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ACUTE CORONARY SYNDROME / EXPERIMENTAL RESEARCH
Association of AT1R mediated TGF β1/Smad axis down regulation with anti fibrotic and functional benefits of extended exercise after myocardial infarction
1
Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, China
2
Guangdong Provincial Key Laboratory of Food, Nutrition, and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
Submission date: 2026-04-14
Final revision date: 2026-05-27
Acceptance date: 2026-06-18
Online publication date: 2026-09-30
Corresponding author
Moussa Ide Nasser
Department of Cardiology Guangdong Cardiovascular Institute Guangdong Academy of Medical Sciences Guangdong Provincial People’s Hospital Southern Medical University Guangzhou, China
Department of Cardiology Guangdong Cardiovascular Institute Guangdong Academy of Medical Sciences Guangdong Provincial People’s Hospital Southern Medical University Guangzhou, China
Xuyu He
Department of Cardiology Guangdong Cardiovascular Institute Guangdong Academy of Medical Sciences Guangdong Provincial People’s Hospital Southern Medical University Guangzhou, China
Department of Cardiology Guangdong Cardiovascular Institute Guangdong Academy of Medical Sciences Guangdong Provincial People’s Hospital Southern Medical University Guangzhou, China
KEYWORDS
exercise trainingmyocardial infarctioncardiac fibrosisTGF-β1SMAD signallingangiotensin II type 1 receptorrat modelcardiac pathologyechocardiographysystolic function
TOPICS
ABSTRACT
Introduction:
Exercise training (ET) has cardioprotective effects after myocardial infarction (MI), but the associated molecular pathways remain incompletely defined. The novel aspect of this work is the comparison of short-term and extended post-MI ET while examining the angiotensin II type 1 receptor (AT1R)/TGF-β1/Smad axis as an associated anti-fibrotic pathway.
Material and methods:
Sprague-Dawley rats were assigned to four groups: sham control, MI-sedentary, MI with 4-week ET (MIex1), and MI with 12-week ET (MIex3). ET began three days after coronary artery ligation. After 12 weeks, echocardiography and haemodynamic measurements were performed, and left ventricular (LV) tissue was collected for histological and molecular analyses.
Results:
Compared with MI-sedentary rats, MIex1 rats showed increased LV systolic pressure, ±dP/dtmax, ejection fraction, and fractional shortening, along with decreased LV end-diastolic pressure and LV diameters. Twelve-week ET further enhanced functional outcomes. Both ET groups reduced collagen volume fraction and collagen I/III expression. ET was also associated with lower cardiac Ang II, AT1R, TGF-β1, and phosphorylated Smad2/3, with stronger effects after 12 weeks of ET.
Conclusions:
Exercise reduces myocardial fibrosis following MI and preserves cardiac function, an effect that may be amplified by extended exercise training. Downregulation of AT1R-mediated TGF-β1/Smad signalling may be associated with these cardioprotective effects.
Exercise training (ET) has cardioprotective effects after myocardial infarction (MI), but the associated molecular pathways remain incompletely defined. The novel aspect of this work is the comparison of short-term and extended post-MI ET while examining the angiotensin II type 1 receptor (AT1R)/TGF-β1/Smad axis as an associated anti-fibrotic pathway.
Material and methods:
Sprague-Dawley rats were assigned to four groups: sham control, MI-sedentary, MI with 4-week ET (MIex1), and MI with 12-week ET (MIex3). ET began three days after coronary artery ligation. After 12 weeks, echocardiography and haemodynamic measurements were performed, and left ventricular (LV) tissue was collected for histological and molecular analyses.
Results:
Compared with MI-sedentary rats, MIex1 rats showed increased LV systolic pressure, ±dP/dtmax, ejection fraction, and fractional shortening, along with decreased LV end-diastolic pressure and LV diameters. Twelve-week ET further enhanced functional outcomes. Both ET groups reduced collagen volume fraction and collagen I/III expression. ET was also associated with lower cardiac Ang II, AT1R, TGF-β1, and phosphorylated Smad2/3, with stronger effects after 12 weeks of ET.
Conclusions:
Exercise reduces myocardial fibrosis following MI and preserves cardiac function, an effect that may be amplified by extended exercise training. Downregulation of AT1R-mediated TGF-β1/Smad signalling may be associated with these cardioprotective effects.
REFERENCES (45)
1.
Gerber Y, Weston SA, Enriquez-Sarano M, et al. Mortality associated with heart failure after myocardial infarction. Circ Hear Fail 2016; 9: e002460.
2.
