"Brassard","year":"2005","journal-title":"Hypertension"},{"key":"2020071612370888700_R31","doi-asserted-by":"crossref","first-page":"H2337","DOI":"10.1152\/ajpheart.2001.281.6.H2337","article-title":"Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide","volume":"281","author":"Berry","year":"2001","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2020071612370888700_R32","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0031-6997(24)01434-0","article-title":"Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases.","volume":"52","author":"Kim","year":"2000","journal-title":"Pharmacol Rev"},{"key":"2020071612370888700_R33","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1161\/hh0202.104109","article-title":"Adenoviral-directed expression of the type 1A angiotensin receptor promotes cardiomyocyte hypertrophy via transactivation of the epidermal growth factor receptor.","volume":"90","author":"Thomas","year":"2002","journal-title":"Circ Res"},{"key":"2020071612370888700_R34","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1161\/01.RES.86.8.841","article-title":"Functional deletion mutation of the 5\u2032-flanking region of type A human natriuretic peptide receptor gene and its association with essential hypertension and left ventricular hypertrophy in the Japanese.","volume":"86","author":"Nakayama","year":"2000","journal-title":"Circ Res"},{"key":"2020071612370888700_R35","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.jacc.2005.12.081","article-title":"Association of atrial natriuretic peptide and type A natriuretic peptide receptor gene polymorphisms with left ventricular mass in human essential hypertension.","volume":"48","author":"Rubattu","year":"2006","journal-title":"J Am Coll Cardiol"},{"key":"2020071612370888700_R36","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1291\/hypres.31.89","article-title":"Association of CT dinucleotide repeat polymorphism in the 5\u2032-flanking region of the guanylyl cyclase (GC)-A gene with essential hypertension in the Japanese.","volume":"31","author":"Usami","year":"2008","journal-title":"Hypertens Res"},{"key":"2020071612370888700_R37","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/0735-1097(92)90005-8","article-title":"Uncoupling of atrial natriuretic peptide extraction and cyclic guanosine monophosphate production in the pulmonary circulation in patients with severe heart failure.","volume":"20","author":"Tsutamoto","year":"1992","journal-title":"J Am Coll Cardiol"},{"key":"2020071612370888700_R38","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1161\/01.CIR.87.1.70","article-title":"Possibility of down-regulation of atrial natriuretic peptide receptor coupled to guanylate cyclase in peripheral vascular beds of patients with chronic severe heart failure.","volume":"87","author":"Tsutamoto","year":"1993","journal-title":"Circulation"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/150\/8\/3759\/9008236\/endo3759.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/150\/8\/3759\/9008236\/endo3759.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,9]],"date-time":"2025-02-09T00:33:50Z","timestamp":1739061230000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/150\/8\/3759\/2456454"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,4,16]]},"references-count":38,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2009,8,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2008-1353","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"type":"print","value":"0013-7227"},{"type":"electronic","value":"1945-7170"}],"subject":[],"published":{"date-parts":[[2009,4,16]]}}}