期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 2, 期 4, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.113.000249
关键词
angiogenesis; cardiomyopathy; heart failure; ischemia-reperfusion injury; myocardial infarction
资金
- Canadian Institute for Health Research [86602, 53319]
- Alberta Innovates-Health Solutions
- Natural Sciences and Engineering Research Council of Canada
- EuGeneHeart (EU 6th Framework Programs)
- Austrian National Bank
- Institute of Molecular Biotechnology, Austria
- Alberta Innovates [201200927, 201201024, 201200957] Funding Source: researchfish
Background-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. Methods and Results-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. Conclusions-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.
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