Minocycline Blunts Isoproterenol‐Induced Cardiac Hypertrophy

Abstract

IntroductionExcess and chronic activation of the sympathetic nervous system often results in progressive adverse remodeling and heart failure development. Here we investigated whether chronic administration of isoproterenol (Iso), a β‐AR agonist, would promote hypertrophy, fibrosis, and dysfunction, and whether these maladaptive changes are prevented by minocycline, an FDA‐approved antibiotic, that has been shown to have cardioprotective effects outside of its antibacterial properties.MethodsWild‐type male C57BL/6J mice were subcutaneously implanted with osmotic minipumps, delivering either 30 mg/kg body weight per day of isoproterenol, or vehicle control. Following pump implantation, mice received daily intraperitoneal (I.P.) injections of either sterile saline or 50 mg/kg of minocycline. After 21 days, cardiac function was assessed by echocardiography, and hearts were collected for further analysis. A transverse slice of the ventricles was fixed for histology, and a portion of the left ventricle was used for RNA isolation, and mRNA and miRNA sequencing.ResultsEchocardiography revealed that isoproterenol increased heart rate, heart weight (hypertrophy), ejection fraction and fractional shortening, without leading to significant changes in fibrosis. Minocycline prevented the hypertrophic remodeling and changes in systolic function without affecting heart rate. While mRNA sequencing revealed that isoproterenol enriched gene networks associated with changes in inflammation, the miRNA sequencing showed that minocycline enhanced miR‐26b expression, which is reported to suppress GATA4‐mediated hypertrophy.ConclusionMinocycline mitigates isoproterenol‐induced cardiac hypertrophy while preserving contractility, as well as induces changes in RNA and miRNA pathways involved with inflammation and cardiac remodeling