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

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 ß-adrenergic receptors (ß-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 ß-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. Overall design: 12 week old C57BL6J mice received isoproterenol (30 mg/kg/day body weight) or sterile saline via osmotic pump. Mice also received daily IP injections of minocycline (50 mg/kg/body) or sterile saline. After 21 days, mice were echoed and cardiac tissue collected for sequencing.