Description
The adult mammalian heart is a post-mitotic organ that has a very limited capacity to regenerate. Following injury, such as from a myocardial infarction, there is massive cardiomyocyte death which cannot be regenerated resulting in compromised cardiac function. The heart compensates with the loss of cardiomyocytes by replacing the lost myocardium with fibrotic scar tissue, which lacks the contractile function. Over time, the heart undergoes maladaptive remodeling that is accompanied with biochemical, molecular, structural, and metabolic changes in the heart that puts chronic strain on the cardiomyocytes, ultimately leading to heart failure. The focus of this thesis will be to explore one facet of cardiac repair aimed at survival and protection. Pim-1 is a cardioprotective kinase that regulates many cellular processes crucial for antagonizing cellular senescence including cell cycle progression, survival signaling, anti-apoptotic signaling, preservation of mitochondrial integrity, telomere preservation, and blunting pathological hypertrophy. Another cardioprotective protein identified in the heart is c-Kit. C-Kit binds to its ligand stem cell factor to activate ERK and Akt pathways which are involved with cell proliferation and survival. The relationship between Pim-1 and c-Kit has not been explored in cardiomyocytes. This study delineates the interaction between Pim-1 and c-Kit and the resulting cardioprotective mechanism in cardiomyocytes. Elevated c-Kit expression was demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1. Co- immunoprecipitation and proximity ligation assay revealed a protein-protein interaction between PIM1 and c-Kit. Following treatment with stem cell factor, PIM1 overexpressing cardiomyocytes displayed elevated levels of activated ERK. Functionally, elevated c-Kit expression conferred enhanced protection against oxidative stress in vitro. PIM1 and c-Kit act independently and synergistically to promote resistance against oxidative stress. This study identifies a link between PIM1 and c-Kit in cardiomyocytes. Furthermore, this study demonstrates yet another facet of cardioprotection regulated by Pim-1 kinase.
