{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T20:51:46Z","timestamp":1792270306663,"version":"4.4.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"published-print":{"date-parts":[[2013,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>M<jats:sub>3<\/jats:sub> muscarinic acetylcholine receptor (M<jats:sub>3<\/jats:sub>-mAChR) is stably expressed in the myocardium, but its pathophysiological role remains largely undefined. This study aimed to investigate the role of M<jats:sub>3<\/jats:sub>-mAChR in cardiac hypertrophy induced by angiotensin II (Ang II) and elucidate the underlying mechanisms.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Cardiac-specific M<jats:sub>3<\/jats:sub>-mAChR overexpression transgenic (TG) mice and rat H9c2 cardiomyoblasts with ectopic expression of M<jats:sub>3<\/jats:sub>-mAChR were established. Models of cardiac hypertrophy were induced by transverse aortic constriction (TAC) or Ang II infusion in the mice <jats:italic>in vivo<\/jats:italic>, and by isoproterenol (ISO) or Ang II treatment of H9c2 cells <jats:italic>in vitro<\/jats:italic>. Cardiac hypertrophy was evaluated by electrocardiography (ECG) measurement, hemodynamic measurement and histological analysis. mRNA and protein expression were detected by real-time RT-PCR and Western blot analysis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>M<jats:sub>3<\/jats:sub>-mAChR was upregulated in hypertrophic heart, while M<jats:sub>2<\/jats:sub>-mAChR expression did not change significantly. M<jats:sub>3<\/jats:sub>-mAChR overexpression significantly attenuated the increased expression of atrial natriuretic peptide and \u03b2-myosin heavy chain induced by Ang II both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. In addition, M<jats:sub>3<\/jats:sub>-mAChR overexpression downregulated AT<jats:sub>1<\/jats:sub> receptor expression and inhibited the activation of MAPK signaling in the heart.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The upregulation of M<jats:sub>3<\/jats:sub>-mAChR during myocardial hypertrophy could relieve the hypertrophic response provoked by Ang II, and the mechanism may involve the inhibition of MAPK signaling through the downregulation of AT<jats:sub>1<\/jats:sub> receptor.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1479-5876-11-209","type":"journal-article","created":{"date-parts":[[2013,9,12]],"date-time":"2013-09-12T18:14:30Z","timestamp":1379009670000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Upregulation of M3 muscarinic receptor inhibits cardiac hypertrophy induced by angiotensin II"],"prefix":"10.1186","volume":"11","author":[{"given":"Yan","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoxin","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengzhou","family":"Hang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanlan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Huo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjie","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimin","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,9,12]]},"reference":[{"key":"1602_CR1","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1161\/01.CIR.0000120390.68287.BB","volume":"109","author":"N Frey","year":"2004","unstructured":"Frey N, Katus HA, Olson EN, Hill JA: Hypertrophy of the heart: a new therapeutic target?. Circulation. 2004, 109: 1580-1589. 10.1161\/01.CIR.0000120390.68287.BB.","journal-title":"Circulation"},{"key":"1602_CR2","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/nrm1983","volume":"7","author":"J Heineke","year":"2006","unstructured":"Heineke J, Molkentin JD: Regulation of cardiac hypertrophy by intracellular signaling pathways. Nat Rev Mol Cell Biol. 2006, 7: 589-600.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"1602_CR3","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1093\/cvr\/cvq014","volume":"86","author":"R Gilsbach","year":"2010","unstructured":"Gilsbach R, Schneider J, Lother A, Schickinger S, Leemhuis J, Hein L: Sympathetic \u03b12 -adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload. Cardiovasc Res. 2010, 86: 432-442. 