Genetic Mechanisms of Cardiac Adaptation To Hypoxia

Notch通路以及潜在的调节剂或效应物HIF α/Notch信号传导已经出现， 尤其与在缺氧应激条件下建立和维持心脏功能相关。我们 在多个心脏隔室中产生/收集HIF α和Notch信号传导的突变。我们有 收集的数据表明，小鼠心肌中Notch途径活性的基因消融不 导致心肌梗死引起的低氧条件下心脏重塑，但 对心肌梗塞后的心肌细胞有保护作用。此外，在果蝇心脏模型中， 当Notch信号转导被激活时，对缺氧的反应（心率减慢）不会发生。 慢性缺氧导致心脏的非收缩性、梗塞样状况。与此相反， 小鼠心外膜中的HIF/Notch突变对心脏功能有害，因为对 经主动脉收缩加重，心脏肥大增加。因此，心外膜也发挥作用， 在心脏对缺氧的反应中起关键作用。因此，HIF以及Notch信号转导的调节在 各种心脏隔室对于心脏响应和耐受缺氧条件是至关重要的。我们 假设HIF和Notch通路之间的相互作用是调节反应的关键， 对于缺氧，HIF/Notch信号传导在心肌中引起与心外膜不同的独特反应， HIF/Notch依赖性机制保护心脏功能。在本建议中，我们会研究 HIF和Notch信号通路在缺氧耐受性和缺氧易感性中的作用及其相互作用 心脏基于缺氧反应的进化保守性， 在果蝇心脏中识别的反应，涉及HIF和Notch信号，承诺与人类的免疫反应有关。 哺乳动物心脏在这里获得的见解可能会导致寻找治疗方法的新途径， 缺氧引起的心脏损伤

The Notch pathway, as well as potential regulators or effectors HIFa/Notch signaling, have emerged as particulariy relevant for establishing and maintaining heart funcfion under hypoxic stress conditions. We generated/collected mutafions of HIFa and Notch signaling in mulfiple cardiac compartments. We have gathered data suggesfing that genefic ablation of Notch pathway acfivity in the mouse myocardium does not lead to cardiac remodeling in response to hypoxic condifions caused by myocardial infarcfion, but rather has a protective effect on cardiomyocytes after the infarct. Moreover, in the Drosophila heart model, an acute response to hypoxia (slowing of the heart rate) does not occur when Notch signaling is acfivated in the heart, and chronic hypoxia leads to a non-contracfile, infarct-like condition of the heart. In contrast, HIF/Notch mutafions in the mouse epicardium are deleterious to heart funcfion, in that the response to transaortic constricfion is aggravated and cardiac hypertrophy is increased. Thus, the epicardium plays also a crifical role in the cardiac response to hypoxia. Thus, modulafion of HIF as well as Notch signaling in various cardiac compartments is crifical for the heart to respond and tolerate hypoxic conditions. We hypothesize that the interaction between HIF and Notch pathways are key to the regulafion of the response to hypoxia, that HIF/Notch signaling elicits unique responses in the myocardium versus the epicardium, and that the HIF/Notch-dependent mechanisms protect cardiac function. In this proposal, we will study the respective contribution and interacfions of HIF and Notch signaling to hypoxia tolerance and susceptibility in the heart. Based on the evolufionary conservafion of the hypoxia response, mechanisms of cardiac hypoxia responses identified in the fly heart, involving HIF and Notch signaling, promise to be of relevance to the mammalian heart. Insights gained here are likely to lead to new avenues for finding treatments for hypoxia-induced cardiac injury.