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Effect of depletion of Endothelial Cell STING in response to pressure overload induced heart failure

ABSTRACT: Capillary rarefaction and cardiomyocyte (CM) hypertrophy are hallmarks of the complex syndrome of heart failure (HF), a leading cause of hospitalization and death. Molecular signals within and between cellular components of the heart have emerged as central hubs that modulate cardiac pathophysiology. Here, we discovered that the Stimulator of Interferon Genes (STING) is highly expressed in human and mouse cardiac endothelial cells (EC) and is activated in the onset of HF. Using global and inducible EC-specific STING-/- mice, we report that EC STING is required for contractile dysfunction in an experimental model of HF induced by transverse aortic constriction (TAC), through the regulation of CM hypertrophy and capillary rarefaction. We report that ECs sorted from TAC EC-STING-/- mice are enriched in gene sets related to integrin and cell adhesion pathways to extracellular matrix (ECM) compared to controls and have decreased expression of the pro-hypertrophic gene IL-6. CellChat analysis of human cardiac cells from patients with non-ischemic cardiomyopathy revealed EC-CM communication, and mechanistically, we found that STING activation induces IL-6 secretion, and that EC derived IL-6 is necessary to induce pro-hypertrophic gene expression in CMs in a STING dependent manner. Our study demonstrates a novel role for STING in ECs contributing to hypertrophy and contractile dysfunction in experimental HF.

ORGANISM(S): Mus musculus

PROVIDER: GSE296709 | GEO | 2025/06/12

REPOSITORIES: GEO

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Project description:BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles (EVs) including small EVs, or exosomes and their molecular cargo are known to modulate cell to cell communication during multiple cardiac diseases. However, the role of systemic EV biogenesis inhibition in the models of HF is not well documented and remains unclear. METHODS: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of Tipifarnib (Tip), a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a, nSmase2 and Alix) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery, were randomly assigned to groups with and without Tip treatment (10 mg/kg three times/week) and monitored for 8 weeks and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. RESULTS: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular (LV) dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced LV dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of Tip in TAC mice reduced circulating exosomes to baseline and remarkably improved LV functions, hypertrophy, and fibrosis. Tip treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR331-5p which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR331-5p is crucial for inhibiting fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR331-5p that acts as potent repressor for one of the fibrotic mechanisms mediated by HOXC8. CONCLUSIONS: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling to HF.

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Effect of depletion of Endothelial Cell STING in response to pressure overload induced heart failure

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