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2016 ; 7
(47
): 76398-76414
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Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced
cardiac dysfunction through deacetylation of PGC-1?
#MMPMID27634872
Hu N
; Ren J
; Zhang Y
Oncotarget
2016[Nov]; 7
(47
): 76398-76414
PMID27634872
show ga
Insulin resistance contributes to the high prevalence of type 2 diabetes
mellitus, leading to cardiac anomalies. Emerging evidence depicts a pivotal role
for mitochondrial injury in oxidative metabolism and insulin resistance.
Mitochondrial aldehyde dehydrogenase (ALDH2) is one of metabolic enzymes
detoxifying aldehydes although its role in insulin resistance remains elusive.
This study was designed to evaluate the impact of ALDH2 overexpression on insulin
resistance-induced myocardial damage and mechanisms involved with a focus on
autophagy. Wild-type (WT) and transgenic mice overexpressing ALDH2 were fed
sucrose or starch diet for 8 weeks and cardiac function and intracellular Ca2+
handling were assessed using echocardiographic and IonOptix systems. Western blot
analysis was used to evaluate Akt, heme oxygenase-1 (HO-1), PGC-1? and Sirt-3.
Our data revealed that sucrose intake provoked insulin resistance and compromised
fractional shortening, cardiomyocyte function and intracellular Ca2+ handling (p
< 0.05) along with unaltered cardiomyocyte size (p > 0.05), mitochondrial injury
(elevated ROS generation, suppressed NAD+ and aconitase activity, p < 0.05 for
all), the effect of which was ablated by ALDH2. In vitro incubation of the ALDH2
activator Alda-1, the Sirt3 activator oroxylin A and the histone
acetyltransferase inhibitor CPTH2 rescued insulin resistance-induced changes in
aconitase activity and cardiomyocyte function (p < 0.05). Inhibiting Sirt3
deacetylase using 5-amino-2-(4-aminophenyl) benzoxazole negated Alda-1-induced
cardioprotective effects. Taken together, our data suggest that ALDH2 serves as
an indispensable cardioprotective factor against insulin resistance-induced
cardiomyopathy with a mechanism possibly associated with facilitation of the
Sirt3-dependent PGC-1? deacetylation.
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