Abstract
Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial isozyme of the heart involved in the metabolism of toxic aldehydes produced from oxidative stress. We hypothesized that hyperglycemia-mediated decrease in ALDH2 activity may impair mitochondrial respiration and ultimately result in cardiac damage. A single dose (65 mg/kg; i.p.) streptozotocin injection to rats resulted in hyperglycemia with blood glucose levels of 443 ± 9 mg/dl versus 121 ± 7 mg/dl in control animals, p<0.0001, N = 7–11. After 6 months of diabetes mellitus (DM) induction, the rats were sacrificed after recording the functionality of their hearts. Increase in the cardiomyocyte cross sectional area (446 ± 32 μm2 Vs 221 ± 10 μm2; p<0.0001) indicated cardiac hypertrophy in DM rats. Both diastolic and systolic dysfunctions were observed with DM rats compared to controls. Most importantly, myocardial ALDH2 activity and levels were reduced, and immunostaining for 4HNE protein adducts was increased in DM hearts compared to controls. The mitochondrial oxygen consumption rate (OCR), an index of mitochondrial respiration, was decreased in mitochondria isolated from DM hearts compared to controls (p<0.0001). Furthermore, the rate of mitochondrial respiration and the increase in carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP)-induced maximal respiration were also decreased with chronic hyperglycemia. Chronic hyperglycemia reduced mitochondrial OXPHOS proteins. Reduced ALDH2 activity was correlated with mitochondrial dysfunction, pathological remodeling and cardiac dysfunction, respectively. Our results suggest that chronic hyperglycemia reduces ALDH2 activity, leading to mitochondrial respiratory dysfunction and consequently cardiac damage and dysfunction.
Highlights
Hyperglycemia, the increase in blood glucose levels, is a common symptom of both type-1 and type-2 diabetes mellitus (DM)
A single dose (65 mg/kg; i.p.) injection of STZ resulted in hyperglycemia, as evident from increased blood glucose levels {443 ± 9 mg/dl in DM versus 121 ± 7 mg/dl in control animals} within a week, which persisted for 6 months
We found reduced ALDH2 activity correlated with decreased mitochondrial respiration and their reserve capacity in the myocardium of chronic hyperglycemic rats
Summary
Hyperglycemia, the increase in blood glucose levels, is a common symptom of both type-1 and type-2 diabetes mellitus (DM). Chronic hyperglycemia-induced oxidative stress is considered to be one of the major causes of diabetic cardiovascular complications [11, 12]. Hyperglycemia-induced overproduction of reactive oxygen species (ROS) by the mitochondrial electron-transport chain is a key aspect of the pathogenesis of diabetic cardiac damage [13]. Oxidative stress-induced ROS increases the generation of toxic reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE) in the mitochondria [14]. We found that 4HNE forms adducts with ALDH2 itself and attenuates its activity, thereby contributing to cardiac hypertrophy in a non-genetic model of type-2 DM [15]. ALDH2 activation by a small molecule activator, Alda-1, protected ischemia-reperfusion induced myocardial injury. This compound was known to attenuate 4HNE-induced ALDH2 impairment [19]. ALDH2 activity seems to be vital in preventing 4-HNE-induced cardio toxicity irrespective of origin of the diseases
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