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Int J Biol Sci 2011; 7(2):154-167. doi:10.7150/ijbs.7.154

Research Paper

Olmesartan, an AT1 Antagonist, Attenuates Oxidative Stress, Endoplasmic Reticulum Stress and Cardiac Inflammatory Mediators in Rats with Heart Failure Induced by Experimental Autoimmune Myocarditis

Vijayakumar Sukumaran1, Kenichi Watanabe1, , Punniyakoti T. Veeraveedu1,2, Narasimman Gurusamy3, Meilei Ma1, Rajarajan A. Thandavarayan1, Arun Prasath Lakshmanan1, Ken'ichi Yamaguchi4, Kenji Suzuki5, Makoto Kodama6

1. Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
2. 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

Studies have demonstrated that angiotensin II has been involved in immune and inflammatory responses which might contribute to the pathogenesis of immune-mediated diseases. Recent evidence suggests that oxidative stress may play a role in myocarditis. Here, we investigated whether olmesartan, an AT1R antagonist protects against experimental autoimmune myocarditis (EAM) by suppression of oxidative stress, endoplasmic reticulum (ER) stress and inflammatory cytokines. EAM was induced in Lewis rats by immunization with porcine cardiac myosin, were divided into two groups and treated with either olmesartan (10 mg/kg/day) or vehicle for a period of 21 days. Myocardial functional parameters measured by hemodynamic and echocardiographic analyses were significantly improved by the treatment with olmesartan compared with those of vehicle-treated rats. Treatment with olmesartan attenuated the myocardial mRNA expressions of proinflammatory cytokines, [Interleukin (IL)-1β, monocyte chemoattractant protein-1, tumor necrosis factor-α and interferon-γ)] and the protein expression of tumor necrosis factor-α compared with that of vehicle-treated rats. Myocardial protein expressions of AT1R, NADPH oxidase subunits (p47phox, p67phox, gp91phox) and the expression of markers of oxidative stress (3-nitrotyrosine and 4-hydroxy-2-nonenal), and the cardiac apoptosis were also significantly decreased by the treatment with olmesartan compared with those of vehicle-treated rats. Furthermore, olmesartan treatment down-regulated the myocardial expressions of glucose regulated protein-78, growth arrest and DNA damage-inducible gene, caspase-12, phospho-p38 mitogen-activated protein kinase (MAPK) and phospho-JNK. These findings suggest that olmesartan protects against EAM in rats, at least in part via suppression of oxidative stress, ER stress and inflammatory cytokines.

Keywords: Experimental autoimmune myocarditis, oxidative stress, endoplasmic reticulum stress, inflammation, olmesartan

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How to cite this article:
Sukumaran V, Watanabe K, Veeraveedu PT, Gurusamy N, Ma M, Thandavarayan RA, Lakshmanan AP, Yamaguchi K, Suzuki K, Kodama M. Olmesartan, an AT1 Antagonist, Attenuates Oxidative Stress, Endoplasmic Reticulum Stress and Cardiac Inflammatory Mediators in Rats with Heart Failure Induced by Experimental Autoimmune Myocarditis. Int J Biol Sci 2011; 7(2):154-167. doi:10.7150/ijbs.7.154. Available from http://www.ijbs.com/v07p0154.htm