Crosstalk of ischemic cardiomyocytes to the coronary microcirculation: roles of ANP and BNP

缺血心肌细胞与冠状动脉微循环的串扰：ANP 和 BNP 的作用

• 批准号: 456297023
• 负责人: Professorin Dr. Michaela Kuhn
• 金额: --
• 依托单位: Physiologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/456297023?language=en
• 关键词: Crosstalk; ischemic; cardiomyocytes; coronary; microcirculation

Microvascular dysfunction after acute myocardial infarction (MI) is a major clinical problem. Although primary percutaneous coronary intervention (PCI) has markedly improved patients survival, despite epicardial reperfusion more than 30% of patients show signs of microvascular dysfunction leading to adverse left ventricular remodeling and heart failure. Acutely, vasoconstriction and thrombotic occlusion can reduce microvascular perfusion within the distal myocardium (“no-reflow”). Later, impaired angiogenesis can contribute to myocardial tissue damage. Based on experimental studies, several clinical trials aimed to improve myocardial angiogenesis via intracoronary administration of vascular growth factors, gene transfer or bone marrow mononuclear cells, in patients who had successful primary PCI, but the results were disappointing. A better knowledge of the cellular pathways regulating myocardial (re)perfusion after ischemia is necessary to search for therapeutic strategies capable to restore the microvascular network and flow. The here proposed project aims to elucidate the role of atrial (ANP) and B-type natriuretic peptides (BNP) in the paracrine communication of cardiomyocytes with coronary microcirculatory endothelial cells and pericytes, as well as the potential pharmacological, therapeutical implications. Based on our previous observations in the retinal and skeletal muscle microcirculation we hypothesize that: i) these cardiomyocyte hormones can prevent acute pericyte-mediated microcirculatory constrictions and stimulate pericyte-endothelial interactions and thereby angiogenesis induction; ii) chronic ischemia and inflammation may impair the microcirculatory actions of ANP and BNP through altered receptor signaling and enhanced peptide clearance; and iii) pharmacological or genetic rescue of such alterations improves myocardial reperfusion after MI.

急性心肌梗塞（MI）后的微血管功能障碍是一个主要的临床问题。尽管原发性经皮冠状动脉干预（PCI）显着提高了患者的存活率，但目的地心膜再灌注超过30％的患者表现出微血管功能障碍的迹象，导致左心室不良重塑和心力衰竭。急性，血管收缩和血小板闭塞可以减少心肌远端内部的微血管灌注（“无流量”）。后来，血管生成受损会导致心肌组织损伤。基于实验研究，几项旨在通过冠状动脉内给药，基因转移或骨髓单核细胞来改善心肌血管生成的临床试验，但结果令人失望，但结果令人失望。需要更好地了解缺血后调节心肌（RE）灌注的细胞途径，对于寻找能够恢复微血管网络和流动的治疗策略。拟议的项目旨在阐明心房（ANP）和B型Natriateric Pepper（BNP）在心肌细胞与冠状动脉微循环内皮细胞和周围的旁分泌通信中的作用，以及潜在的药物治疗方法。根据我们先前在视网膜和骨骼肌微循环中的观察结果，我们假设：i）这些心肌细胞恐怖可以防止急性周期介导的微循环限制并刺激周期 - 内皮相互作用，从而诱导血管生成； ii）慢性缺血和注射可能会通过改变受体信号传导和增强的肽清除率来损害ANP和BNP的微循环作用； iii）药理学或遗传拯救此类改变可改善MI后心肌再灌注。