CTRP9 Ameliorates Atrial Inflammation, Fibrosis, and Vulnerability to Atrial Fibrillation in Post-Myocardial Infarction Rats
CTRP9 Ameliorates Atrial Inflammation, Fibrosis, and Vulnerability to Atrial Fibrillation in Post-Myocardial Infarction Rats
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DOI：
10.1161/jaha.119.013133
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发表时间：
2019-11-05
影响因子：
5.4
通讯作者：
Huang, Congxin
中科院分区：
文献类型：
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作者：
Liu, Mingxin;Li, Wei;Huang, Congxin
背景-炎症和纤维化在心肌梗死（MI）后心房颤动（AF）的发病机制中发挥重要作用。 CTRP9（C1q/肿瘤坏死因子相关蛋白-9）作为一种分泌性糖蛋白，可以逆转心肌梗死后的左心室重塑，但其对心肌梗死引起的心房炎症、纤维化和相关房颤的影响尚不清楚。 方法和结果-MI模型大鼠通过颈静脉注射腺病毒补充CTRP9（Ad-CTRP9）。心肌梗死后3天或7天检测心房的心脏功能、炎症和纤维化指标及相关信号通路、电生理特性以及体内和离体心房的AF诱导能力。将shCTRP9（短发夹CTRP9）和shRNA注射入大鼠体内，并在第5天或第10天进行类似的检测。MI和Ad-GFP（编码绿色荧光蛋白的腺病毒）+MI大鼠均诱导不良心房炎症和纤维化、心功能不全。全身 CTRP9 治疗改善了 MI 后的心功能障碍。在 MI 后 3 天，CTRP9 通过下调白细胞介素 1b 和白细胞介素 6 以及上调白细胞介素 10 显着改善巨噬细胞浸润并减弱炎症反应；心肌梗死后 7 天内，通过降低 I 型和 III 型胶原蛋白、α-SMA 和转化生长因子 β 1 的表达，可能通过抑制 Toll 样受体 4/核因子-κ B 和 Smad2/3 信号通路，从而抑制左心房纤维化。电生理记录显示，CTRP9 减弱了 MI 引起的 AF 诱导性和持续时间的增加以及心房传导时间的延长；此外，CTRP9与IL-1b和AF持续时间呈负相关。 CTRP9下调会加重心房炎症、纤维化、房颤易感性和房间传导时间延长，但不影响心功能。结论：CTRP9能有效减轻心房炎症和纤维化，可能是通过其对Toll样受体4/核因子-kappa B和Smad2/3信号通路的抑制作用，并可能是其原始上游 MI 早期阶段的 AF 治疗。
Background-Inflammation and fibrosis play an important role in the pathogenesis of atrial fibrillation (AF) after myocardial infarction (MI). CTRP9 (C1q/tumor necrosis factor-related protein-9) as a secreted glycoprotein can reverse left ventricle remodeling post-MI, but its effects on MI-induced atrial inflammation, fibrosis, and associated AF are unknown.Methods and Results-MI model rats received adenoviral supplementation of CTRP9 (Ad-CTRP9) by jugular-vein injection. Cardiac function, inflammatory, and fibrotic indexes and related signaling pathways, electrophysiological properties, and AF inducibility of atria in vivo and ex vivo were detected in 3 or 7 days after MI. shCTRP9 (short hairpin CTRP9) and shRNA were injected into rat and performed similar detection at day 5 or 10. Adverse atrial inflammation and fibrosis, cardiac dysfunction were induced in both MI and Ad-GFP (adenovirus-encoding green fluorescent protein)+MI rats. Systemic CTRP9 treatment improved cardiac dysfunction post-MI. CTRP9 markedly ameliorated macrophage infiltration and attenuated the inflammatory responses by downregulating interleukin-1b and interleukin-6, and upregulating interleukin-10, in 3 days post-MI; depressed left atrial fibrosis by decreasing the expressions of collagen types I and III, alpha-SMA, and transforming growth factor beta 1 in 7 days post-MI possibly through depressing the Toll-like receptor 4/nuclear factor-kappa B and Smad2/3 signaling pathways. Electrophysiologic recordings showed that increased AF inducibility and duration, and prolongation of interatrial conduction time induced by MI were attenuated by CTRP9; moreover, CTRP9 was negatively correlated with interleukin-1b and AF duration. Downregulation of CTRP9 aggravated atrial inflammation, fibrosis, susceptibility of AF and prolonged interatrial conduction time, without affecting cardiac function.Conclusions-CTRP9 is effective at attenuating atrial inflammation and fibrosis, possibly via its inhibitory effects on the Toll-like receptor 4/nuclear factor-kappa B and Smad2/3 signaling pathways, and may be an original upstream therapy for AF in early phase of MI.