Fan X, Xie J, Tian J
Department of Medicine, Center for Hypertension and Personalized Medicine, University of Toledo, Ohio 43614, USA.
Cardiovasc Pharm Open Access. 2017;6(1). doi: 10.4172/2329-6607.1000204. Epub 2017 Jan 31.
Cardiac fibrosis is a common pathological process in cardiac disease and may lead to heart failure. It can also cause sudden death even in those without cardiac symptoms. Tissue fibrosis can be categorized into two categories: replacement fibrosis (also called reparative fibrosis) and reactive fibrosis. In replacement fibrosis, infiltration of inflammatory cells and accumulation of Extracellular Matrix (ECM) proteins are the initial steps in forming scarlike fibrotic tissue after acute cardiac injury and cardiac cell necrosis. Reactive fibrosis can be formed in response to hormonal change and pressure or volume overload. Experimental studies in animals have identified important pathways such as the Renin-Angiotensin-Aldosterone System (RAAS) and the endothelin pathway that contribute to fibrosis formation. Despite the fact that clinical trials using RAAS inhibitors as therapies for reducing cardiac fibrosis and improving cardiac function have been promising, heart failure is still the leading cause of deaths in the United States. Intensive efforts have been made to find novel targets and to develop new treatments for cardiac fibrosis and heart failure in the past few decades. The Na/K-ATPase, a canonical ion transporter, has been shown to also function as a signal transducer and prolonged activation of Na/K-ATPase signaling has been found to promote the formation of cardiac fibrosis. Novel tools that block the activation of Na/K-ATPase signaling have been developed and have shown promise in reducing cardiac fibrosis. This review will discuss the recent development of novel molecular targets, focusing on the Na/K-ATPase signaling complex as a therapeutic target in treatment of cardiac fibrosis.
心脏纤维化是心脏疾病中常见的病理过程，可能导致心力衰竭。它甚至可能导致无症状者猝死。组织纤维化可分为两类：替代性纤维化（也称为修复性纤维化）和反应性纤维化。在替代性纤维化中，炎症细胞浸润和细胞外基质（ECM）蛋白积累是急性心脏损伤和心肌细胞坏死后形成瘢痕样纤维化组织的初始步骤。反应性纤维化可因激素变化、压力或容量超负荷而形成。动物实验研究已确定了肾素-血管紧张素-醛固酮系统（RAAS）和内皮素途径等导致纤维化形成的重要途径。尽管使用RAAS抑制剂作为减少心脏纤维化和改善心脏功能的治疗方法的临床试验前景良好，但心力衰竭仍是美国的主要死因。在过去几十年中，人们一直在努力寻找新的靶点并开发治疗心脏纤维化和心力衰竭的新疗法。钠钾ATP酶是一种典型的离子转运体，已被证明还具有信号转导功能，并且发现钠钾ATP酶信号的长期激活会促进心脏纤维化的形成。已开发出阻断钠钾ATP酶信号激活的新型工具，并在减少心脏纤维化方面显示出前景。本综述将讨论新型分子靶点的最新进展，重点关注钠钾ATP酶信号复合物作为治疗心脏纤维化的治疗靶点。
