MDM2-HIF signaling in pathological ventricular remodeling

点击翻译按钮获取中文摘要

Project Summary: Multiple acquired and genetic conditions can lead to pathological left ventricular hypertrophy (LVH). Importantly, it has been recognized for over 50 years that pathological LVH is associated with heart failure and increased mortality in the human population. In addition, LVH is strongly associated with both heart failure with preserved systolic function (HFpEF) and heart failure with reduced systolic function (HFrEF). At the tissue level, the primary cause of LVH is cardiomyocyte hypertrophy and there are a multitude of intracellular signaling pathways involved in hypertrophic cardiomyocyte growth. However, non-cardiomyocyte myocardial cell populations also contribute to the pathological remodeling in LVH and the downstream sequelae of this condition. For example, in many forms of human cardiomyopathy there are reductions in myocardial capillary density which is thought to contribute to myocardial dysfunction in these diseases. Therefore, it is not only critical to understand the primary causes of pathological cardiomyocyte growth but also how the myocardial microenvironment responds to these changes. To uncover the mechanisms regulating LVH and pathological remodeling in the mammalian heart, we utilized murine models that allow manipulation of the sarcomere protein, cardiac myosin binding protein 3 (MYBPC3). We discovered that loss of MYBPC3 protein causes rapid changes in cardiomyocyte growth through dysregulated cell cycle pathways causing cardiomyocyte endoreplication (DNA replication without cell division). We then determined that the dysregulated cardiomyocyte DNA synthesis in sarcomeric cardiomyopathy leads to replication stress induced DNA damage in cardiomyocytes and activation of DNA damage response (DDR) pathways. We have now identified that the DDR effector protein, murine double mutant 2 (MDM2), plays a crucial role in pathological left ventricular remodeling in both genetic and acquired forms of left ventricular hypertrophy. We hypothesize that dynamic changes in MDM2 and HIF signaling accelerate pathological hypertrophic remodeling by altering both the myocardial microvasculature and cardiac metabolism. To test this hypothesis, we will pursue the following aims: Aim 1: Define the role of MDM2 and the HIF switch in altering the myocardial microvasculature in genetic forms of LVH. Aim 2: Determine if MDM2 and the HIF switch alters cardiomyocyte metabolism in genetic forms of LVH. Aim 3: Define which components of cardiomyocyte MDM2-HIF signaling are regulating pathological LV remodeling in acquired forms of LVH. At the conclusion of these innovative and high impact studies, we will have defined a novel role for MDM2-HIF signaling during key periods of pathological left ventricular hypertrophy secondary to both genetic and acquired causes. Through selective modulation of key components of this pathway our goal is to disrupt key maladaptive myocardial remodeling responses and uncover novel therapeutic opportunities for both genetic and non-genetic forms of human cardiomyopathy.