MDM2-HIF signaling in pathological ventricular remodeling

项目总结： 多重获得性和遗传性疾病可导致病理性左心室肥厚。 重要的是，50多年来，人们已经认识到病理性左心室肥厚与心力衰竭和 人类人口死亡率的增加。此外，左心室肥厚与心力衰竭和 收缩功能保留(HFpEF)和心力衰竭伴收缩功能降低(HFrEF)。在组织上 左心室肥厚的主要原因是心肌细胞肥大，细胞内有大量的 参与肥大心肌细胞生长的信号通路。然而，非心肌细胞心肌 细胞群也参与了左心室肥厚的病理重塑及其下游后遗症 条件。例如，在许多形式的人类心肌病中，心肌毛细血管减少。 密度，这被认为是导致这些疾病的心肌功能障碍的原因。因此，它不仅是 了解病理性心肌细胞生长的主要原因，也是了解心肌细胞如何 微环境对这些变化做出了反应。揭示左心室肥厚的调节机制及其病理基础 在哺乳动物心脏的重塑中，我们利用了允许操纵肌节的小鼠模型 心肌肌球蛋白结合蛋白3(MYBPC3)。我们发现MYBPC3蛋白的丢失会导致快速 通过引起心肌细胞的细胞周期异常途径改变心肌细胞的生长 内复制(不进行细胞分裂的DNA复制)。然后我们确定，不受监管的 肌节型心肌病心肌细胞DNA合成导致复制应激诱导的DNA损伤 并激活DNA损伤反应(DDR)通路。我们现在已经确定， DDR效应蛋白--小鼠双突变体2(MDM2)在病理性左心室中起重要作用 遗传性和获得性左心室肥厚的重构。我们假设这种动态 MDM2和HIF信号的改变加速病理性肥厚重构 心肌微血管与心脏代谢。为了验证这一假设，我们将进行以下工作 目的：目的1：明确MDM2和HIF开关在遗传性心肌微血管改变中的作用 各种类型的左心室肥厚。目的2：确定MDM2和HIF开关是否以遗传形式改变心肌细胞新陈代谢 左心室肥厚。目的3：明确心肌细胞MDM2-HIF信号的哪些成分调节病理性左心室 获得性左心室肥厚的重塑。在这些创新性和高影响力的研究结束后，我们将 明确了MDM2-HIF信号在病理性左心室关键时期的新作用 继发于遗传和后天原因的肥大。通过对关键部件的选择性调制 在这一途径中，我们的目标是破坏关键的非适应性心肌重塑反应，并发现新的 遗传性和非遗传性人类心肌病的治疗机会。

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.