Abstract P1151: Exploring The Role Of Bh3-like Motif Containing Cell Death Inducer In Cardiomyocyte Death: Insights From Human Failing Hearts And Ipsc-derived Cardiomyocytes

Abstract

Background: Cardiac cell death plays a critical role in the development and progression of heart failure. Identifying new molecular targets to limit cardiac cell death could improve patient lives. BLID (BH3-Like Motif-Containing Cell Death Inducer) is a member of the BCL family of proapoptotic genes containing a BH3-like motif that induces cell death. Previous studies have shown that in many human cancers, downregulation of BLID is associated with tumor progression, while overexpression promotes cell death through a caspase-dependent mechanism. However, its role in cardiomyocyte death under various stress conditions is unknown. Methods and Results: Our RNAseq data from human failing and non-failing hearts revealed that mRNA expression of the BLID gene was significantly upregulated in human heart failure. We further validated our RNAseq findings by measuring the expression of BLID in RNA and protein isolated from the same set of human failing and non-failing hearts. As expected, the expression of BLID was significantly upregulated at both the mRNA and protein levels in human failing hearts compared to non-failing hearts. Furthermore, in cultured human cardiomyocytes (AC16 cells) and iPSC-derived cardiomyocytes exposed to stressors (such as hypoxia or H 2 O 2 ) for 2 hours, we observed a significant upregulation of BLID expression at both the mRNA and protein levels. We also overexpressed human BLID protein in human cardiomyocytes, leading to cardiomyocyte death. To determine their localization, we fractionated the overexpressed BLID proteins into cytoplasmic, nuclear, and mitochondrial fractions. We found that BLID was localized in the cytoplasm, nucleus, and mitochondria, with higher levels in the nucleus and mitochondria. These findings suggest that increased expression of BLID in failing human hearts may lead to cardiomyocyte death. Conclusion: Our data suggest that increased expression of BLID in human heart failure may be a key molecule that drives cardiomyocyte death. Inhibiting its expression during heart failure could mitigate cardiomyocyte death and improve cardiomyocyte function and survival.