Aldehyde dehydrogenase 2 augments adiponectin signaling in coronary angiogenesis in HFpEF associated with diabetes

4‐hydroxy‐2‐nonenal (4HNE), an oxidative stress byproduct, is elevated in diabetes which decreases coronary angiogenesis, and this was rescued by the 4HNE detoxifying enzyme, aldehyde dehydrogenase 2 (ALDH2). Adiponectin (APN), an adipocytokine, has pro‐angiogenic properties and its loss of function is critical in diabetes and its complications. Coronary endothelial cell (CEC) damage is the initiating step of diabetes‐mediated heart failure with preserved ejection fraction (HFpEF) pathogenesis. Thus, we hypothesize that ALDH2 restores 4HNE‐induced downregulation of APN signaling in CECs and subsequent coronary angiogenesis in diabetic HFpEF. Treatment with disulfiram, an ALDH2 inhibitor, exacerbated 4HNE‐mediated decreases in APN‐induced increased coronary angiogenesis and APN‐signaling cascades, whereas pretreatment with alda1, an ALDH2 activator, rescued the effect of 4HNE. We employed control mice (db/m), spontaneous type‐2 diabetic mice (db/db), ALDH2*2 knock‐in mutant mice with intrinsic low ALDH2 activity (AL), and diabetic mice with intrinsic low ALDH2 activity (AF) mice that were created by crossing db/db and AL mice to test our hypothesis in vivo. AF mice exhibited heart failure with preserved ejection fraction (HFpEF)/severe diastolic dysfunction at 6 months with a preserved systolic function compared with db/db mice as well as 3 months of their age. Decreased APN‐mediated coronary angiogenesis, along with increased circulatory APN levels and decreased cardiac APN signaling (index of APN resistance) were higher in AF mice relative to db/db mice. Alda1 treatment improved APN‐mediated angiogenesis in AF and db/db mice. In summary, 4HNE‐induces APN resistance and a subsequent decrease in coronary angiogenesis in diabetic mouse heart which was rescued by ALDH2.