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.

急性心肌梗死（MI）后微血管功能障碍是一个主要的临床问题。尽管直接经皮冠状动脉介入治疗（PCI）显著提高了患者的生存率，但尽管心外膜再灌注，仍有超过30%的患者显示出微血管功能障碍的迹象，导致不良的左心室重塑和心力衰竭。急性时，血管收缩和血栓性闭塞可减少远端心肌内的微血管灌注（“无复流”）。随后，受损的血管生成可导致心肌组织损伤。在实验研究的基础上，一些临床试验旨在通过冠状动脉内给予血管生长因子、基因转移或骨髓单个核细胞来改善直接PCI患者的心肌血管生成，但结果令人失望。更好地了解缺血后调节心肌（再）灌注的细胞通路对于寻找能够恢复微血管网络和流动的治疗策略是必要的。本研究旨在阐明心房肽（ANP）和B型利钠肽（BNP）在心肌细胞与冠状动脉微循环内皮细胞和周细胞的旁分泌通讯中的作用，以及潜在的药理学和治疗学意义。基于我们先前在视网膜和骨骼肌微循环中的观察，我们假设：i）这些心肌细胞激素可以防止急性周细胞介导的微循环收缩并刺激周细胞-内皮相互作用，从而诱导血管生成; ii）慢性缺血和炎症可以通过改变受体信号传导和增强肽清除来损害ANP和BNP的微循环作用;和iii）这些改变的药理学或遗传学挽救改善了MI后的心肌再灌注。