Developing New Cardioprotective Strategies for Prevention of Chemotherapy-induced Cardiotoxicity

Abstract

Cardiovascular diseases stand as the leading cause of morbidity and mortality worldwide. Heart failure (HF) is the end stage of numerous cardiovascular diseases including coronary artery disease and hypertension. The quest for effective treatment is an ongoing endeavor. While current drugs used in clinical settings serve to slow down the disease progression, they fall short of offering a definitive cure. The limited proliferative capacity of cardiomyocytes post-maturity, coupled with scar formation in response to stress or injury, poses a significant challenge in finding a definitive treatment. This thesis aims to investigate the potential of a newly identified nucleoside analogue, LCB-2122, as a cardioprotective agent in different HF and cardiomyocyte stress models. In vivo and in vitro cell and molecular techniques were employed for this. First, we show that LCB-2122 enhances cardiac functions in acute and chronic mouse models of HF. In doxorubicin (Dox) treated mice and transgenic mice overexpressing the angiotensin II type 1 receptor (AT1R), treatment with LCB-2122 reduced the expression of cardiac stress markers and enhanced ejection fraction (%EF). We further investigated the mechanism of cardioprotection of LCB-2122. In AT1R transgenic mice treated with LCB-2122, transmission electron microscopy shows improved structural organization of myofibrils and mitochondrial ultrastructure. In neonatal rat cardiomyocytes, treatment with LCB-2122 decreases Dox-induced elevation in reactive oxygen species and maintains metabolite homeostasis. Furthermore, co-treatment with Dox and LCB-2122 preserves mitochondrial respiration and function. The mechanism of cardioprotection of LCB-2122 is linked to an indirect activation of the AMP-activated protein kinase (AMPK) pathway and its downstream targets. Lastly, the study of structure-function relationship using LCB-2122 derivatives ruled out that LCB-2122 is a prodrug and identified the essential functional groups of this molecule to help enhance its pharmacological properties. Together, this study introduces nucleoside analogues as new therapeutic strategies for the treatment of acute and chronic HF. LCB-2122 effect on mitochondrial health and survival pathways highlights its potential as a promising candidate for further investigation in HF therapy.