Cell-Cell Interaction in Heart Failure

心肌梗死后左室重构导致心力衰竭，这是一种主要的 全球范围内的死因。基本的细胞尺度机制有助于产生 心力衰竭包括心肌细胞肥大和细胞凋亡，蛋白水解酶释放增加导致 细胞外基质降解和脑室扩张，以及由 肌成纤维细胞等。我们最近报道了一项在小鼠和 患者：炎性髓系细胞(单核细胞、巨噬细胞)不仅急性侵袭 心肌梗死后缺血区也可见远端。令人惊讶的是，我们发现了他们的 心肌梗死后数月出现衰竭的非缺血心肌，反映慢性炎症。 它们在其他慢性炎症条件下的已知功能，如动脉粥样硬化和 自身免疫性疾病使髓系细胞成为组织重塑的主要协调者，如 它们释放促炎细胞因子，携带高水平的蛋白水解酶，并引发纤维化。 髓系细胞在衰竭心肌中的作用；然而，尚不清楚。我们的初步数据 表明衰竭心脏中的巨噬细胞是炎性CCR2单核细胞的后代， 而且它们的中和作用减弱了心肌梗死后的重塑。因此，我们假设 心肌白细胞的存在可能反映了一种病因--和新的治疗发作点-- 心肌梗塞后心力衰竭。我们将研究白细胞的存在、表型、亚群及其影响 关于疾病进展的。我们假设髓系细胞指示驻留细胞，包括 具有促炎和促纤维化信号的成纤维细胞、肌细胞和内皮细胞 是降解基质的蛋白酶的来源。调查巡逻、招募和相声 远端心肌中的白细胞到实质细胞，我们将跟踪免疫细胞的 用体内多通道荧光研究它们在未受干扰的微环境中的行为 心脏跳动的显微镜。偏远地区分离细胞的基因表达研究 会给出他们的关键信号。我们将使用体内RNAi疗法来击倒循环中的CCR2 单核细胞，从而限制了它们的招募和单核细胞衍生的有害影响 巨噬细胞对心肌梗死后重塑的影响。表型鉴定将使用多尺度成像技术 显微镜、荧光分子断层成像、电影和标记磁共振成像。

Left ventricular remodeling after myocardial infarction leads to heart failure, a predominant cause of death worldwide. Basic cellular-scale mechanisms contributing to the generation of heart failure include myocyte hypertrophy and apoptosis, heightened protease release leading to extracellular matrix degradation and ventricular dilation, and fibrosis caused by myofibroblasts, among others. We have recently reported a novel observation in mice and patients: inflammatory myeloid cells (monocytes, macrophages) invade not only the acutely ischemic myocardium but also the remote zone after MI. Strikingly, we have detected their presence in failing non-ischemic myocardium months after MI, reflecting chronic inflammation. Their known functions in other chronic inflammatory conditions such as atherosclerosis and autoimmune disease position myeloid cells as master orchestrators of tissue remodeling, as they release pro-inflammatory cytokines, carry a high protease payload, and instigate fibrosis. The role of myeloid cells in the failing myocardium; however, is unknown. Our preliminary data show that macrophages in failing hearts are descendants of inflammatory CCR2+ monocytes, and that their neutralization attenuates post-MI remodeling. We thus hypothesize that myocardial leukocyte presence may reflect a cause -- and new therapeutic point of attack -- for post-MI heart failure. We will study leukocyte's presence, phenotype, subsets and their impact on disease progression. We hypothesize that myeloid cells instruct resident cells, including fibroblasts, myocytes, and endothelial cells with pro-inflammatory and pro-fibrotic signals and are a source of matrix-degrading proteases. To investigate patrolling, recruitment, and cross-talk of leukocytes to parenchymal cells in the remote myocardium, we will follow immune cell's behavior in their undisturbed microenvironment with in vivo multi-channel fluorescence microscopy of the beating heart. Gene expression studies of cells isolated from the remote zone will yield their key signals. We will use in vivo RNAi therapy to knock down CCR2 in circulating monocytes, thus limiting their recruitment and the detrimental effect of monocyte-derived macrophages on post-MI remodeling. Phenotyping will employ multi-scale imaging with intravital microscopy, fluorescence molecular tomography, cine and tagging magnetic resonance imaging.