Porter Karen E, Turner Neil A
Multidisciplinary Cardiovascular Research Centre (MCRC), Division of Cardiovascular and Neuronal Remodelling, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds LS29JT, UK.
Pharmacol Ther. 2009 Aug;123(2):255-78. doi: 10.1016/j.pharmthera.2009.05.002. Epub 2009 May 19.
Cardiac fibroblasts are the most prevalent cell type in the heart and play a key role in regulating normal myocardial function and in the adverse myocardial remodeling that occurs with hypertension, myocardial infarction and heart failure. Many of the functional effects of cardiac fibroblasts are mediated through differentiation to a myofibroblast phenotype that expresses contractile proteins and exhibits increased migratory, proliferative and secretory properties. Cardiac myofibroblasts respond to proinflammatory cytokines (e.g. TNFalpha, IL-1, IL-6, TGF-beta), vasoactive peptides (e.g. angiotensin II, endothelin-1, natriuretic peptides) and hormones (e.g. noradrenaline), the levels of which are increased in the remodeling heart. Their function is also modulated by mechanical stretch and changes in oxygen availability (e.g. ischaemia-reperfusion). Myofibroblast responses to such stimuli include changes in cell proliferation, cell migration, extracellular matrix metabolism and secretion of various bioactive molecules including cytokines, vasoactive peptides and growth factors. Several classes of commonly prescribed therapeutic agents for cardiovascular disease also exert pleiotropic effects on cardiac fibroblasts that may explain some of their beneficial outcomes on the remodeling heart. These include drugs for reducing hypertension (ACE inhibitors, angiotensin receptor blockers, beta-blockers), cholesterol levels (statins, fibrates) and insulin resistance (thiazolidinediones). In this review, we provide insight into the properties of cardiac fibroblasts that underscores their importance in the remodeling heart, including their origin, electrophysiological properties, role in matrix metabolism, functional responses to environmental stimuli and ability to secrete bioactive molecules. We also review the evidence suggesting that certain cardiovascular drugs can reduce myocardial remodeling specifically via modulatory effects on cardiac fibroblasts.
心脏成纤维细胞是心脏中最普遍的细胞类型，在调节正常心肌功能以及高血压、心肌梗死和心力衰竭时发生的不良心肌重塑中起关键作用。心脏成纤维细胞的许多功能作用是通过分化为肌成纤维细胞表型来介导的，该表型表达收缩蛋白并表现出增强的迁移、增殖和分泌特性。心脏肌成纤维细胞对促炎细胞因子（如肿瘤坏死因子α、白细胞介素 -1、白细胞介素 -6、转化生长因子 -β）、血管活性肽（如血管紧张素 II、内皮素 -1、利钠肽）和激素（如去甲肾上腺素）产生反应，而这些物质在重塑的心脏中水平会升高。它们的功能也受到机械牵张和氧供应变化（如缺血 - 再灌注）的调节。肌成纤维细胞对这些刺激的反应包括细胞增殖、细胞迁移、细胞外基质代谢的变化以及包括细胞因子、血管活性肽和生长因子在内的各种生物活性分子的分泌。几类常用的心血管疾病治疗药物也对心脏成纤维细胞产生多效性作用，这可能解释了它们对重塑心脏产生的一些有益效果。这些药物包括用于降低高血压的药物（血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂、β受体阻滞剂）、胆固醇水平的药物（他汀类药物、贝特类药物）和胰岛素抵抗的药物（噻唑烷二酮类药物）。在本综述中，我们深入探讨了心脏成纤维细胞的特性，强调了它们在重塑心脏中的重要性，包括它们的起源、电生理特性、在基质代谢中的作用、对环境刺激的功能反应以及分泌生物活性分子的能力。我们还综述了证据，表明某些心血管药物可以通过对心脏成纤维细胞的调节作用来特异性地减少心肌重塑。