Bulluck H, Dharmakumar R, Arai AE, Berry C, Hausenloy DJ. Cardiovascular magnetic resonance in acute ST-segment-elevation myocardial infarction: recent advances, controversies, and future directions. Circulation 2018; 137: 1949-64.
3.
Prabhu SD, Frangogiannis NG, Service M, Einstein A. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res 2017; 119: 91-112.
4.
Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction – from repair and remodeling to regeneration. Cell Tissue Res 2016; 365: 563-81.
5.
Frangogiannis NG. Pathophysiology of myocardial infarction. Compr Physiol 2015; 5: 1841-75.
6.
Aras O, Messina SA, Shirani J, Eckelman WC, Dilsizian V. The role and regulation of cardiac angiotensin-converting enzyme for noninvasive molecular imaging in heart failure. Curr Cardiol Rep 2007; 9: 150-8.
7.
Rosenkranz S. TGF-1 and angiotensin networking in cardiac remodeling. Cardiovasc Res 2004; 63: 423-32.
8.
Meng XM, Tang PMK, Li J, Lan HY. TGF-ß/Smad signaling in renal fibrosis. Front Physiol 2015; 6: 82.
9.
Miyazawa K, Miyazono K. Regulation of TGF- family signaling by inhibitory smads. Cold Spring Harb Perspect Biol 2017; 9: a022095.
10.
He X, Zhang K, Gao X, et al. Rapid atrial pacing induces myocardial fibrosis by down-regulating Smad7 via microRNA-21 in rabbit. Heart Vessels 2016; 31: 1696-708.
11.
He X, Gao X, Peng L, et al. Atrial fibrillation induces myocardial fibrosis through angiotensin II type 1 receptor-specific Arkadia-mediated downregulation of Smad7. Circ Res 2011; 108: 164-75.
12.
Zhang K, He X, Zhou Y, et al. Atorvastatin ameliorates radiation-induced cardiac fibrosis in rats. Radiat Res 2015; 184: 611-20.
13.
Giallauria F, Acampa W, Ricci F, et al. Effects of exercise training started within 2 weeks after acute myocardial infarction on myocardial perfusion and left ventricular function: a gated SPECT imaging study. Eur J Prev Cardiol 2012; 19: 1410-9.
14.
Tucker WJ, Beaudry RI, Liang Y, et al. Meta-analysis of exercise training on left ventricular ejection fraction in heart failure with reduced ejection fraction: a 10-year update. Prog Cardiovasc Dis 2019; 62: 163-71.
15.
Lawler PR, Filion KB, Eisenberg MJ. Efficacy of exercise-based cardiac rehabilitation post-myocardial infarction: a systematic review and meta-analysis of randomized controlled trials. Am Heart J 2011; 162: 571-84.e2.
16.
Zucker IH, Schultz HD, Patel KP, Wang H. Modulation of angiotensin II signaling following exercise training in heart failure. Am J Physiol Hear Circ Physiol 2015; 308: H781-91.
17.
Wan W, Powers AS, Li J, Ji L, Erikson JM, Zhang JQ. Effect of post-myocardial infarction exercise training on the renin-angiotensin-aldosterone system and cardiac function. Am J Med Sci 2007; 334: 265-73.
18.
Puhl SL, Müller A, Wagner M, et al. Exercise attenuates inflammation and limits scar thinning after myocardial infarction in mice. Am J Physiol Hear Circ Physiol 2015; 309: H345-59.
19.
Jia D, Hou L, Lv Y, Xi L, Tian Z. Postinfarction exercise training alleviates cardiac dysfunction and adverse remodeling via mitochondrial biogenesis and SIRT1/PGC-1/PI3K/Akt signaling. J Cell Physiol 2019; 234: 23705-18.
20.
Kraljevic J, Marinovic J, Pravdic D, et al. Aerobic interval training attenuates remodelling and mitochondrial dysfunction in the post-infarction failing rat heart. Cardiovasc Res 2013; 99: 55-64.
21.
Kröpfl JM, Spengler CM, Frobert A, Ajalbert G, Giraud MN. Myocardial infarction does not affect circulating haematopoietic stem and progenitor cell self-renewal ability in a rat model. Exp Physiol 2018; 103: 1-8.
22.
Xu X, Wan W, Ji L, et al. Exercise training combined with angiotensin II receptor blockade limits post-infarct ventricular remodelling in rats. Cardiovasc Res 2008; 78: 523-32.
23.
Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072-83.
24.
Rennison JH, McElfresh TA, Okere IC, et al. High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction. Am J Physiol Hear Circ Physiol 2007; 292: 1498-506.