10.1093\/cvr\/cvq014.","journal-title":"Cardiovasc Res"},{"key":"1602_CR4","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1093\/eurheartj\/ehm048","volume":"28","author":"S Kasama","year":"2007","unstructured":"Kasama S, Toyama T, Hatori T, Sumino H, Kumakura H, Takayama Y, Ichikawa S, Suzuki T, Kurabayashi M: Evaluation of cardiac sympathetic nerve activity and left ventricular remodelling in patients with dilated cardiomyopathy on the treatment containing carvedilol. Eur Heart J. 2007, 28: 989-995. 10.1093\/eurheartj\/ehm048.","journal-title":"Eur Heart J"},{"key":"1602_CR5","doi-asserted-by":"publisher","first-page":"2061","DOI":"10.1016\/j.jacc.2005.08.046","volume":"46","author":"S Ohshima","year":"2005","unstructured":"Ohshima S, Isobe S, Izawa H, Nanasato M, Ando A, Yamada A, Yamada K, Kato TS, Obata K, Noda A, Nishizawa T, Kato K, Nagata K, Okumura K, Murohara T, Yokota M: Cardiac sympathetic dysfunction correlates with abnormal myocardial contractile reserve in dilated cardiomyopathy patients. J Am Coll Cardiol. 2005, 46: 2061-2068. 10.1016\/j.jacc.2005.08.046.","journal-title":"J Am Coll Cardiol"},{"key":"1602_CR6","first-page":"497","volume":"55","author":"H Shi","year":"1999","unstructured":"Shi H, Wang HZ, Wang ZG: Identification and characterization of multiple subtypes of muscarinic acetylcholine receptors and their physiological functions in canine hearts. Mol Pharmacol. 1999, 55: 497-507.","journal-title":"Mol Pharmacol"},{"key":"1602_CR7","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1038\/sj.bjp.0702486","volume":"126","author":"HZ Wang","year":"1999","unstructured":"Wang HZ, Shi H, Lu YJ, Yang BF, Wang ZG: Pilocarpine modulates the cellular electrical properties of mammalian hearts by activating a cardiac M3 receptor and a K+ current. Br J Pharmacol. 1999, 126: 1725-1734. 10.1038\/sj.bjp.0702486.","journal-title":"Br J Pharmacol"},{"key":"1602_CR8","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/sj.bjp.0705787","volume":"142","author":"ZG Wang","year":"2004","unstructured":"Wang ZG, Shi H, Wang HZ: Functional M3 muscarinic acetylcholine receptors in mammalian hearts. Br J Pharmacol. 2004, 142: 395-408. 10.1038\/sj.bjp.0705787.","journal-title":"Br J Pharmacol"},{"key":"1602_CR9","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1139\/Y08-094","volume":"86","author":"Y Liu","year":"2008","unstructured":"Liu Y, Sun HL, Li DL, Wang LY, Gao Y, Wang YP, Du ZM, Lu YJ, Yang BF: Choline produces antiarrhythmic actions in animal models by cardiac M3 receptors: improvement of intracellular Ca2+ handling as a common mechanism. Can J Physiol Pharmacol. 2008, 86: 860-865. 10.1139\/Y08-094.","journal-title":"Can J Physiol Pharmacol"},{"key":"1602_CR10","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1111\/j.1440-1681.2012.05672.x","volume":"39","author":"S Wang","year":"2012","unstructured":"Wang S, Han HM, Jiang YN, Wang C, Song HX, Pan ZY, Fan K, Du J, Fan YH, Du ZM, Liu Y: Activation of cardiac M3 muscarinic acetylcholinereceptors has cardioprotective effects against ischaemia-induced arrhythmias. Clin Exp Pharmacol Physiol. 2012, 39: 343-349. 10.1111\/j.1440-1681.2012.05672.x.","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"1602_CR11","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1007\/s00210-008-0376-6","volume":"379","author":"Y Liu","year":"2009","unstructured":"Liu Y, Du J, Gao Y, Zhang Y, Cai BZ, Zhao H, Q HP, Du ZM, Lu YJ, Yang BF: Role of M3 receptor in aconitine\/barium-chloride-induced preconditioning against arrhythmias in rats. Naunyn Schmiedebergs Arch Pharmacol. 2009, 379: 511-515. 10.1007\/s00210-008-0376-6.","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"1602_CR12","first-page":"84","volume":"36","author":"Y Liu","year":"2001","unstructured":"Liu Y, Wang Y, Ma ML, Zhang Y, Li HW, Chen QW, Yang BF: Cardiac hemodynamic effects of M3 receptor agonist on rat and rabbit hearts. Yao Xue Xue Bao. 2001, 36: 84-87.","journal-title":"Yao Xue Xue Bao"},{"key":"1602_CR13","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1016\/S0140-6736(08)61171-X","volume":"372","author":"K Fox","year":"2008","unstructured":"Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R: Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomized controlled trial. Lancet. 2008, 372: 817-821. 