Chung C-C, Kao Y-H, Yao C-J, Lin Y-K, Chen Y-J
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Acta Physiol (Oxf). 2017 Aug;220(4):432-445. doi: 10.1111/apha.12835. Epub 2017 Jan 16.
Atrial fibrosis plays a pivotal role in the pathophysiology of heart failure (HF). The left atrium (LA) experiences greater fibrosis than the right atrium (RA) during HF. It is not clear whether LA cardiac fibroblasts contain distinctive activities that predispose LA to fibrosis.
LA and RA fibrosis were evaluated in healthy and isoproterenol-induced HF Sprague Dawley rats. Rat LA and RA primary isolated fibroblasts were subjected to proliferation assay, oxidative stress assay, cell migration analysis, collagen measurement, cytokine array and Western blot.
Healthy rat LA and RA had a similar extent of collagen deposition. HF significantly increased fibrosis to a greater severity in LA than in RA. Compared to isolated RA fibroblasts, the in vitro experiments showed that isolated LA fibroblasts had higher oxidative stress and exhibited higher collagen, transforming growth factor-β1, connective tissue growth factor production and less vascular endothelial growth factor (VEGF) production, but had similar migration, myofibroblast differentiation and proliferation activities. VEGF significantly increased the collagen production ability of LA fibroblasts, but not RA fibroblasts. LA fibroblasts had more phosphorylated ERK1/2 and P38 expression. ERK inhibitor (PD98059, 50 μmol L ) significantly attenuated collagen production and increased VEGF production in RA fibroblasts but not in LA fibroblasts. P38 inhibitor (SB203580, 30 μmol L ) significantly attenuated collagen production in LA fibroblasts but not in RA fibroblasts. P38 inhibitor also significantly increased VEGF production in RA and LA fibroblasts.
Differences in profibrotic activity between LA and RA fibroblasts may be caused by different responses to mitogen-activated protein kinase signalling.
心房纤维化在心力衰竭（HF）的病理生理学中起关键作用。在HF期间，左心房（LA）比右心房（RA）经历更严重的纤维化。尚不清楚LA心脏成纤维细胞是否具有使LA易发生纤维化的独特活性。
在健康和异丙肾上腺素诱导的HF斯普拉格-道利大鼠中评估LA和RA纤维化。对大鼠LA和RA原代分离的成纤维细胞进行增殖测定、氧化应激测定、细胞迁移分析、胶原蛋白测量、细胞因子阵列和蛋白质印迹分析。
健康大鼠的LA和RA胶原蛋白沉积程度相似。HF显著增加了纤维化程度，LA比RA更严重。与分离的RA成纤维细胞相比，体外实验表明，分离的LA成纤维细胞具有更高的氧化应激，并且表现出更高的胶原蛋白、转化生长因子-β1、结缔组织生长因子产生，而血管内皮生长因子（VEGF）产生较少，但具有相似的迁移、肌成纤维细胞分化和增殖活性。VEGF显著增加LA成纤维细胞的胶原蛋白产生能力，但不增加RA成纤维细胞的。LA成纤维细胞具有更多的磷酸化ERK1/2和P38表达。ERK抑制剂（PD98059，50 μmol/L）显著减弱RA成纤维细胞中的胶原蛋白产生并增加VEGF产生，但对LA成纤维细胞无效。P38抑制剂（SB203580，30 μmol/L）显著减弱LA成纤维细胞中的胶原蛋白产生，但对RA成纤维细胞无效。P38抑制剂还显著增加RA和LA成纤维细胞中的VEGF产生。
LA和RA成纤维细胞之间促纤维化活性的差异可能是由对丝裂原活化蛋白激酶信号传导的不同反应引起的。
