Abstract
We appreciate Dr. Sun and Dr. Ren’s interest in our recent publication, MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy. The goal of our study was to understand the molecular mechanisms regulating microvascular dysfunction in hypertrophic cardiomyopathy. Utilizing murine models expressing mutations in either Mybpc3 (cardiac myosin binding protein C3) or Myh6 (myosin heavy chain 6), we identified the protein MDM2 (murine double minute 2) as a key regulator of microvascular dysfunction through its regulation of the proteins HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1). Specifically, we found that MDM2 directly reduced the cardiomyocyte levels of HIF1α through increasing the polyubiquitination of this protein. In contrast, protein levels of HIF2α were increased secondary to MDM2 increasing the polyubiquitination of VHL (von Hippel-Lindau) which led to reduced VHL protein levels and reduced VHL polyubiquitination of HIF2α. These dynamic changes in HIF1α and HIF2α were associated with decreased expression of multiple proangiogenic genes. Genetic or pharmacologic reduction of cardiomyocyte MDM2, was associated with normalization of HIF1α and HIF2α protein levels, increased left ventricular capillary levels, and prevention of microvascular dysfunction in these preclinical HCM models.