Graduation Date

Fall 12-18-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Integrative Physiology & Molecular Medicine

First Advisor

Paras Kumar Mishra

Abstract

Diabetes mellitus (DM) increases the risk of heart failure 2-4-fold. Intensive glycemic control does not abate this risk in DM patients, suggesting that DM-induced heart failure is beyond hyperglycemia. DM silently induces cardiac muscle disorder termed diabetic cardiomyopathy (DMCM), which progresses to heart failure. The objective of this dissertation is to understand the mechanistic underpinnings of DMCM to develop new solutions to diagnose and treat heart failure in DM.

The heart pumps blood due to the contraction and relaxation of terminally differentiated cardiomyocytes with limited regenerative capacity. The DM environment of hyperglycemia, hyperlipidemia, and inflammation causes cardiomyocyte death and leads to hypertrophy, fibrosis, and heart failure progression. Apoptosis, the most studied form of cell death, contributes minimally (0.025%) to cardiomyocyte death in the failing heart. Thus, non-apoptotic forms of cell death predominate, but their molecular mechanisms are unclear in the DM heart.

Pyroptosis is an inflammatory non-apoptotic cell death pathway shown to occur in cardiomyopathies. Ferroptosis is a newly discovered form of cell death, which is triggered by the accumulation of intracellular iron, lipids, and oxidative stress. Although inflammation, lipotoxicity, iron overload, and oxidative stress are hallmarks of DMCM, the role of cardiac pyroptosis and ferroptosis in DMCM remains unclear.

Hydrogen sulfide (H₂S) is a gaseous signaling molecule that has been shown to inhibit multiple forms of cell death. Systemic and cardiac levels of H₂S are reduced in DM. We hypothesized that DM induces non-apoptotic cell death which may be prevented by elevating endogenous H₂S. We also investigated if exercise training has cardioprotective effects in DMCM via H₂S upregulation.

Our results demonstrated that reduced expression of H₂S biosynthesis enzymes increased pyroptosis and caused cardiac remodeling. DM hearts also demonstrated increased pyroptosis and ferroptosis. H₂S donor treatment or exercise training increased cardiac H₂S levels, inhibited pyroptosis and ferroptosis signaling, and prevented adverse cardiac remodeling and dysfunction.

Our studies demonstrate how myocardial cell death contributes to DMCM progression. We conclude that targeting cell death, specifically by H₂S donor treatment and/or exercise, could be a novel approach to mitigate DMCM and heart failure.

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Available for download on Monday, November 29, 2021

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