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 对血压升高的反应，心脏表现出肥大性生长以改善心室壁 应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，在一项研究中， 心肌梗塞引起心脏的显著结构损伤。常见的临床实践来治疗 通过冠状动脉恢复的心脏缺血导致额外的再灌注损伤。缺血损伤 和再灌注一起显著削弱心脏的泵送功能。尽管有广泛的兴趣和 由于临床需求的迫切性，我们对心力衰竭发展机制的理解仍然有限。 病理性心脏重构是高血压性心脏病和缺血性心脏病的共同途径。在 无论是对需求增加或心脏损伤的反应，心脏发动急性反应，以弥补 心脏收缩力的丧失。然而，在持续的压力下，会发生代偿失调， 发展起来的以前的研究表明，代谢改变先于大多数，如果不是所有的其他变化， 病理性心脏重塑然而，代谢重构在心脏中的作用及其机制尚不清楚， 失败仍然是难以捉摸的。 这里的初步结果表明，从头嘧啶生物合成急剧和显着增强 在结构和电生理改变之前，心脏对压力过载的反应。此外，委员会认为， 作为限速酶的Cad（氨甲酰磷酸合成酶2、天冬氨酸转氨甲酰酶和二氢乳清酸酶） 该途径的酶被强烈诱导。另一方面，从头嘧啶生物合成也是 缺血后再灌注上调。根据以前的研究结果和这些试点数据， 嘧啶生物合成在病理性心脏重塑中的作用已被阐明。得与失， 已经产生了功能小鼠模型，其将用于测试1）Cad的作用和从头 嘧啶在压力超负荷诱导的心肌病中的生物合成，2）Cad和从头嘧啶的作用 在心肌缺血/再灌注引起的病理性心脏重塑中，以及3）使用Cad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。体外 将进行使用原代心肌细胞培养物的实验以证实体内测试。阐发 在病理性心脏重塑和心力衰竭过程中从头嘧啶生物合成的作用将 推进我们对高血压和缺血性心脏病的病理生理学的理解， for novel新颖，more effective有效therapeutic治疗design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.