10.1016\/S0140-6736(08)61171-X.","journal-title":"Lancet"},{"key":"1602_CR14","doi-asserted-by":"publisher","first-page":"3012","DOI":"10.1093\/eurheartj\/ehm489","volume":"28","author":"M Cucherat","year":"2007","unstructured":"Cucherat M: Quantitative relationship between resting heart rate reduction and magnitude of clinical benefits in postmyocardial infarction: a meta-regression of randomized clinical trials. Eur Heart J. 2007, 28: 3012-3019. 10.1093\/eurheartj\/ehm489.","journal-title":"Eur Heart J"},{"key":"1602_CR15","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1161\/01.ATV.0000130661.82773.ca","volume":"24","author":"KG Lamping","year":"2004","unstructured":"Lamping KG, Wess J, Cui Y, Nuno DW, Faraci FM: Muscarinic (M) receptors in coronary circulation: gene-targeted mice define the role of M2 and M3 receptors in response to acetylcholine. Arterioscler Thromb Vasc Biol. 2004, 24: 1253-1258. 10.1161\/01.ATV.0000130661.82773.ca.","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"1602_CR16","doi-asserted-by":"publisher","first-page":"166","DOI":"10.2143\/AC.63.2.2029523","volume":"63","author":"QY Zhao","year":"2008","unstructured":"Zhao QY, Huang CX, Jiang H, Okello E, Tang YH, Wang ZW, Wu ZY: M2 and M3-muscarinic acetylcholine receptors remodeling in patients with a dilated atrium. Acta Cardiol. 2008, 63: 166-170. 10.2143\/AC.63.2.2029523.","journal-title":"Acta Cardiol"},{"key":"1602_CR17","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.2119\/molmed.2011.00093","volume":"17","author":"Y Liu","year":"2011","unstructured":"Liu Y, Sun LH, Pan ZW, Bai YL, Wang N, Zhao JL, Xu CQ, Li Z, Li BX, Du ZM, Lu YJ, Gao X, Yang BF: Over-expression of M3 muscarinic receptor is a novel strategy for preventing sudden cardiac death in transgenic mice. Mol Med. 2011, 17: 1179-1187.","journal-title":"Mol Med"},{"key":"1602_CR18","doi-asserted-by":"publisher","first-page":"2587","DOI":"10.1161\/CIRCULATIONAHA.107.711317","volume":"116","author":"D Frank","year":"2007","unstructured":"Frank D, Kuhn C, van Eickels M, Gehring D, Hanselmann C, Lippl S, Will R, Katus HA, Frey N: Calsarcin-1 protects against angiotensin-II induced cardiac hypertrophy. Circulation. 2007, 116: 2587-2596. 10.1161\/CIRCULATIONAHA.107.711317.","journal-title":"Circulation"},{"key":"1602_CR19","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1067\/S0894-7317(03)00471-1","volume":"16","author":"JN Rottman","year":"2003","unstructured":"Rottman JN, Ni G, Khoo M, Wang Z, Zhang W, Anderson ME, Madu EC: Temporal changes in ventricular function assessed echocardiographically in conscious and anesthetized mice. J Am Soc Echocardiogr. 2003, 16: 1150-1157. 10.1067\/S0894-7317(03)00471-1.","journal-title":"J Am Soc Echocardiogr"},{"key":"1602_CR20","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1093\/cvr\/cvn113","volume":"79","author":"S Grote-Wessels","year":"2008","unstructured":"Grote-Wessels S, Baba HA, Boknik P, El-Armouche A, Fabritz L, Gillmann HJ, Kucerova D, Matus M, M\u00fcller FU, Neumann J, Schmitz M, St\u00fcmpel F, Theilmeier G, Wohlschlaeger J, Schmitz W, Kirchhefer U: Inhibition of protein phosphatase 1 by inhibitor-2 exacerbates progression of cardiac failure in a model with pressure overload. Cardiovasc Res. 2008, 79: 464-471. 10.1093\/cvr\/cvn113.","journal-title":"Cardiovasc Res"},{"key":"1602_CR21","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/S0008-6363(99)00196-0","volume":"44","author":"BR Kwak","year":"1999","unstructured":"Kwak BR, van Kempen MJ, Th\u00e9veniau-Ruissy M, Gros DB, Jongsma HJ: Connexin expression in cultured neonatal rat myocytes reflects the pattern of the intact ventricle. Cardiovasc Res. 1999, 44: 370-380. 10.1016\/S0008-6363(99)00196-0.","journal-title":"Cardiovasc Res"},{"key":"1602_CR22","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1161\/01.RES.0000079794.57578.F1","volume":"93","author":"H Tomita","year":"2003","unstructured":"Tomita H, Nazmy M, Kajimoto K, Yehia G, Molina CA, Sadoshima J: Inducible cAMP early repressor (ICER) is a negative-feedback regulator of cardiac hypertrophy and an important mediator of cardiac myocyte apoptosis in response to \u03b2-adrenergic receptor stimulation. Circ Res. 2003, 93: 12-22. 10.1161\/01.RES.0000079794.57578.F1.","journal-title":"Circ Res"},{"key":"1602_CR23","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.1016\/S0735-1097(03)00471-6","volume":"41","author":"C Heymes","year":"2003","unstructured":"Heymes C, Bendall JK, Ratajczak P, Cave AC, Samuel JL, Hasenfuss G, Shah AM: Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol. 2003, 41: 2164-2171. 