Abstract P3017: Aldehyde Dehydrogenase 2 Augments Adiponectin Signaling In Coronary Angiogenesis In Hfpef Associated With Diabetes

4-hydroxy-2-nonenal (4HNE), a reactive aldehyde, is elevated in diabetes that decreases coronary angiogenesis and this was rescued by aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme that detoxifies 4HNE. Adiponectin (APN), a pleiotropic hormone, has pro-angiogenic properties which was shown to be critical in diabetes and its complications. However, the interaction between ALDH2 and APN signaling in coronary angiogenesis is unknown. 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. First of all, APN significantly increased coronary angiogenesis. However, 4HNE treatment significantly decreased the levels of APN signaling molecules including adiponectin receptor (AdipoR)1, APPL1, phospho-AMPK, AMPK, phospho-AKT, and AKT in mouse CECs. Treatment with disulfiram (DSF), 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 (db/m) mice, spontaneous type-2 diabetic (db/db) mice, ALDH2*2 knock-in mutant mice with intrinsic low ALDH2 activity (AL), and diabetic mice with intrinsic low ALDH2 activity (AF) that were created by crossing db/db and AL mice to test our hypothesis in vivo. AF mice exhibit severe HFpEF at 6 months compared to age-matched db/db mice as well as 3 months-old AF mice. At 6m, db/db, AL & AF mice significantly decreased APN response to coronary angiogenesis along with increased serum APN levels and decreased cardiac tissue levels of AdipoR1, APPL1, P-AMPK, and P-AKT implicating occurrence of APN resistance which was higher in AF mice. Alda-1 treatment improved APN-mediated angiogenesis significantly in db/db and AF mice. In conclusion, 4HNE-induces APN resistance and subsequently decreases coronary angiogenesis in diabetic HFpEF which was rescued by ALDH2 activation.