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Int J Biol Sci 2011; 7(8):1077-1092. doi:10.7150/ijbs.7.1077

Research Paper

Cardioprotective Effects of Telmisartan against Heart Failure in Rats Induced By Experimental Autoimmune Myocarditis through the Modulation of Angiotensin-Converting Enzyme-2/Angiotensin 1-7/Mas Receptor Axis

Vijayakumar Sukumaran1, Punniyakoti T. Veeraveedu1,2, Narasimman Gurusamy3, Ken'ichi Yamaguchi4, Arun Prasath Lakshmanan1, Meilei Ma1, Kenji Suzuki5, Makoto Kodama6, Kenichi Watanabe1✉

1. Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
2. Department of Single Molecule Imaging, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
3. Department of Anesthesiology and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4. Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
5. Department of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
6. First Department of Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Abstract

Angiotensin-converting enzyme-2 (ACE-2) is a homolog of ACE that preferentially forms angiotensin-(ANG)-1-7 from angiotensin II (ANG II). We investigated the cardioprotective effects of telmisartan, a well-known angiotensin receptor blockers (ARBs) against experimental autoimmune myocarditis (EAM). EAM was induced in Lewis rats by immunization with porcine cardiac myosin. The rats were divided into two groups and treated with telmisartan (10 mg/kg/day) or vehicle for 21 days. Myocardial functional parameters were significantly improved by treatment with telmisartan compared with vehicle-treated rats. Telmisartan lowered myocardial protein expressions of NADPH oxidase subunits 3-nitrotyrosine, p47phox, p67 phox, Nox-4 and superoxide production significantly than vehicle-treated rats. In contrast myocardial protein levels of ACE-2, ANG 1-7 mas receptor were upregulated in the telmisartan treated group compared with those of vehicle-treated rats. The myocardial protein expression levels of tumor necrosis factor receptor (TNFR)-associated factor (TRAF)-2, C/EBP homologous protein (CHOP) and glucose-regulated protein (GRP) 78 were decreased in the telmisartan treated rats compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly decreased the protein expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho (MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, telmisartan significantly decreased the production of proinflammatory cytokines, myocardial apoptotic markers and caspase-3 positive cells compared with those of vehicle-treated rats. Therefore, we suggest that telmisartan was beneficial protection against heart failure in rats, at least in part by suppressing inflammation, oxidative stress, ER stress as well as signaling pathways through the modulation of ACE2/ANG1-7/Mas receptor axis.

Keywords: Experimental autoimmune myocarditis, endoplasmic reticulum stress, inflammation, telmisartan, oxidative stress, signaling pathways

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How to cite this article:
Sukumaran V, Veeraveedu PT, Gurusamy N, Yamaguchi K, Lakshmanan AP, Ma M, Suzuki K, Kodama M, Watanabe K. Cardioprotective Effects of Telmisartan against Heart Failure in Rats Induced By Experimental Autoimmune Myocarditis through the Modulation of Angiotensin-Converting Enzyme-2/Angiotensin 1-7/Mas Receptor Axis. Int J Biol Sci 2011; 7(8):1077-1092. doi:10.7150/ijbs.7.1077. Available from http://www.ijbs.com/v07p1077.htm