Department of Echocardiology, Fujian Institute of Hypertension, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Department of Echocardiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
ESC Heart Fail. 2023 Dec;10(6):3622-3636. doi: 10.1002/ehf2.14532. Epub 2023 Oct 5.
Left ventricular remodelling subsequent to myocardial infarction (MI) constitutes a pivotal underlying cause of heart failure. Intervention with the nontoxic endogenous aryl hydrocarbon receptor (AHR) agonist 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) in the acute phase of MI has been shown to ameliorate cardiac function, but its role in the chronic phase remains obscured. This study explores the beneficial role of ITE in delaying the progression of heart failure in the chronic phase of MI.
MI rats established by ligating the left anterior descending coronary artery were treated with the indicated concentration of the AHR agonist ITE or vehicle alone. Echocardiography was performed to determine cardiac structure and function; myocardial morphology and fibrosis were observed by haematoxylin and eosin and Masson's trichrome staining; serum biochemical indices, BNP, and inflammatory cytokine levels were detected by enzyme-linked immunosorbent assay; F4/80 iNOS M1 macrophages and F4/80 CD206 M2 macrophages were detected by immunofluorescence; the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay was used to detect the apoptosis of cardiomyocytes; ultrastructural changes in myocardial tissue were observed by transmission electron microscopy; and Cyp1a1, Akt, P-Akt, p70S6K, P-p70S6K, Bcl-2, Bax, caspase-3, and cleaved caspase-3 protein levels were determined via Western blotting. We found that therapy with the AHR agonist ITE rescued cardiac remodelling and dysfunction in rats with MI and attenuated myocardial fibrosis, inflammation, and mitochondrial damage. Further studies confirmed that ITE dose-dependently improved myocardial cell apoptosis after MI, as demonstrated by reduced levels of the apoptosis-related proteins cleaved caspase-3 and Bax but increased expression levels of Bcl-2. These effects were attributed to ITE-induced activation of AHR receptors, leading to the down-regulation of Akt and p70S6K phosphorylation.
The AHR agonist ITE alleviates cardiomyocyte apoptosis through the Akt/p70S6K signalling pathway, thereby rescuing left ventricular adverse remodelling and cardiac dysfunction after MI.
心肌梗死后的左心室重构是心力衰竭的主要潜在原因。在心肌梗死后的急性期，干预非毒性内源性芳烃受体（AHR）激动剂 2-（1'H-吲哚-3'-羰基）-噻唑-4-羧酸甲酯（ITE）已被证明可以改善心功能，但它在慢性期的作用仍不清楚。本研究探讨了 ITE 在延迟心肌梗死后慢性期心力衰竭进展中的有益作用。
结扎左前降支冠状动脉建立心肌梗死大鼠模型，用指定浓度的 AHR 激动剂 ITE 或单独载体处理。通过超声心动图测定心脏结构和功能；通过苏木精和伊红及 Masson 三色染色观察心肌形态和纤维化；通过酶联免疫吸附试验检测血清生化指标、BNP 和炎症细胞因子水平；通过免疫荧光检测 F4/80 iNOS M1 巨噬细胞和 F4/80 CD206 M2 巨噬细胞；通过末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记法检测心肌细胞凋亡；通过透射电子显微镜观察心肌组织超微结构变化；通过 Western blot 检测 Cyp1a1、Akt、P-Akt、p70S6K、P-p70S6K、Bcl-2、Bax、caspase-3 和 cleaved caspase-3 蛋白水平。我们发现，AHR 激动剂 ITE 治疗可挽救心肌梗死后大鼠的心脏重构和功能障碍，并减轻心肌纤维化、炎症和线粒体损伤。进一步的研究证实，ITE 剂量依赖性地改善心肌梗死后的心肌细胞凋亡，表现为凋亡相关蛋白 cleaved caspase-3 和 Bax 水平降低，而 Bcl-2 表达水平升高。这些作用归因于 ITE 诱导的 AHR 受体激活，导致 Akt 和 p70S6K 磷酸化下调。
AHR 激动剂 ITE 通过 Akt/p70S6K 信号通路减轻心肌细胞凋亡，从而挽救心肌梗死后的左心室不良重构和心功能障碍。
