Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
J Am Heart Assoc. 2013 Jul 1;2(4):e000249. doi: 10.1161/JAHA.113.000249.
Coronary artery disease leading to myocardial ischemia is the most common cause of heart failure. Apelin (APLN), the endogenous peptide ligand of the APJ receptor, has emerged as a novel regulator of the cardiovascular system.
Here we show a critical role of APLN in myocardial infarction (MI) and ischemia-reperfusion (IR) injury in patients and animal models. Myocardial APLN levels were reduced in patients with ischemic heart failure. Loss of APLN increased MI-related mortality, infarct size, and inflammation with drastic reductions in prosurvival pathways resulting in greater systolic dysfunction and heart failure. APLN deficiency decreased vascular sprouting, impaired sprouting of human endothelial progenitor cells, and compromised in vivo myocardial angiogenesis. Lack of APLN enhanced susceptibility to ischemic injury and compromised functional recovery following ex vivo and in vivo IR injury. We designed and synthesized two novel APLN analogues resistant to angiotensin converting enzyme 2 cleavage and identified one analogue, which mimicked the function of APLN, to be markedly protective against ex vivo and in vivo myocardial IR injury linked to greater activation of survival pathways and promotion of angiogenesis.
APLN is a critical regulator of the myocardial response to infarction and ischemia and pharmacologically targeting this pathway is feasible and represents a new class of potential therapeutic agents.
导致心肌缺血的冠状动脉疾病是心力衰竭的最常见原因。Apelin（APLN）是 APJ 受体的内源性肽配体，已成为心血管系统的新型调节剂。
在这里，我们展示了 APLN 在患者和动物模型中的心肌梗死（MI）和缺血再灌注（IR）损伤中的关键作用。缺血性心力衰竭患者的心肌 APLN 水平降低。APLN 的缺失增加了与 MI 相关的死亡率、梗死面积和炎症，同时严重减少了存活途径，导致收缩功能障碍和心力衰竭更严重。APLN 缺乏会减少血管生成，损害人内皮祖细胞的生成，并损害体内心肌血管生成。缺乏 APLN 会增加对缺血损伤的敏感性，并损害体外和体内 IR 损伤后的功能恢复。我们设计并合成了两种对血管紧张素转换酶 2 切割具有抗性的新型 APLN 类似物，并鉴定出一种类似物，该类似物模拟了 APLN 的功能，对体外和体内心肌 IR 损伤具有显著的保护作用，与存活途径的更大激活和促进血管生成有关。
APLN 是心肌对梗塞和缺血反应的关键调节剂，靶向该途径具有可行性，代表了一类新的潜在治疗药物。
