Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
J Cardiovasc Transl Res. 2012 Dec;5(6):768-82. doi: 10.1007/s12265-012-9404-5. Epub 2012 Sep 27.
The cardiac fibroblast (CF) has historically been thought of as a quiescent cell of the heart, passively maintaining the extracellular environment for the cardiomyocytes (CM), the functional cardiac cell type. The increasingly appreciated role of the CF, however, extends well beyond matrix production, governing many aspects of cardiac function including cardiac electrophysiology and contractility. Importantly, its contributions to cardiac pathophysiology and pathologic remodeling have created a shift in the field's focus from the CM to the CF as a therapeutic target in the treatment of cardiac diseases. In response to cardiac injury, the CF undergoes a pathologic phenotypic transition into a myofibroblast, characterized by contractile smooth muscle proteins and upregulation of collagens, matrix proteins, and adhesion molecules. Further, the myofibroblast upregulates expression and secretion of a variety of pro-inflammatory, profibrotic mediators, including cytokines, chemokines, and growth factors. These mediators act in both an autocrine fashion to further activate CFs, as well as in a paracrine manner on both CMs and circulating inflammatory cells to induce myocyte dysfunction and chronic inflammation, respectively. Together, cell-specific cytokine-induced effects exacerbate pathologic remodeling and progression to HF. A better understanding of this dynamic intercellular communication will lead to novel targets for the attenuation of cardiac remodeling. Current strategies aimed at targeting cytokines have been largely unsuccessful in clinical trials, lending insights into ways that such intercellular cross talk can be more effectively attenuated. This review will summarize the current knowledge regarding CF functions in the heart and will discuss the regulation and signaling behind CF-mediated cytokine production and function. We will then highlight clinical trials that have exploited cytokine cross talk in the treatment of heart failure and provide novel strategies currently under investigation that may more effectively target pathologic CF-CM communication for the treatment of cardiac disease. This review explores novel mechanisms to directly attenuate heart failure progression through inhibition of signaling downstream of pro-inflammatory cytokines that are elevated after cardiac injury.
心脏成纤维细胞（CF）在历史上一直被认为是心脏的静止细胞，被动地维持心肌细胞（CM）的细胞外环境，CM 是心脏的功能细胞类型。然而，CF 的作用越来越受到重视，其作用远远超出了基质产生，它控制着心脏功能的许多方面，包括心脏电生理学和收缩性。重要的是，它对心脏病理生理学和病理性重塑的贡献导致该领域的重点从 CM 转移到 CF，将其作为治疗心脏疾病的治疗靶点。在心脏损伤后，CF 经历病理性表型转变为肌成纤维细胞，其特征是收缩性平滑肌蛋白的上调和胶原蛋白、基质蛋白和黏附分子的上调。此外，肌成纤维细胞上调表达和分泌多种促炎、促纤维化介质，包括细胞因子、趋化因子和生长因子。这些介质以自分泌方式进一步激活 CF，以旁分泌方式作用于 CM 和循环炎症细胞，分别诱导心肌细胞功能障碍和慢性炎症。总之，细胞特异性细胞因子诱导的作用加剧了病理性重塑和向 HF 的进展。更好地了解这种动态细胞间通讯将为衰减心脏重塑提供新的靶点。针对细胞因子的当前策略在临床试验中基本不成功，这为深入了解这种细胞间串扰可以更有效地衰减提供了线索。这篇综述总结了 CF 在心脏中的功能的现有知识，并讨论了 CF 介导的细胞因子产生和功能的调节和信号转导。然后，我们将重点介绍利用细胞因子交叉对话治疗心力衰竭的临床试验，并提供目前正在研究的新策略，这些策略可能更有效地针对病理性 CF-CM 通讯，用于治疗心脏疾病。这篇综述探讨了通过抑制心脏损伤后升高的促炎细胞因子下游信号来直接减弱心力衰竭进展的新机制。
