DOI

https://doi.org/10.25772/FBF1-F362

Defense Date

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Physiology and Biophysics

First Advisor

Dr. Fadi N. Salloum

Second Advisor

Dr. Clive Baumgarten

Third Advisor

Dr. Antonio Abbate

Fourth Advisor

Dr. Srinivasa Karnam

Fifth Advisor

Dr. Javier Gonzalez-Maeso

Abstract

Ischemic heart disease is characterized by reduced perfusion of oxygenated blood to the myocardium, potentially resulting in infarction upon occlusion of coronary arteries. While prompt reperfusion and advances in in-hospital care have led to a decline in short term mortality, sustained damage to the ventricle, along with reperfusion injury, can lead to progressive deterioration in cardiac function. Limiting the extent of this initial ischemia-reperfusion injury and combating the course of adverse remodeling remains the scope of several preclinical studies geared towards improving cardiac health after MI. To this, relaxin-2 – the peptide hormone that regulates maternal hemodynamic function during pregnancy – has been effective in preclinical studies in countering several of the inflammatory, pro-fibrotic and pro-arrhythmogenic changes in the infarcted heart. Nevertheless, several factors affect the translational potential of using recombinant relaxin (serelaxin) in the clinical setting, including cost, short half-life, and the need for parenteral administration. The role of RXFP1 – the cognate receptor for relaxin in the heart – has not been studied or characterized in the context of ischemic heart disease. Finally, the intersection of relaxin biology with novel mechanisms implicated in the pathophysiology of IHD, including ER stress and sphingolipid signaling, have not been investigated yet.

To further the understanding of relaxin signaling in IHD, the current work is divided into three major studies: 1) The impact of overexpressing RXFP1 in the heart through AAV9 vectors to evaluate changes in cardiac physiology and chart the course of IR induced adverse remodeling; 2) Assessing the efficacy of utilizing alternative – potentially biased – ligands such as B7-33 at RXFP1 to elucidate novel signaling paradigms post IR injury; and 3) Monitor the impact of chronic serelaxin therapy on bio-active sphingolipid biology in a murine model of ischemic heart failure.

Our results show that 1) upregulation of RXFP1 through cardiotropic AAV9 vectors is feasible and is capable of conferring cardioprotection in the absence of exogenously administered agonist, 2) the functionally selective ligand B7-33 mitigates the extent of adverse remodeling when administered during reperfusion and reduces ER stress in an Erk 1/2 dependent manner, and 3) chronic treatment with serelaxin in IHF enhances the availability of cardiac and plasma S1P and is potentially associated with reducing autophagy to prevent long-term remodeling. These findings encourage further study of RXFP1, its interaction with relaxin and alternative ligands, and previously unexamined downstream targets in the context of IHD.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

3-9-2020

Available for download on Saturday, March 08, 2025

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