Abstract 4144061: BubR1 Insufficiency Recapitulates Changes Associated with Age-Related Cardiac Pathologies

Cardiovascular diseases (CVDs) continue to be the leading cause of mortality worldwide, surpassing all other conditions in annual fatalities. Aging is a significant risk factor for CVDs, as it induces structural and functional alterations in the cardiovascular system. BubR1, a serine/threonine protein kinase, plays a crucial role in regulating the spindle assembly checkpoint during mitosis. Previous studies have shown that BubR1 insufficiency results in premature aging phenotypes, including kyphosis, cataracts, and reduced lifespan. BubR1 hypomorphic mice, which express approximately 10% of normal BubR1 protein levels, display conduction abnormalities such as a prolonged QTc interval, and suffer from sudden cardiac death. Given that BubR1 protein levels decline with age, we hypothesize that BubR1 is essential for maintaining adult cardiac structure and function, and its loss may drive age-related cardiac pathophysiology. In this study, we characterized the tissue, cellular, and molecular phenotypes present in hearts isolated from BubR1 hypomorphic mice. Structural analysis revealed that these mice exhibit cardiac hypertrophy, as shown by increased heart weight and ventricular cardiomyocyte size. Masson’s trichrome staining indicated elevated fibrosis in both the ventricular and perivascular regions of BubR1 hypomorphic hearts. At the molecular level, these hearts showed increased levels of p21 and phospho-γH2AX, markers of cellular senescence and DNA damage. Transcriptomic profiling further indicated that BubR1 insufficiency leads to dysregulation of pathways critical to cardiac function, including those related to voltage-gated ion channel activity, contractile fiber organization, and extracellular matrix organization. A comparative analysis between BubR1 hypomorphic hearts and aged hearts revealed a set of common dysregulated genes, suggesting shared mechanisms underlying BubR1 insufficiency and cardiac aging. Since the risk of heart failure increases with age, we conducted additional comparison between BubR1 hypomorphic mice and end-stage heart failure patients which suggested that BubR1 insufficiency mimics the transcriptomic changes associated with heart failure, such as increased expression of Nppa and Nppb genes. Overall, our findings suggest that BubR1 is a key regulator of age-related cardiac pathologies and represents a potential therapeutic target for CVDs.