Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1–7 mas receptor

• Published in: Molecular and cellular endocrinology 2012-04, Vol.351 (2), p.208-219
• Main Authors: Sukumaran, Vijayakumar, Veeraveedu, Punniyakoti T., Gurusamy, Narasimman, Lakshmanan, Arun Prasath, Yamaguchi, Ken’ichi, Ma, Meilei, Suzuki, Kenji, Nagata, Masaki, Takagi, Ritsuo, Kodama, Makoto, Watanabe, Kenichi
• Format: Article
• Language: English
• Subjects: Angiotensin 1–7; Angiotensin I - genetics; Angiotensin I - metabolism; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin-converting enzyme-2; Angiotensin-II; Animals; apoptosis; Apoptosis - drug effects; Autoimmune Diseases - drug therapy; Autoimmune Diseases - metabolism; cardioprotective effect; Cardiotonic Agents - pharmacology; endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Experimental autoimmune myocarditis; gene expression regulation; heart failure; Heart Failure - drug therapy; Heart Failure - metabolism; Imidazoles - pharmacology; inflammation; Inflammation - drug therapy; JNK Mitogen-Activated Protein Kinases - biosynthesis; MAPK signaling pathways; Membrane Glycoproteins; messenger RNA; mitogen-activated protein kinase; myocarditis; Myocarditis - drug therapy; Myocarditis - immunology; Myocarditis - metabolism; NAD(P)H oxidase (H2O2-forming); NADPH Oxidase 4; NADPH Oxidases - biosynthesis; Olmesartan; oxidative stress; Oxidative Stress - drug effects; p38 Mitogen-Activated Protein Kinases - biosynthesis; Peptide Fragments - genetics; Peptide Fragments - metabolism; peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - biosynthesis; Peptidyl-Dipeptidase A - genetics; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - biosynthesis; Phosphoproteins - biosynthesis; Proto-Oncogene Proteins c-akt - biosynthesis; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1 - metabolism; Receptors, Interleukin-1; renin; RNA, Messenger - biosynthesis; signal transduction; Tetrazoles - pharmacology; therapeutics
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2011.12.010

Angiotensin-converting enzyme 2 (ACE-2) is a membrane-associated carboxy-peptidase catalyzes the conversion of the vasoconstrictor angiotensin (ANG)-II to the vasodilatory peptide ANG 1–7. In view of the expanding axis of the renin angiotensin system, we have investigated the cardioprotective effects of olmesartan (10mg/kg/day) in experimental autoimmune myocarditis. Olmesartan treatment effectively suppressed the myocardial protein expressions of inflammatory markers in comparison to the vehicle-treated rats. However, the protein and mRNA levels of ACE-2 and ANG 1–7, and its receptor Mas were upregulated in olmesartan treated group compared to vehicle-treated rats. Olmesartan medoxomil treatment significantly decreased the 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, vehicle-treated rats were shown to be up-regulated protein expressions of NADPH oxidase subunits (p47phox, p67phox and Nox-4), myocardial apoptotic markers and endoplasmic reticulum stress markers in comparison to those of normal and all these effects are expectedly down-regulated by an olmesartan. In addition, attenuated protein levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt in the vehicle-treated EAM rats were prevented by olmesartan treatment. Our results suggest that beneficial effects of olmesartan treatment was more effective therapy in combating the inflammation, oxidative stress, apoptosis and signaling pathways associated with heart failure at least in part via the modulation of ANG 1–7 mas receptor.