Access Type

Open Access Dissertation

Date of Award

January 2022

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Physiology

First Advisor

Suresh Palaniyandi

Abstract

Coronary endothelial cell (CECs) damage and rarefaction of coronary microvasculature are implicated in diabetes-induced heart failure with preserved ejection fraction (HFpEF). 4-hydroxy-2-nonenal (4-HNE), a reactive aldehyde that is increased in diabetic hearts, contributes to CEC dysfunction and cardiotoxicity. Aldehyde dehydrogenase (ALDH) 2, a mitochondrial enzyme that detoxifies 4-HNE and confers cardioprotection. However, ALDH2 activity is decreased in diabetic hearts, which results in the augmentation of 4HNE-induced cardiotoxicity. Thus, we hypothesize that activation of ALDH2 in CECs reduces 4-HNE-mediated cell signaling aberrations and preserves coronary angiogenesis. We employed cell culture studies and animal models to test our hypothesis. In our cell culture studies, we showed that 4-HNE treatment significantly decreased cell migration and coronary angiogenesis along with the downregulation of several proangiogenic factors, including vascular endothelial growth factor receptor (VEGFR2)2, SIRTUIN1, Ets-related gene, TIPE1, angiomotin Like 2, adiponectin receptor 1 (AdipoR1), adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1), phospho AMP-activated protein kinase (P-AMPK) and phosphoprotein kinase B (P-AKT) in mouse CECs (MCECs). Additionally, treatment with angiotensin II, which is elevated in severe diabetes, increased 4-HNE adduct levels in MCECs and subsequently decreased angiogenesis through the downregulation of VEGFR1 and VEGFR2. Inhibition of ALDH2 activity exacerbates the 4HNE-mediated effect in coronary angiogenesis, whereas activation of ALDH2 rescues the 4HNE-mediated effect. To recapitulate our cell culture study in an animal model, 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. AF mice exhibit heart failure with preserved ejection fraction (HFpEF) at 6 months with a preserved systolic function compared to db/db mice and 3 months of age. At 6m, db/db, AL & AF mice significantly decreased APN response to increased coronary angiogenesis along with Increased serum APN levels and decreased cardiac tissue levels of AdipoR1, APPL1, P-AMPK, and P-AKT were found in AF mice compared to other groups implicating increased APN resistance. Finally, we conclude that ALDH2 activation can be a potential therapeutic strategy to improve coronary angiogenesis to ameliorate cardiometabolic diseases.

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