Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1-7 mas receptor.
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.
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan. svkumar1979@yahoo.com
Vijayakumar
V
Sukumaran
Punniyakoti T
PT
Veeraveedu
Narasimman
N
Gurusamy
Arun Prasath
AP
Lakshmanan
Ken'ichi
K
Yamaguchi
Meilei
M
Ma
Kenji
K
Suzuki
Masaki
M
Nagata
Ritsuo
R
Takagi
Makoto
M
Kodama
Kenichi
K
Watanabe
D000803:Angiotensin I / Q000235:genetics / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D008562:Membrane Glycoproteins; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D017472:Receptors, Interleukin-1; D013777:Tetrazoles / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
D000803:Angiotensin I; D047228:Angiotensin II Type 1 Receptor Blockers; D000085962:Angiotensin-Converting Enzyme 2; D002316:Cardiotonic Agents; D007093:Imidazoles; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D010446:Peptide Fragments; D007703:Peptidyl-Dipeptidase A; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D017472:Receptors, Interleukin-1; D013777:Tetrazoles; D048051:p38 Mitogen-Activated Protein Kinases; C434984:TIRAP protein, human; C079789:neutrophil cytosol factor 67K; C437965:olmesartan; C498911:Nox4 protein, rat; C060505:neutrophil cytosolic factor 1; C000705307:ACE2 protein, human; C000705329:Ace2 protein, rat; C118790:angiotensin I (1-7)