Type-2 diabetic aldehyde dehydrogenase 2 mutant mice (ALDH 2*2) exhibiting heart failure with preserved ejection fraction phenotype can be determined by exercise stress echocardiography

Abstract

E487K point mutation of aldehyde dehydrogenase (ALDH) 2 (ALDH2*2) in East Asians intrinsically lowers ALDH2 activity. ALDH2*2 is associated with diabetic cardiomyopathy. Diabetic patients exhibit heart failure of preserved ejection fraction (HFpEF) i.e. while the systolic heart function is preserved in them, they may exhibit diastolic dysfunction, implying a jeopardized myocardial health. Currently, it is challenging to detect cardiac functional deterioration in diabetic mice. Stress echocardiography (echo) in the clinical set-up is a procedure used to measure cardiac reserve and impaired cardiac function in coronary artery diseases. Therefore, we hypothesized that high-fat diet fed type-2 diabetic ALDH2*2 mutant mice exhibit HFpEF which can be measured by cardiac echo stress test methodology. We induced type-2 diabetes in 12-week-old male C57BL/6 and ALDH2*2 mice through a high-fat diet. At the end of 4 months of DM induction, we measured the cardiac function in diabetic and control mice of C57BL/6 and ALDH2*2 genotypes by conscious echo. Subsequently, we imposed exercise stress by allowing the mice to run on the treadmill until exhaustion. Post-stress, we measured their cardiac function again. Only after treadmill running, but not at rest, we found a significant decrease in % fractional shortening and % ejection fraction in ALDH2*2 mice with diabetes compared to C57BL/6 diabetic mice as well as non-diabetic (control) ALDH2*2 mice. The diabetic ALDH2*2 mice also exhibited poor maximal running speed and distance. Our data suggest that high-fat fed diabetic ALDH2*2 mice exhibit HFpEF and treadmill exercise stress echo test is able to determine this HFpEF in the diabetic ALDH2*2 mice.

Mitochondrial ROS Formation in the Pathogenesis of Diabetic Cardiomyopathy

“…MAO-dependent oxidative stress may lead to the inhibition of aldehyde dehydrogenase 2 (ALDH2) resulting in further accumulation of toxic and reactive aldehydes (37). In that regard, it has been demonstrated that stimulation of ALDH2 activity protects from streptozotocin-induced cardiac damage (172), suggesting that accumulation of aldehydes may promote cardiac remodeling in diabetes independently or in concert with high ROS levels (173).…”

Aldehyde dehydrogenase 2 activator augments the beneficial effects of empagliflozin in diabetes associated HFpEF

“…In fact, a recent clinical study in East Asians with ALDH2*2 mutation demonstrated an association between ALDH2*2 and HFpEF in patients having diabetes and other comorbidities [17]. Even before this study, we were the rst to demonstrate that ALDH2*2 mutant mice with type-2 DM exhibited exacerbation of HFpEF features relative to wild-type mice with type-2 DM [10]. Thus, we employed the same high-fat diet (HFD)-fed ALDH2*2 mutant diabetic mice in this study as well.…”

“…ALDH2*2 knock-in mutant mice (with C57BL/6J background) either male or female around 3-4 months of age were fed an HFD (60% of calories from fat, D12492, Research Diets) as we published earlier [10].…”

“…For instance, reactive aldehydes such as acrolein, malondialdehyde, glyoxal and 4-hydroxy-2-nonenal (4HNE) are increased in diabetic tissue [7]. 4HNE is known to form adducts with proteins, DNA and extracellular matrix and we have shown increased 4HNE adducts in both type-1 and type-2 diabetic hearts compared to controls [8][9][10], which contribute to cardiac damage and dysfunction [4]. Thus, interventions to reduce the accumulation of 4HNE either by decreasing its generation or enhancing its detoxi cation have potential to protect the myocardium from diabetes-related damage.…”

Expression, purification and crystallization of the novel Xenopus tropicalis ALDH16B1, a homologue of human ALDH16A1

“…Through this enzymatic function, the human ALDH isoenzymes participate in biochemical pathways regulating alcohol detoxification, neuronal function, vitamin and amino acid metabolism and the synthesis of γ-aminobutyric acid and retinoic acid [1][2][3]. Abnormalities in the catalytic activity of ALDHs have been associated with severe disorders, including cancer, neurodegenerative conditions, cardiovascular diseases, diabetes, and stroke [4][5][6][7].…”