Yang Hongjie, Shen Xiaoyan, Wang Huibo, Shuai Wei
Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan 430060, Hubei, P.R. of China.
Department of Anesthesiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan 430060, Hubei, P.R. of China.
Europace. 2024 Dec 26;27(1). doi: 10.1093/europace/euaf002.
Ventricular arrhythmias (VAs), which can lead to sudden cardiac death, are the primary cause of mortality in patients with heart failure (HF). However, the precise mechanisms underlying these arrhythmias are not well understood. Recent studies have implicated tumour necrosis factor alpha-induced protein 3-interacting protein 3 (TNIP3) in pathological cardiac hypertrophy. Nevertheless, its role in isoproterenol (ISO)-associated VAs remains elusive.
We overexpressed TNIP3 in the myocardium using an adeno-associated virus 9 system, administered via tail vein injection. C57BL/6 mice received daily subcutaneous injections of ISO for two consecutive weeks to establish an HF model. We performed histopathology and electrophysiological studies to assess ventricular structural remodelling, electrical remodelling, and susceptibility to VAs. Additionally, RNA sequencing (RNA-Seq) and western blot analysis were conducted to elucidate the underlying mechanisms. The expression of TNIP3 was up-regulated following ISO treatment. TNIP3 overexpression significantly reversed ISO-induced cardiac dysfunction, fibrosis, electrical remodelling, and VAs susceptibility. Accordingly, RNA-Seq identifies that the inflammatory response takes an important role in ISO-induced Vas, and TNIP3 overexpression could alleviate ISO-induced cardiac proinflammatory response by promoting M1 to M2 macrophage polarization. Mechanistically, PI3K/Akt/NF-κB signalling is responsible for the protective effect of TNIP3 overexpression on ISO-induced HF. And PI3K/Akt signalling activation offset the protective effect of TNIP3 overexpression on ISO-induced cardiac inflammation and VAs.
The findings of this study highlight the critical role of TNIP3 in ISO-associated cardiac remodelling and VAs, which are induced by the inhibited activation of the PI3K/Akt/NF-κB signalling pathway.
室性心律失常（VAs）可导致心源性猝死，是心力衰竭（HF）患者死亡的主要原因。然而，这些心律失常的确切机制尚不完全清楚。最近的研究表明肿瘤坏死因子α诱导蛋白3相互作用蛋白3（TNIP3）与病理性心肌肥大有关。然而，其在异丙肾上腺素（ISO）相关室性心律失常中的作用仍不清楚。
我们使用腺相关病毒9系统通过尾静脉注射在心肌中过表达TNIP3。C57BL/6小鼠连续两周每天皮下注射ISO以建立HF模型。我们进行了组织病理学和电生理研究，以评估心室结构重塑、电重塑和对室性心律失常的易感性。此外，还进行了RNA测序（RNA-Seq）和蛋白质免疫印迹分析以阐明潜在机制。ISO处理后TNIP3的表达上调。TNIP3过表达显著逆转了ISO诱导的心脏功能障碍、纤维化、电重塑和室性心律失常易感性。因此，RNA-Seq表明炎症反应在ISO诱导的室性心律失常中起重要作用，TNIP3过表达可通过促进M1巨噬细胞向M2巨噬细胞极化来减轻ISO诱导的心脏促炎反应。机制上，PI3K/Akt/NF-κB信号通路负责TNIP3过表达对ISO诱导的HF的保护作用。而PI3K/Akt信号通路的激活抵消了TNIP3过表达对ISO诱导的心脏炎症和室性心律失常的保护作用。
本研究结果突出了TNIP3在ISO相关心脏重塑和室性心律失常中的关键作用，这些作用是由PI3K/Akt/NF-κB信号通路的激活受到抑制所诱导的。
