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.

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Publisher Full Text

Publisher Full Text

Authors

Patel VB, Bodiga S, Fan D, Das SK, Wang Z, Wang W, Basu R, Zhong J, Kassiri Z, Oudit GY

Institution

Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.

Source

Hypertension 59:6 2012 Jun pg 1195-203

MeSH

Angiotensin I
Angiotensin II Type 1 Receptor Blockers
Animals
Antihypertensive Agents
Biphenyl Compounds
Blood Pressure
Blotting, Western
Cardiotonic Agents
Cells, Cultured
Drug Synergism
Enzyme Activation
Female
Heart
Heart Failure
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardium
NADPH Oxidase
Peptide Fragments
Peptidyl-Dipeptidase A
Reverse Transcriptase Polymerase Chain Reaction
Superoxides
Systole
Tetrazoles

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22508831