Role of de novo pyrimidine biosynthesis in pathological cardiac remodeling

项目摘要 高血压和缺血性心脏病是心力衰竭的两个最重要的危险因素。在……里面 对血压升高的反应，心脏表现为肥大生长以改善室壁 压力。这种曾经的适应性反应可能会失代偿，并进展为心力衰竭。另一方面， 心肌梗死会对心脏造成严重的结构性损害。常见的临床治疗方法 冠状动脉重建导致的心脏缺血会导致额外的再灌注损伤。缺血所致的侮辱 和再灌流一起显著削弱心脏的泵血功能。尽管有广泛的兴趣和 由于临床的迫切需要，我们对心力衰竭发生机制的了解仍然有限。 病理性心脏重构是高血压和缺血性心脏病的常见途径。在……里面 对需求增加或心脏损伤的反应，心脏会产生一种急性反应，以补偿 心脏收缩能力的丧失。然而，在持续的压力下，会发生失代偿和心力衰竭。 发展起来。以前的研究表明，代谢变化先于大多数其他变化，如果不是所有其他变化 病理性心脏重塑。然而，心脏代谢重塑的贡献和机制 失败仍然难以捉摸。 初步结果表明，从头开始的嘧啶生物合成显著增加。 心脏对压力超负荷的反应，在结构和电生理改变之前。此外， 以CAD(氨基甲酰-磷酸合成酶2、天冬氨酸转氨酶和二氢转氨酶)为限速酶 该途径的酶被强烈诱导。另一方面，从头开始的嘧啶生物合成也是 缺血后再灌流上调。根据之前的发现和这些试点数据，一个假设是 在病理性心脏重塑中，嘧啶的生物合成已被阐明。既有得也有失- 已经生成了功能小鼠模型，将用于测试1)Cad和De-novo的角色 嘧啶生物合成在压力超负荷心肌病中的作用(2)Cad和从头开始的嘧啶 在心脏缺血/再灌流引起的病理性心脏重构中的作用，以及3)使用冠状动脉介入治疗的可行性 在高血压和缺血性心脏病条件下阻止心力衰竭发展的抑制剂。离体 将进行使用原代心肌细胞培养的实验，以证实体内测试。澄清 新生物合成在病理性心脏重塑和心力衰竭中的作用 促进我们对高血压和缺血性心脏病的病理生理学的认识，并为 寻求新颖、更有效的治疗设计。

Project Summary Hypertensive and ischemic heart diseases are the two most important risk factors of heart failure. In response to elevated blood pressure, the heart manifests hypertrophic growth to ameliorate ventricular wall stress. This once adaptive response may decompensate and progress into heart failure. On the other hand, myocardial infarction causes significant structural damage of the heart. The common clinical practice to treat cardiac ischemia via restoration of coronary arteries leads to additional reperfusion injury. Insults from ischemia and reperfusion together significantly weaken the pumping function of the heart. Despite extensive interests and urgent clinical needs, our understanding of the mechanisms for heart failure development remains limited. Pathological cardiac remodeling is a common route of both hypertensive and ischemic heart diseases. In response to either elevated demand or cardiac damage, the heart mounts an acute reaction to compensate for the loss of cardiac contractility. Under persistent stress, however, decompensation occurs and heart failure develops. Previous studies have shown that metabolic alteration precedes most if not all other changes during pathological cardiac remodeling. However, the contribution and mechanism of metabolic remodeling in heart failure is still elusive. Preliminary results here show that de novo pyrimidine biosynthesis is acutely and significantly augmented in the heart in response to pressure overload, preceding structural and electrophysiological alterations. Moreover, Cad (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) as the rate-limiting enzyme of this pathway is strongly induced. On the other hand, de novo pyrimidine biosynthesis is also upregulated by reperfusion after ischemia. Based on previous findings and these pilot data, a hypothesis of pyrimidine biosynthesis in pathological cardiac remodeling has been formulated. Both gain-of and loss-of- function mouse models have been generated that will be employed to test 1) the role of Cad and de novo pyrimidine biosynthesis in pressure overload-induced cardiomyopathy, 2) the role of Cad and de novo pyrimidine in cardiac ischemia/reperfusion-caused pathological cardiac remodeling, and 3) the feasibility of using a Cad inhibitor to arrest heart failure development under hypertensive and ischemic heart disease conditions. In vitro experiments using primary cardiac myocyte culture will be performed to corroborate the in vivo tests. Elucidation of the role of de novo pyrimidine biosynthesis during pathological cardiac remodeling and heart failure will advance our understanding of the pathophysiology of hypertensive and ischemic heart diseases and pave a way for novel, more effective therapeutic design.