In:
Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 3, No. 5 ( 2014-09-16)
Abstract:
Increasing evidence suggests a critical role for mitochondrial aldehyde dehydrogenase 2 ( ALDH 2) in protection against cardiac injuries; however, the downstream cytosolic actions of this enzyme are largely undefined. Methods and Results Proteomic analysis identified a significant downregulation of mitochondrial ALDH 2 in the heart of a rat heart failure model after myocardial infarction. The mechanistic insights underlying ALDH 2 action were elucidated using murine models overexpressing ALDH 2 or its mutant or with the ablation of the ALDH 2 gene ( ALDH 2 knockout) and neonatal cardiomyocytes undergoing altered expression and activity of ALDH 2. Left ventricle dilation and dysfunction and cardiomyocyte death after myocardial infarction were exacerbated in ALDH 2 ‐knockout or ALDH 2 mutant‐overexpressing mice but were significantly attenuated in ALDH 2‐overexpressing mice. Using an anoxia model of cardiomyocytes with deficiency in ALDH 2 activities, we observed prominent cardiomyocyte apoptosis and increased accumulation of the reactive aldehyde 4‐hydroxy‐2‐nonenal (4‐ HNE ). We subsequently examined the impacts of mitochondrial ALDH 2 and 4‐ HNE on the relevant cytosolic protective pathways. Our data documented 4‐ HNE ‐stimulated p53 upregulation via the phosphorylation of JNK , accompanying increased cardiomyocyte apoptosis that was attenuated by inhibition of p53. Importantly, elevation of 4‐ HNE also triggered a reduction of the cytosolic HSP 70, further corroborating cytosolic action of the 4‐ HNE instigated by downregulation of mitochondrial ALDH 2. Conclusions Downregulation of ALDH 2 in the mitochondria induced an elevation of 4‐ HNE , leading to cardiomyocyte apoptosis by subsequent inhibition of HSP 70, phosphorylation of JNK , and activation of p53. This chain of molecular events took place in both the mitochondria and the cytosol, contributing to the mechanism underlying heart failure.
Type of Medium:
Online Resource
ISSN:
2047-9980
DOI:
10.1161/JAHA.113.000779
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
2653953-6
