MDM2-HIF signaling in pathological ventricular remodeling

Project Summary: Multiple acquired and genetic conditions can lead to pathological left ventricular hypertrophy (LVH). It has been recognized for over 50 years that pathological LVH is associated with increased mortality in the human population, and it 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 cell populations also contribute to pathological ventricular remodeling in LVH and the downstream sequelae of this disease. Therefore, it is critical to understand not only the primary causes of pathological cardiomyocyte growth but also how the myocardial microenvironment responds to these changes. To uncover mechanisms regulating pathological LV remodeling, we utilize multiple murine models that harbor sarcomere gene mutations which are common genetic causes of LVH in humans. Previously, we discovered that loss of the sarcomere protein MYBPC3 causes rapid changes in early post-natal cardiomyocyte growth through dysregulated cell cycle pathways causing cardiomyocyte endoreplication (DNA replication without cell division). Next, we found that dysregulated cardiomyocyte cell cycle activity leads to replication stress induced DNA damage and activation of DNA damage response (DDR) pathways in cardiomyocytes. We have now discovered that the DDR effector protein, murine double mutant 2 (MDM2), plays an important role in regulating pathological LV remodeling in both genetic and pressure overload LVH models. We hypothesize that the MDM2-HIF signaling axis is a key regulator of pathological ventricular remodeling in genetic and acquired forms of myocardial hypertrophy. To test this hypothesis, we will pursue the following aims: Aim 1: Define how MDM2-HIF signaling regulates microvasculature dysfunction and LV remodeling in genetic models of LVH. Aim 2: Determine how MDM2-HIF signaling regulates myocardial metabolism in genetic models of LVH. Aim 3: Define how cardiomyocyte MDM2-HIF signaling regulates pathological LV remodeling secondary to pressure overload in the adult heart. At the conclusion of these innovative and high impact studies, we will have defined a novel role for MDM2-HIF signaling during key stages of pathological left ventricular remodeling in both genetic and acquired causes. Through selective modulation of key components of this pathway our goal is to disrupt maladaptive myocardial remodeling responses and uncover novel therapeutic opportunities for both genetic and non-genetic forms of human cardiomyopathy.