MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy.
MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy.
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MDM2对缺氧诱导因子（HIF）信号通路的调控导致肥厚型心肌病中的微血管功能障碍。
DOI：
10.1161/circulationaha.123.064332
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发表时间：
2023-12-05
期刊：
影响因子：
37.8
通讯作者：
Becker, Jason R.
中科院分区：
文献类型：
--
作者：
Shridhar, Puneeth;Glennon, Michael S.;Pal, Soumojit;Waldron, Christina J.;Chetkof, Ethan J.;Basak, Payel;Clavere, Nicolas G.;Banerjee, Dipanjan;Gingras, Sebastien;Becker, Jason R.
关键词：
微血管功能障碍是心脏病理性重构中的常见现象，被认为在肥厚型心肌病（HCM）的发病机制中发挥重要作用，而肥厚型心肌病是由肌节基因突变所致。我们假设，HCM中的微血管功能障碍继发于微血管生长异常，且可能独立于心室肥厚而发生。
我们采用多种成像方法，追踪携带肌节基因Mybpc3（心肌肌球蛋白结合蛋白C3）或Myh6（肌球蛋白重链6）突变的HCM小鼠模型中微血管功能障碍的发生时间顺序。我们运用互补的分子生物学方法评估蛋白质含量、相互作用及翻译后修饰，以确定调节这一反应的机制。我们在体内利用遗传学和药理学方法调控特定分子通路，对这些机制进行验证。
我们发现，在我们的HCM模型中，微血管功能障碍继发于出生后早期心肌毛细血管生长减少，且可能在心肌肥厚发生之前就已出现。我们发现，E3泛素蛋白连接酶MDM2（小鼠双微体2）通过经典及非经典机制，动态调节HIF1α（缺氧诱导因子1α）和HIF2α（缺氧诱导因子2α）/EPAS1（内皮PAS结构域蛋白1）的蛋白质稳定性。由此产生的HIF失衡，导致心肌毛细血管生长关键时期促血管生成基因表达减少。通过遗传学或药理学方法降低MDM2蛋白水平，可使HIF蛋白水平恢复正常，并预防两种HCM模型中微血管功能障碍的发生。
我们的研究结果表明，肌节突变在疾病最早期即诱导心肌细胞MDM2信号传导，这会导致心肌微环境发生长期变化。
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. 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 C3) 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. 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. 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.
影响因子：
4.2
作者：
Nicolas N;Roux E
通讯作者：
Roux E
影响因子：
6
作者：
Venkatesan T;Alaseem A;Chinnaiyan A;Dhandayuthapani S;Kanagasabai T;Alhazzani K;Dondapati P;Alobid S;Natarajan U;Schwartz R;Rathinavelu A
通讯作者：
Rathinavelu A