Booz G W, Baker K M
Weis Center for Research, Geisinger Clinic, Danville, PA 17822, USA.
Cardiovasc Res. 1995 Oct;30(4):537-43.
Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.
心脏成纤维细胞在心脏细胞外基质（ECM）的产生和维持过程中似乎起着重要作用。与高血压和心肌梗死相关的心脏成纤维细胞异常增殖以及ECM蛋白胶原蛋白的沉积，可能会对心脏功能产生不利影响。有几组因素会影响胶原蛋白基因表达和/或心脏成纤维细胞的生长。血管紧张素II、醛固酮和内皮素在高血压时ECM重塑过程中起核心作用，并会降低培养细胞中的胶原酶活性和/或增加胶原蛋白合成。通常在损伤部位升高的调节肽，如转化生长因子β1（TGF-β1）和血小板衍生生长因子（PDGF），会增加胶原蛋白合成和/或刺激有丝分裂。机械拉伸可增强胶原蛋白表达和细胞增殖，这种反应部分可能是由于整合素激活所致。细胞因子可能刺激或抑制细胞生长，后者是通过前列腺素的形成来实现的。血管紧张素II是体内心脏纤维增生以及ECM蛋白胶原蛋白和纤连蛋白合成的主要决定因素。心脏成纤维细胞具有与血管紧张素II结合的G蛋白偶联AT1受体，该受体与多种信号通路的激活相关，包括：磷脂酶C-β，随后从细胞内储存中释放Ca2+并激活蛋白激酶C、丝裂原活化蛋白激酶、酪氨酸激酶、磷脂酶D、磷脂酸形成以及转录因子STAT家族。心脏成纤维细胞对血管紧张素II的反应是增生/肥大生长，并增加胶原蛋白、纤连蛋白和整合素的表达。尽管AT1受体可能在某些层面与整合素和细胞因子受体相互作用，但该受体激活多种信号通路的机制尚不清楚。AT1受体的不同信号通路可能有助于不同的细胞反应，如促有丝分裂、ECM合成或炎症/应激反应。AT1受体的信号通路与G蛋白、细胞因子和生长因子受体的信号通路之间的相互作用，可能决定细胞的最终反应。
