title: Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1-7 in experimental heart failure in angiotensin-converting enzyme 2-null mice.
abstract: Loss of angiotensin (Ang)-converting enzyme 2 (ACE2) and inability to metabolize Ang II to Ang 1-7 perpetuate the actions of Ang II after biomechanical stress and exacerbate early adverse myocardial remodeling. Ang receptor blockers are known to antagonize the effect of Ang II by blocking Ang II type 1 receptor (AT(1)R) and also by upregulating the ACE2 expression. We directly compare the benefits of AT(1)R blockade versus enhancing Ang 1-7 action in pressure-overload-induced heart failure in ACE2 knockout mice. AT(1)R blockade and Ang 1-7 both resulted in marked recovery of systolic dysfunction in pressure-overloaded ACE2-null mice. Similarly, both therapies attenuated the increase in NADPH oxidase activation by downregulating the expression of Nox2 and p47(phox) subunits and also by limiting the p47(phox) phosphorylation. Biomechanical stress-induced increase in protein kinase C-α expression and phosphorylation of extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3, Akt, and glycogen synthase kinase 3β were normalized by irbesartan and Ang 1-7. Ang receptor blocker and Ang 1-7 effectively reduced matrix metalloproteinase 2 activation and matrix metalloproteinase 9 levels. Ang II-mediated cellular effects in cultured adult cardiomyocytes and cardiofibrolasts isolated from pressure-overloaded ACE2-null hearts were inhibited to similar degree by AT(1)R blockade and stimulation with Ang 1-7. Thus, treatment with the AT(1)R blocker irbesartan and Ang 1-7 prevented the cardiac hypertrophy and improved cardiac remodeling in pressure-overloaded ACE2-null mice by suppressing NADPH oxidase and normalizing pathological signaling pathways.
authors.affiliation: Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.forename: Sreedhar
authors.initials: S
authors.lastname: Bodiga
authors.forename: Dong
authors.initials: D
authors.lastname: Fan
authors.forename: Subhash K
authors.initials: SK
authors.lastname: Das
authors.forename: Zuocheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.forename: JiuChang
authors.initials: J
authors.lastname: Zhong
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000803:Angiotensin I / Q000378:metabolism / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D000077405:Irbesartan; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D013599:Systole; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents; D010446:Peptide Fragments; D013777:Tetrazoles; D013481:Superoxides; D000803:Angiotensin I; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D000077405:Irbesartan