Aldehyde dehydrogenase activator attenuates diabetic cardiomyopathy; a role in improving the quality of resident cardiac stem cells?

Abstract

BackgroundHyperglycemia due to diabetes leads to the production of reactive aldehydes such as 4‐hydroxy‐2‐nonenal (HNE). These toxic aldehydes form adducts on proteins, leading to cell damage and organ dysfunction such as cardiomyopathy. Activation of aldehyde dehydrogenases (ALDHs) which metabolize toxic aldehydes into non‐toxic acids, can ameliorate diabetic cardiomyopathy.MethodsNeonatal cardiomyocytes were subjected to high glucose stress (25mM) and treated with Alda‐1 (20 μM), a small molecule ALDH activator that we discovered. Diabetic cardiomyopathy was induced in DBA mice at 8 weeks of age by injecting streptozotocin. The mice with a significant hyperglycemia were treated from 12 week onwards for three months without (n=18) or with (n=24) Alda‐1 (16mg/Kg/day) using Alzet osmotic pumps.Results and DiscussionWe found that Alda‐1 treatment increased ALDH activity and decreased HNE‐protein adducts formation in vitro and vivo. Alda‐1 reduced adverse cardiac remodeling and myocardial dysfunction. Alda‐1 increased the number of resident cardiac stem cells in the tissue. Human heart samples from patients with cardiomyopathy and diabetes also showed decreased ALDH activity and increased HNE‐protein adducts formationConclusionActivator of ALDH attenuated diabetic cardiomyopathy in mice. Finally, ALDH activators have potential to be a therapeutic agent to prevent diabetic cardiomyopathy.