title: Candesartan cilexetil protects from cardiac myosin induced cardiotoxicity via reduction of endoplasmic reticulum stress and apoptosis in rats: involvement of ACE2-Ang (1-7)-mas axis.
abstract: Candesartan cilexetil, an angiotensin (Ang) II receptor 1 blocker was reported to suppress the myocardial damage in various cardiovascular complications but the mode by which it is effective in preventing the progression of dilated cardiomyopathy (DCM) is unknown. Emerging evidences suggest that, at least, part of the benefits observed with the use of AT1 receptor blockers could be attributed to the increased Ang (1-7) levels observed during administration of these agents. Identification of the novel components of the RAS, ACE2 and Ang (1-7) receptor mas, provided essential elements for considering the existence of a vasodilator arm of the RAS, represented by the ACE2-Ang (1-7)-mas axis. In this study, rat model of DCM was prepared by injection with porcine cardiac myosin. Twenty-eight days after immunization, candesartan cilexetil was administered intraperitoneally at 1 or 10mg/kg/day to rats for four weeks. Myocardial expression of Ang receptors and markers of calcium homeostasis, endoplasmic reticulum (ER) stress and apoptosis were measured by Western blotting and histopathological staining techniques. Candesartan improved the functional markers in a dose-dependent manner and also upregulated Ang (1-7), ACE2 and mas1 in the myocardium of DCM rats. Various ER stress and apoptosis markers were attenuated and the number apoptotic cells were significantly lower in the candesartan treated rats compared with those of the vehicle group. These findings suggest that candesartan treatment prevented the progression of DCM by activation of the counter regulatory arm of the RAS and possibly through modulation of ER stress and subsequently, cardiac apoptosis.
authors: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan. somasundaram143@rediffmail.com
authors: Somasundaram
authors: S
authors: Arumugam
authors: Rajarajan A
authors: RA
authors: Thandavarayan
authors: Suresh S
authors: SS
authors: Palaniyandi
authors: Vijayasree V
authors: VV
authors: Giridharan
authors: Wawaimuli
authors: W
authors: Arozal
authors: Flori R
authors: FR
authors: Sari
authors: Vivian
authors: V
authors: Soetikno
authors: Meilei
authors: M
authors: Harima
authors: Kenji
authors: K
authors: Suzuki
authors: Makoto
authors: M
authors: Kodama
authors: Kenichi
authors: K
authors: Watanabe
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000096:biosynthesis; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000517:prevention & control; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D009205:Myocarditis / Q000139:chemically induced / Q000517:prevention & control; D009218:Myosins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010446:Peptide Fragments / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D051017:Apoptosis Regulatory Proteins; C506948:Atp2a2 protein, rat; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C000715472:Mas1 protein, rat; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D013777:Tetrazoles; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D009218:Myosins; C118790:angiotensin I (1-7); C077793:candesartan cilexetil