25.
Luo J, Gao X, Peng L, Sun H, Dai G. Effects of hydrochlorothiazide on cardiac remodeling in a rat model of myocardial infarction-induced congestive heart failure. Eur J Pharmacol 2011; 667: 314-21.
26.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-CT method. Methods 2001; 25: 402-8.
27.
Anderson L, Oldridge N, Thompson DR, et al. Exercise-based cardiac rehabilitation for coronary heart disease cochrane systematic review and meta-analysis. J Am Coll Cardiol 2016; 67: 1-12.
28.
Belardinelli R, Georgiou D, Cianci G, Purcaro A. 10-year exercise training in chronic heart failure: a randomized controlled trial. J Am Coll Cardiol 2012; 60: 1521-8.
29.
Wang Y, Tian M, Mi C, et al. Exercise protects the heart against myocardial infarction through upregulation of miR-1192. Biochem Biophys Res Commun 2020; 521: 1061-9.
30.
Guizoni DM, Oliveira-Junior SA, Noor SLR, et al. Effects of late exercise on cardiac remodeling and myocardial calcium handling proteins in rats with moderate and large size myocardial infarction. Int J Cardiol 2016; 221: 406-12.
31.
Marijianowski MMH, Teeling P, Becker AE. Remodeling after myocardial infarction in humans is not associated with interstitial fibrosis of noninfarcted myocardium. J Am Coll Cardiol 1997; 30: 76-82.
32.
Van Aelst LNL, Voss S, Carai P, et al. Osteoglycin prevents cardiac dilatation and dysfunction after myocardial infarction through infarct collagen strengthening. Circ Res 2015; 116: 425-36.
33.
Yengo CM1, Zimmerman SD, McCormick RJ TD. Exercise training post-MI favorably modifies heart extracellular matrix in the rat. Med Sci Sport 2012; 44: 1005-12.
34.
Solomon SD, Skali H, Anavekar NS, et al. Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation 2005; 111: 3411-9.
35.
Granger CB, McMurray JJV, Yusuf S, et al. CHARM-Alternative trial (ARB CHF). Lancet 2003; 362: 772-6.
36.
Lim BK, Park J, Park SJ, et al. Fimasartan for remodeling after myocardial infarction. J Clin Med 2019; 8: 366.
37.
Huang BS, Chen A, Ahmad M, Wang HW, Leenen FHH. Mineralocorticoid and AT1 receptors in the paraventricular nucleus contribute to sympathetic hyperactivity and cardiac dysfunction in rats post myocardial infarct. J Physiol 2014; 592: 3273-86.
38.
Haack KKV, Engler CW, Papoutsi E, Pipinos II, Patel KP, Zucker IH. Parallel changes in neuronal at1r and grk5 expression following exercise training in heart failure. Hypertension 2012; 60: 354-61.
39.
Lee Y, Kwak HB, Hord J, Kim JH, Lawler JM. Exercise training attenuates age-dependent elevation of angiotensin II type 1 receptor and Nox2 signaling in the rat heart. Exp Gerontol 2015; 70: 163-73.
40.
Liang ZG, Yao H, Xie RS, Gong CL, Tian Y. MicroRNA-20b-5p promotes ventricular remodeling by targeting the TGF-/Smad signaling pathway in a rat model of ischemia-reperfusion injury. Int J Mol Med 2018; 42: 975-87.
41.
Hang PZ. 7,8-Dihydroxyflavone alleviates cardiac fibrosis by restoring circadian signals via downregulating Bmal1/Akt pathway. Eur J Pharmacol 2023; 938: 175405.
42.
Zhu Y, Ran Y, Fu T, et al. Cardiomyocyte-derived BDNFrestricts cardiac fibrosis by decreasing the activity of the TGF- /Smad2/3 pathway and increasing Smad7 expression. Front Cell Dev Biol 2026; 14: 1786720.
43.
Paravlic AH, Drole K. Effects of aerobic training on brachial artery flow mediated dilation in healthy adults: a meta analysis of inter individual response differences in randomized controlled trials. BMC Sports Sci Med Rehabil 2025; 17: 72.
44.
Andrews KL, Triggle CR, Ellis A. NO and the vasculature: where does it come from and what does it do? Heart Fail Rev 2002; 7: 423-45.
45.
Heger J, Warga B, Meyering B, et al. TGF receptor activation enhances cardiac apoptosis via SMAD activation and concomitant NO release. J Cell Physiol 2011; 226: 2683-90.
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| ISSN: | 1734-1922 |
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