Abstract
Congenital heart defects and cardiac diseases associated with aging such as heart failure are leading contributors to morbidity and mortality worldwide, yet their underlying molecular mechanisms remain incompletely understood. This dissertation investigates the role of BubR1, a mitotic checkpoint protein, in cardiac morphogenesis, cardiac aging, intercellular communication, and wound healing, uncovering novel regulatory pathways that contribute to both developmental and degenerative cardiac conditions. Our findings demonstrate that BubR1 is indispensable for embryonic cardiac development. Cardiac-specific deletion of BubR1 in mice results in embryonic lethality with severe defects in chamber wall formation, septation, and trabeculation. Single-cell RNA sequencing analysis revealed disrupted differentiation trajectories, suppressed cardiogenesis genes, and hyperactivation of Wnt signaling in cardiac specific BubR1 knockout embryonic hearts, underscoring the critical role of BubR1 in maintaining signaling homeostasis during heart morphogenesis. Beyond cardiac development, we also assessed the role of BubR1 in the adult heart and during cardiac aging where we identified that BubR1 insufficiency leads to pathological changes, including hypertrophy, fibrosis, and cellular senescence in the heart. Transcriptomic analyses through bulk RNA sequencing identified dysregulated pathways essential for cardiac function, including cardiac contraction and cytoskeletal organization in BubR1 deficient adult hearts, implicating BubR1 in the maintenance of cardiac functions. Comparative studies linked BubR1 deficiency to gene networks shared with aged murine hearts and human heart failure, positioning BubR1 as a key regulator of cardiac aging, as well as a potential biomarker and therapeutic target for age-associated cardiac decline. Notably, BubR1 protein levels naturally decline with age in the heart and is also reduced in heart failure, suggesting that the loss of BubR1 contributes to progressive cardiac dysfunction due to aging and disease. In addition to its roles in cardiac development and aging, our study demonstrated that BubR1 acts as an upstream regulator of the PKCµ–Cx43 pathway, in which PKCµ directly phosphorylates Cx43 at serine 368. This phosphorylation is essential for maintaining gap junction function including intercellular communication, cellular migration, and supporting effective wound healing. Given the established importance of PKCµ and Cx43 in myocardial biology, the BubR1–PKCµ–Cx43 signaling axis represents a previously unrecognized regulatory mechanism that warrants further investigation in the context of cardiac physiology.Collectively, these findings highlight the pivotal roles played by BubR1 in cardiogenesis, cardiac aging, intercellular communication, and cellular migration, offering new therapeutic insights aimed at improving outcomes in patients with congenital heart defects and degenerative cardiac conditions associated with aging such as heart failure.