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Tectochrysin alleviates Ang II-induced pathological cardiac hypertrophy by binding to STING and inhibiting STING/NFκB-mediated inflammation

ABSTRACT: Angiotensin II (Ang II)-induced cardiac inflammation plays a pivotal role in the pathogenesis of pathological cardiac hypertrophy and hypertension-related heart failure. Tectochrysin (Tec) is a flavonoid natural compound exhibiting significant anti-inflammatory activity. However, the role of Tec in hypertensive heart failure and its molecular targets remain unclear. The therapeutic efficacy of Tec was assessed in the Ang II-induced mouse model using echocardiography, histopathological staining, and serological tests. Its anti-hypertrophic effect was further examined in vitro by phalloidin staining. Investigate the mechanism of action of Tec through transcriptome sequencing. The interaction of Tec with STING was detected by DARTS, CETSA, and SPR assays. Western blotting assay detected the effect of Tec on Ang II-induced activation of the STING/NFκB pathway. The functional dependency of Tec on STING was demonstrated using the STING inhibitor H151. In vivo experiments confirmed that Tec alleviates Ang II-induced myocardial inflammation, pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Further in vitro studies revealed the efficacy of Tec in inhibiting cardiomyocyte hypertrophy. Mechanistically, Tec significantly suppressed Ang II-induced activation of the STING/NFκB signalling pathway by targeting STING. Crucially, administration of the STING inhibitor H151 alleviates pathological myocardial hypertrophy, however its use diminishes the therapeutic effect of Tec. Our findings confirmed STING as a critical therapeutic target in pathological ventricular remodeling, with Tec exerting its anti-hypertrophic effects through STING inhibition.

ORGANISM(S): Mus musculus

PROVIDER: GSE327509 | GEO | 2026/04/20

REPOSITORIES: GEO

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Project description:Hypertension-mediated left ventricular hypertrophy and cardiac fibrosis often precede heart failure. Recent studies indicate that cytoglobin (Cygb), a globin expressed in the vasculature, increases systemic blood pressure. The present work aims to determine the role of Cygb in angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis in the mouse. Methods: Males and females global Cygb knockout (Cygb−/−), and wildtype (Cygb+/+) mice were treated with Ang II (1.5 µg/kg/day) for two weeks via subcutaneous osmotic minipumps. Cardiac function was assessed through echocardiography, and hearts were analyzed for changes in hypertrophy, fibrosis, and gene expression. Functional studies were also performed in isolated cardiac fibroblasts. Results: Cygb−/− mice from both sexes showed an increase in cardiac hypertrophy over Cygb+/+ mice. Cardiac functions were also depressed in Cygb−/− males with no changes in females. Importantly, genetic deletion of Cygb did not affect systemic blood pressure in mice, at baseline or after Ang II treatment. We established that Cygb was expressed in fibroblasts and pericytes in humans and mice hearts. Finally, we found that Cygb−/− cardiac fibroblast did not upregulate the expression of genes associated with myofibroblasts following treatment with Ang II. This was reversed following expression of human cytoglobin. Conclusions: Our findings indicate that Cygb plays a protective role in the mouse heart during Ang II-induced cardiac stress. This is the first study detailing the function of Cygb in the heart as a regulator of cardiac hypertrophy. This study also reveals a role for Cygb in regulating cardiac fibroblast activation by Ang II. NEW & NOTEWORTHY: We identified cytoglobin as an important globin in cardiac pathophysiology. Genetic deletion of cytoglobin led to exacerbation of angiotensin II-mediated cardiac hypertrophy in the absence of any effect on systemic blood pressure. Cytoglobin is expressed in cardiac fibroblasts and pericytes and is required for cardiac fibroblast activation to myofibroblast. The present study reveals for the first time a role for cytoglobin in regulating angiotensin II signaling.

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Tectochrysin alleviates Ang II-induced pathological cardiac hypertrophy by binding to STING and inhibiting STING/NFκB-mediated inflammation

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