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首页> 外文期刊>Oxidative Medicine and Cellular Longevity >Upregulation of Transient Receptor Potential Canonical Type 3 Channel via AT1R/TGF-β1/Smad2/3 Induces Atrial Fibrosis in Aging and Spontaneously Hypertensive Rats
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Upregulation of Transient Receptor Potential Canonical Type 3 Channel via AT1R/TGF-β1/Smad2/3 Induces Atrial Fibrosis in Aging and Spontaneously Hypertensive Rats

机译：通过AT1R / TGF-β1/ SMAD2 / 3上调瞬时受体潜在的典型典型典型3通道诱导老化和自发性高血压大鼠心房纤维化

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摘要

Fibroblast proliferation and migration are central in atrial fibrillation (AF) promoting structure remodeling, which is strongly associated with aging and hypertension. Transient receptor potential canonical-3 channel (TRPC3) is a key mediator of cardiac fibrosis and the pathogenesis of AF. Here, we have observed the increased TRPC3 expression that induced atrial fibrosis which possibly is either mediated by the aging process or related to hypertensive progression. In this study, we measured the pathological structure remodeling by H&E staining, Masson staining, and transmission electron microscope (TEM). The protein expression levels of fibrotic biomarkers and TRPC3 were measured by Western blotting with atrial tissues from normotensive Wistar Kyoto rats (WKY 4m-o (4 months old)), old WKY (WKY 24m-o (24 months old)), spontaneously hypertensive rat (SHR 4m-o (4 months old)), and old SHR (SHR 24m-o (24 months old)). To illuminate the molecular mechanism of TRPC3 in atrial fibrosis of aging rats and SHR, we detected the inhibited role of TRPC3 selective blocker ethyl-1-(4-(2,3,3-trichloroacrylamide) phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate,pyrazole-3 (Pyr3) on angiotensin II (Ang II) induced fibrosis in neonatal rat atrial fibroblasts. The pathological examination showed that the extracellular matrix (ECM) and collagen fibrils were markedly increased in atrial tissues from aged and hypertensive rats. The protein expressions of fibrotic biomarkers (collagen I, collagen III, and transforming growth factor-β1 (TGF-β1)) were significantly upregulated in atrial tissues from the WKY 24m-o group, SHR 4m-o group, and SHR 24m-o group compared with the WKY 4m-o group. Meanwhile, the expression level of TRPC3 was significantly upregulated in WKY 24m-o and SHR 4m-o atrial tissues compared to WKY 4m-o rats. In isolated and cultured neonatal rat atrial fibroblasts, Ang II induced the atrial fibroblast migration and proliferation and upregulated the expression levels of TRPC3 and fibrotic biomarkers. TRPC3 selected blocker Pyr3 attenuated the migration and proliferation in neonatal rat atrial fibroblasts. Furthermore, Pyr3 significantly alleviated Ang II-induced upregulation of TRPC3, collagen I, collagen III, and TGF-β1 through the molecular mechanism of the TGF-β/Smad2/3 signaling pathway. Similarly, knocking down TRPC3 using short hairpin RNA (shTRPC3) also attenuated Ang II-induced upregulation of TGF-β1. Pyr3 preconditioning decreased Ang II-induced intracellular Ca2+ transient amplitude elevation. Furthermore, AT1 receptor was involved in Ang II-induced TRPC3 upregulation. Hence, upregulation of TRPC3 in aging and hypertension is involved in an atrial fibrosis process. Inhibition of TRPC3 contributes to reverse Ang II-induced fibrosis. TRPC3 may be a potential therapeutic target for preventing fibrosis in aging and hypertension.
机译：成纤维细胞增殖和迁移是心房颤动（AF）促进结构重塑的中枢性，其与老化和高血压强烈相关。瞬态受体潜在的Canonical-3通道（TRPC3）是心肌纤维化的关键介质和AF的发病机制。在这里，我们观察到增加的TRPC3表达，诱导可能由老化过程介导或与高血压进展相关的心房纤维化。在该研究中，我们测量了H＆E染色，Masson染色和透射电子显微镜（TEM）的病理结构重塑。通过从正常的Wistar大鼠（WKY 4M-O（4个月）的心房组织（WKY 4M-O（4个月）），蛋白质印迹测量纤维化生物标志物和TRPC3的蛋白表达水平（WKY 24M-O（24个月）），自发性高血压大鼠（SHR 4M-O（4个月））和旧的SHR（SHR 24M-O（24个月））。为了照亮TRPC3在老化大鼠和SHR的心房纤维化中的分子机制，我们检测了TRPC3选择性阻断剂乙基-1-（4-（2,3-三氯丙烯酰胺）苯基）-5-（三氟甲基）的抑制作用 - 1H-吡唑-4-羧酸盐，吡唑-3（PYR3）血管紧张素II（ANG II）诱导新生大鼠心房成纤维细胞的纤维化。病理检查表明，来自老年人和高血压大鼠的心房组织中，细胞外基质（ECM）和胶原纤维显着增加。来自WKY 24M-O基团，SHR 4M-O组和SHR 24M-O的心房组织显着上调了纤维化生物标志物（胶原I，胶原III和转化生长因子-β1（TGF-β1）的蛋白质表达与WKY 4M-O组相比。同时，与WKY 4M-O大鼠相比，WKY 24M-O和SHR 4M-O心房组织中TRPC3的表达水平显着上调。在孤立和培养的新生大鼠心房成纤维细胞中，Ang II诱导心房成纤维细胞迁移和增殖，并上调TRPC3和纤维化生物标志物的表达水平。 TRPC3选定的阻滞剂Pyr3减弱了新生大鼠心房成纤维细胞中的迁移和增殖。此外，Pyr3通过TGF-β/ Smad2 / 3信号通路的分子机制显着减轻了TrpC3，胶原I，胶原III和TGF-β1的致敏性上调。类似地，使用短发夹RNA（SHTRPC3）敲击TRPC3也衰减了TGF-β1的Ang II诱导的上调。 Pyr3预处理降低了Ang II诱导的细胞内Ca2 +瞬态幅度仰角。此外，AT1受体参与了Ang II诱导的TRPC3上调。因此，在老化和高血压中对TRPC3的上调涉及心房纤维化过程。 TRPC3的抑制有助于反向Ang II诱导的纤维化。 TRPC3可以是预防老化和高血压纤维化的潜在治疗靶标。

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