Diabetic Aldehyde Dehydrogenase 2 Mutant (ALDH2*2) Mice Are More Susceptible to Cardiac Ischemic-Reperfusion Injury Due to 4-Hydroxy-2-Nonenal Induced Coronary Endothelial Cell Damage.

Content Provider	Europe PMC
Author	Pan, Guodong Roy, Bipradas Palaniyandi, Suresh Selvaraj
Abstract	BackgroundAldehyde dehydrogenase‐2 (ALDH2), a mitochondrial enzyme, detoxifies reactive aldehydes such as 4‐hydroxy‐2‐nonenal (4HNE). A highly prevalent E487K mutation in ALDH2 (ALDH2*2) in East Asian people with intrinsic low ALDH2 activity is implicated in diabetic complications. 4HNE‐induced cardiomyocyte dysfunction was studied in diabetic cardiac damage; however, coronary endothelial cell (CEC) injury in myocardial ischemia‐reperfusion injury (IRI) in diabetic mice has not been studied. Therefore, we hypothesize that the lack of ALDH2 activity exacerbates 4HNE‐induced CEC dysfunction which leads to cardiac damage in ALDH2*2 mutant diabetic mice subjected to myocardial IRI.Methods and ResultsThree weeks after diabetes mellitus (DM) induction, hearts were subjected to IRI either in vivo via left anterior descending artery occlusion and release or ex vivo IRI by using the Langendorff system. The cardiac performance was assessed by conscious echocardiography in mice or by inserting a balloon catheter in the left ventricle in the ex vivo model. Just 3 weeks of DM led to an increase in cardiac 4HNE protein adducts and, cardiac dysfunction, and a decrease in the number of CECs along with reduced myocardial ALDH2 activity in ALDH2*2 mutant diabetic mice compared with their wild‐type counterparts. Systemic pretreatment with Alda‐1 (10 mg/kg per day), an activator of both ALDH2 and ALDH2*2, led to a reduction in myocardial infarct size and dysfunction, and coronary perfusion pressure upon cardiac IRI by increasing CEC population and coronary arteriole opening.ConclusionsLow ALDH2 activity exacerbates 4HNE‐mediated CEC injury and thereby cardiac dysfunction in diabetic mouse hearts subjected to IRI, which can be reversed by ALDH2 activation.
Page Count	18
Journal	Journal of the American Heart Association
Volume Number	10
PubMed Central reference number	PMC8649540
Issue Number	18
PubMed reference number	34482710
e-ISSN	20479980
DOI	10.1161/jaha.121.021140
Language	English
Publisher	John Wiley and Sons Inc.
Publisher Date	2021-09-06
Publisher Place	Hoboken
Access Restriction	Open
Rights License	This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
Subject Keyword	aldehyde dehydrogenase‐2 cardiac dysfunction coronary endothelial cells diabetic heart ischemia‐reperfusion injury Langendorff system 4‐hydroxy‐2‐nonenal Angiogenesis Animal Models of Human Disease Ischemia Oxidant Stress Pathophysiology
Content Type	Text
Resource Type	Article
Subject	Cardiology and Cardiovascular Medicine