10.1016\/S0735-1097(03)00471-6.","journal-title":"J Am Coll Cardiol"},{"key":"1602_CR24","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1007\/s10495-010-0549-x","volume":"16","author":"JJ Liu","year":"2011","unstructured":"Liu JJ, Li DL, Zhou J, Sun L, Zhao M, Kong SS, Wang YH, Yu XJ, Zhou J, Zang WJ: Acetylcholine prevents angiotensin II-induced oxidative stress and apoptosis in H9c2 cells. Apoptosis. 2011, 16: 94-103. 10.1007\/s10495-010-0549-x.","journal-title":"Apoptosis"},{"key":"1602_CR25","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1097\/00004872-200018090-00017","volume":"18","author":"C Pellieux","year":"2000","unstructured":"Pellieux C, Sauthier T, Aubert JF, Brunner HR, Pedrazzini T: Angiotensin II induced cardiac hypertrophy is associated with different mitogen-activated protein kinase activation in normotensive and hypertensive mice. J Hypertens. 2000, 18: 1307-1317. 10.1097\/00004872-200018090-00017.","journal-title":"J Hypertens"},{"key":"1602_CR26","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1097\/FJC.0b013e318046f34a","volume":"49","author":"W Bao","year":"2007","unstructured":"Bao W, Behm DJ, Nerurkar SS, Ao Z, Bentley R, Mirabile RC, Johns DG, Woods TN, Doe CP, Coatney RW, Ohlstein JF, Douglas SA, Willette RN, Yue TL: Effects of p38 MAPK inhibitor on angiotensin II-dependent hypertension, organ damage, and superoxide anion production. J Cardiovasc Pharmacol. 2007, 49: 362-368. 10.1097\/FJC.0b013e318046f34a.","journal-title":"J Cardiovasc Pharmacol"},{"key":"1602_CR27","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1159\/000076924","volume":"14","author":"H Shi","year":"2004","unstructured":"Shi H, Wang H, Li D, Nattel S, Wang Z: Differential alterations of receptor densities of three muscarinic acetylcholine receptor subtypes and current densities of the corresponding K+ channels in canine atria with atrial fibrillation induced by experimental congestive heart failure. Cell Physiol Biochem. 2004, 14: 31-40. 10.1159\/000076924.","journal-title":"Cell Physiol Biochem"},{"key":"1602_CR28","doi-asserted-by":"publisher","first-page":"3045","DOI":"10.1172\/JCI25330","volume":"115","author":"PY Zhai","year":"2005","unstructured":"Zhai PY, Yamamoto M, Galeotti J, Liu J, Masurekar M, Thaisz J, Irie K, Holle E, Yu X, Kupershmidt S, Roden DM, Wagner T, Yatani A, Vatner DE, Vatner SF, Sadoshima J: Cardiac-specific overexpression of AT1 receptor mutant lacking Gq\/Gi coupling causes hypertrophy and bradycardia in transgenic mice. J Clin Invest. 2005, 115: 3045-3056. 10.1172\/JCI25330.","journal-title":"J Clin Invest"},{"key":"1602_CR29","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1161\/01.HYP.0000256831.33459.ea","volume":"49","author":"JK Park","year":"2007","unstructured":"Park JK, Fischer R, Dechend R, Shagdarsuren E, Gapeljuk A, Wellner M, Meiners S, Gratze P, Al-Saadi N, Feldt S, Fiebeler A, Madwed JB, Schirdewan A, Haller H, Luft FC, Muller DN: p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. Hypertension. 2007, 49: 481-489. 10.1161\/01.HYP.0000256831.33459.ea.","journal-title":"Hypertension"},{"key":"1602_CR30","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1124\/mol.107.044750","volume":"74","author":"J Luo","year":"2008","unstructured":"Luo J, Busillo JM, Benovic JL: M3 muscarinic acetylcholine receptor-mediated signaling is regulated by distinct mechanisms. Mol Pharmacol. 2008, 74: 338-347. 10.1124\/mol.107.044750.","journal-title":"Mol Pharmacol"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1479-5876-11-209.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T01:31:14Z","timestamp":1630546274000},"score":1,"resource":{"primary":{"URL":"https:\/\/translational-medicine.biomedcentral.com\/articles\/10.1186\/1479-5876-11-209"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,9,12]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,12]]}},"alternative-id":["1602"],"URL":"https:\/\/doi.org\/10.1186\/1479-5876-11-209","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,9,12]]},"assertion":[{"value":"30 April 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2013","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 September 2013","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"209"}}