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Abstract

Cardiovascular diseases significantly contribute to global mortality rates. Cardiovascular disease is primarily attributed to the molecular and cellular modifications occurring within the cardiac system. Therefore, obtaining an in depth understanding of the molecular pathways that underlie clinical scenarios is of paramount significance. I conducted an Express sequence tag (EST) search with the objective of uncovering new cardiac transcripts to aid in the identification of previously unknown genes associated with the heart and investigate their role in cardiac pathology. This was conducted with the purpose of discovering previously unidentified cardiac transcripts. The identification of the SH3BGR protein, distinguished by its elevated levels of SH3 binding glutamic acid, represents a noteworthy advancement in scientific research. The precise function of SH3BGR in the cardiovascular system remains unknown, despite its initial discovery in relation to Down syndrome. The findings of my study indicate that the expression of SH3BGR exhibits a distinct pattern in relation to cardiac disease, deviating from the normal expression profile. The observed phenomenon can be elucidated by an upregulation in the expression of SH3BGR, initiating the RhoA-SRF signalling cascade, ultimately leading to the development of cardiac hypertrophy in neonatal rat ventricular cardiomyocytes (NRVCM). The observed decline in viability of NRVCMs can be attributed to the downregulation of SH3BGR gene expression. This downregulation has significant effects on both the Hippo signalling pathway and the RhoA-SRF axis attributed by reduced downstream targets of SRF resulting in hampered sarcomere stability. Further, increased YAP (Yes associated protein) indicated its translocation to the nucleus resulting in activation of pro-apoptotic genes. Thus, taken together I observed SH3BGR reduction to result in apoptosis by altering SRF-Hippo axis. A yeast two-hybrid screen was conducted to gain a deeper understanding of the interactome associated with SH3BGR. LetM1, a transmembrane protein, characterised by the presence of an EF hand motif and a leucine zipper, has been identified as an interacting protein with SH3BGR. Previous studies have provided evidence linking LetM1 to Wolf Hirschhorn syndrome. However, the specific function of LetM1 in the context of cardiac conditions remains incompletely elucidated. Upon LetM1 alterations I observed negative effect on the mitochondria of cardiomyocytes. This is supported by alterations in energy availability, 13 | P a g e ultimately resulting in a state referred to as mitochondrial dysbiosis. Moreover, due to the lack of LetM1, there was a further substantial decrease in the expression levels of SERCA2a. The restoration of SERCA2a upon LetM1 knockdown levels resulted in a noticeable enhancement in mitochondrial homeostasis, as evidenced by the restoration of mitochondrial gene and protein levels associated with oxidative phosphorylation. The observed phenomenon pertained to an enhancement in mitochondrial homeostasis. Based on the results obtained, it is suggested that SERCA2a may serve as a promising therapeutic target warranting further investigation. Furthermore, the findings from my experiments indicate that mice with cardiac LetM1 deletion exhibit alterations in ion homeostasis and a decrease in action potential duration. These observations suggest potential disturbances in the electrophysiological properties of their cardiac tissue. Consequently, the lack of LetM1 exhibited detrimental effects on cardiac functionality. This study presents a new finding that suggests SERCA2a being a promising therapeutic intervention for mitigating the LetM1 phenotype's deterioration. This study was aimed at understanding the correlation between SH3BGR and LetM1, two proteins that play a role in the pathophysiology of the myocardium.