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Changes in the cardiac transcriptome following isoproterenol infusion and coadministration of minocycline

ABSTRACT: Adverse cardiac remodeling contributes to the development and progression of heart failure (HF) driven, in part, by inappropriate sympathetic nervous system activation. While blockade of β-adrenergic receptors (β-AR) is a common therapeutic strategy in HF, not all patients respond necessitating elucidation of additional therapeutic approaches. Minocycline is an FDA-approved antibiotic with pleiotropic properties, independent of its antimicrobial action, and recent evidence suggests it may act by altering gene expression via changes in miRNA expression. Therefore, we hypothesized that minocycline would prevent adverse cardiac remodeling induced by the β-AR agonist isoproterenol involving relevant alterations in the miRNA-mRNA transcriptome. Male C57BL/6J mice received Iso (30 mg/kg/d, sc) or vehicle for 21 days via osmotic minipump and daily treatment with either minocycline (50 mg/kg, ip) or sterile saline. Isoproterenol infusion induced cardiac hypertrophy, with no change in cardiac function, that was prevented by minocycline. Total mRNA sequencing revealed that isoproterenol altered gene networks associated with inflammation and metabolism while activation of fibrosis was predicted by integrated miRNA-mRNA sequencing, involving miR-21, -30a, -34a, -92a, and -150, among others. Conversely, the cardiac miRNA-mRNA transcriptome predicted inhibition of fibrosis in hearts from mice treated with minocycline plus isoproterenol involving anti-fibrotic shifts in Atf3 and Itgb6 gene expression associated with upregulation of miR-194. Consistent with these gene signatures, picrosirius red staining confirmed isoproterenol-induced cardiac fibrosis and that this was prevented by minocycline. These results demonstrate the therapeutic potential of minocycline to attenuate adverse cardiac remodeling via miRNA-mRNA-dependent mechanisms, especially related to reduced cardiac fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE255532 | GEO | 2024/02/15

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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Changes in the cardiac transcriptome following isoproterenol infusion and coadministration of minocycline

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