Activation of AHR by ITE improves cardiac remodelling and function in rats after myocardial infarction

Abstract

AimsLeft 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.Methods and resultsMI 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.ConclusionsThe AHR agonist ITE alleviates cardiomyocyte apoptosis through the Akt/p70S6K signalling pathway, thereby rescuing left ventricular adverse remodelling and cardiac dysfunction after MI.

Computer‐aided discovery of novel aryl hydrocarbon receptor ligands to regulate CYP1A1 expression in inflammatory macrophages

“…In addition, some studies have shown that downregulation of p70S6K can inhibit apoptosis (Oeing et al., 2021). ITE may down‐regulate the phosphorylation of AKT/P70S6K signaling pathway by activating AhR receptor, thereby reducing cardiomyocyte apoptosis (Lin et al., 2023). In combination with these studies, AE‐411/41415610 may have a role in the AKT‐p70S6K pathway in apoptosis, but this requires further experiments.…”

Inhibition of tartrate-resistant acid phosphatase 5 can prevent cardiac fibrosis after myocardial infarction

“…In patients with MI, excessive remodeling of myocardial fibers can initiate a chain of events leading to myocardial fibrosis and heart failure (Zhang et al 2023 ). Current clinical use of drugs, such as angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and aldosterone antagonists, is hampered by side effects, such as hypotension and bradycardia (Lin et al 2023 ). Therefore, there is an urgent need to study the potential mechanism of myocardial fibrosis after MI and to identify new pharmacological targets to intervene in or delay the process of cardiac fibrosis.…”

Modulation of anti-cardiac fibrosis immune responses by changing M2 macrophages into M1 macrophages

“…The excessive production of reactive oxygen species further exacerbates cardiomyocyte damage and apoptosis. The AHR agonist ITE mitigates cardiomyocyte apoptosis by activating the Akt/p70S6K signaling pathway, thereby attenuating left ventricular remodeling and improving cardiac dysfunction following myocardial infarction (Lin et al 2023 ). Our findings demonstrate that NaW enhances glucose uptake by cardiomyocytes and activates the pentose phosphate pathway (PPP) for NADPH production (Supplementary Fig.…”