Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia/reperfusion injury: role of autophagy paradox and toxic aldehyde.
OBJECTIVE
The present study was designed to examine the mechanism involved in mitochondrial aldehyde dehydrogenase (ALDH2)-induced cardioprotection against ischaemia/reperfusion (I/R) injury with a focus on autophagy.


METHODS
Wild-type (WT), ALDH2 overexpression, and knockout (KO) mice (n = 4-6 for each index measured) were subjected to I/R, and myocardial function was assessed using echocardiographic, Langendroff, and edge-detection systems. Western blotting was used to evaluate AMP-dependent protein kinase (AMPK), Akt, autophagy, and the AMPK/Akt upstream signalling LKB1 and PTEN.


RESULTS
ALDH2 overexpression and KO significantly attenuated and accentuated, respectively, infarct size, factional shortening, and recovery of post-ischaemic left ventricular function following I/R as well as hypoxia/reoxygenation-induced cardiomyocyte contractile dysfunction. Autophagy was induced during ischaemia and remained elevated during reperfusion. ALDH2 significantly promoted autophagy during ischaemia, which was accompanied by AMPK activation and mammalian target of rapamycin (mTOR) inhibition. On the contrary, ALDH2 overtly inhibited autophagy during reperfusion accompanied by the activation of Akt and mTOR. Inhibition and induction of autophagy mitigated ALDH2-induced protection against cell death in hypoxia and reoxygenation, respectively. In addition, levels of the endogenous toxic aldehyde 4-hydroxy-2-nonenal (4-HNE) were elevated by ischaemia and reperfusion, which was abrogated by ALDH2. Furthermore, ALDH2 ablated 4-HNE-induced cardiomyocyte dysfunction and protein damage, whereas 4-HNE directly decreased pan and phosphorylated LKB1 and PTEN expression.


CONCLUSIONS
Our data suggest a myocardial protective effect of ALDH2 against I/R injury possibly through detoxification of toxic aldehyde and a differential regulation of autophagy through AMPK- and Akt-mTOR signalling during ischaemia and reperfusion, respectively.
Ma
Heng
H
Department of Physiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
Guo
Rui
R
Yu
Lu
L
Zhang
Yingmei
Y
Ren
Jun
J
D000444:Aldehyde Dehydrogenase / Q000378:metabolism / Q000502:physiology*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000201:enzymology; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C027576:4-hydroxy-2-nonenal