MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy

Abstract

BACKGROUND: Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy. METHODS: We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes Mybpc3 (cardiac myosin binding protein 3) or Myh6 (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms. RESULTS: We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models. CONCLUSIONS: Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment.

Ubiquitin ligase MDM2 mediates endothelial inflammation in Kawasaki disease vasculitis development

“…Additionally, MDM2 dynamically regulates the protein stability of both hypoxia-inducible factor 1 alpha (HIF1α) and hypoxia-inducible factor 2 alpha (HIF2α)/endothelial PAS domain protein 1 (EPAS1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth ( 38 ). These results together suggest that MDM2 is involved in cardiovascular diseases.…”

Modified Zhenwu Tang delays chronic renal failure progression by modulating oxidative stress and hypoxic responses in renal proximal tubular epithelial cells

“…As TIF progresses, the distance between peritubular capillaries and renal tubules increases, extending the oxygen diffusion distance and exacerbating hypoxia in tubular epithelial cells. This hypoxia activates the HIF-1 pathway, leading to phenotypic transformation and the release of inflammatory mediators such as interleukin (IL) 1β and tumor necrosis factor (TNF) α [ [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] ], which further exacerbate TIF. This creates a vicious cycle of chronic hypoxia, continuous disease progression, and loss of peritubular capillaries.…”