de Oliveira Camargo Rebeca, Abual'anaz Besher, Rattan Sunil G, Filomeno Krista L, Dixon Ian M C
Institute of Cardiovascular Sciences, Albrechtsen Research Centre, Winnipeg, Canada.
Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada.
Wound Repair Regen. 2021 Jul;29(4):667-677. doi: 10.1111/wrr.12947. Epub 2021 Jun 16.
Heart disease with attendant cardiac fibrosis kills more patients in developed countries than any other disease, including cancer. We highlight the recent literature on factors that activate and also deactivate cardiac fibroblasts. Activation of cardiac fibroblasts results in myofibroblasts phenotype which incorporates aSMA to stress fibres, express ED-A fibronectin, elevated PDGFRα and are hypersecretory ECM components. These cells facilitate both acute wound healing (infarct site) and chronic cardiac fibrosis. Quiescent fibroblasts are associated with normal myocardial tissue and provide relatively slow turnover of the ECM. Deactivation of activated myofibroblasts is a much less studied phenomenon. In this context, SKI is a known negative regulator of TGFb /Smad signalling, and thus may share functional similarity to PPARγ activation. The discovery of SKI's potent anti-fibrotic role, and its ability to deactivate and/or myofibroblasts is featured and contrasted with PPARγ. While myofibroblasts are typically recruited from pools of potential precursor cells in a variety of organs, the importance of activation of resident cardiac fibroblasts has been recently emphasised. Myofibroblasts deposit ECM components at an elevated rate and contribute to both systolic and diastolic dysfunction with attendant cardiac fibrosis. A major knowledge gap exists as to specific proteins that may signal for fibroblast deactivation. As SKI may be a functionally pluripotent protein, we suggest that it serves as a scaffold to proteins other than R-Smads and associated Smad signal proteins, and thus its anti-fibrotic effects may extend beyond binding R-Smads. While cardiac fibrosis is causal to heart failure, the treatment of cardiac fibrosis is hampered by the lack of availability of effective pharmacological anti-fibrotic agents. The current review will provide an overview of work highlighting novel factors which cause fibroblast activation and deactivation to underscore putative therapeutic avenues for improving disease outcomes in cardiac patients with fibrosed hearts.
在发达国家，伴有心脏纤维化的心脏病比包括癌症在内的任何其他疾病导致更多患者死亡。我们重点介绍了近期关于激活和失活心脏成纤维细胞的因素的文献。心脏成纤维细胞的激活导致肌成纤维细胞表型，其中包含α平滑肌肌动蛋白（αSMA）形成应力纤维、表达ED-A纤连蛋白、血小板衍生生长因子受体α（PDGFRα）升高且细胞外基质（ECM）成分分泌过多。这些细胞既促进急性伤口愈合（梗死部位），也促进慢性心脏纤维化。静止的成纤维细胞与正常心肌组织相关，并使ECM的更新相对缓慢。激活的肌成纤维细胞的失活是一个研究较少的现象。在这种情况下，SKI是一种已知的转化生长因子β（TGFβ）/Smad信号通路的负调节因子，因此可能与过氧化物酶体增殖物激活受体γ（PPARγ）激活具有功能相似性。SKI强大的抗纤维化作用及其使肌成纤维细胞失活和/或清除的能力被重点介绍，并与PPARγ进行了对比。虽然肌成纤维细胞通常从各种器官中的潜在前体细胞池中募集，但最近已强调了驻留心脏成纤维细胞激活的重要性。肌成纤维细胞以较高的速率沉积ECM成分，并导致收缩和舒张功能障碍以及伴随的心脏纤维化。关于可能发出成纤维细胞失活信号的特定蛋白质，存在重大的知识空白。由于SKI可能是一种功能多能的蛋白质，我们认为它作为一种支架作用于除R-Smads和相关Smad信号蛋白之外的蛋白质，因此其抗纤维化作用可能超出与R-Smads结合的范围。虽然心脏纤维化是心力衰竭的病因，但由于缺乏有效的抗纤维化药物，心脏纤维化的治疗受到阻碍。本综述将概述突出导致成纤维细胞激活和失活的新因素的研究工作，以强调改善患有纤维化心脏的心脏病患者疾病结局的潜在治疗途径。
