Integrated miRNA-mRNA networks underlie attenuation of chronic β-adrenergic stimulation-induced cardiac remodeling by minocycline

• Published in: Physiological genomics 2024-04, Vol.56 (4), p.360-366
• Main Authors: Russell, Jacob J, Mummidi, Srinivas, DeMarco, Vincent G, Grisanti, Laurel A, Bailey, Chastidy A, Bender, Shawn B, Chandrasekar, Bysani
• Format: Article
• Language: English
• Subjects: Activating transcription factor 3; Adrenergic receptors; Congestive heart failure; Fibrosis; Gene expression; Heart failure; Hypertrophy; Isoproterenol; MicroRNAs; Minocycline; miRNA; Sympathetic nervous system; Transcriptomes
• ISSN: 1094-8341; 1531-2267; 1531-2267
• DOI: 10.1152/physiolgenomics.00140.2023

Adverse cardiac remodeling contributes to heart failure development and progression, partly due to inappropriate sympathetic nervous system activation. Although β-adrenergic receptor (β-AR) blockade is a common heart failure therapy, not all patients respond, prompting exploration of alternative treatments. Minocycline, an FDA-approved antibiotic, has pleiotropic properties beyond antimicrobial action. Recent evidence suggests it may alter gene expression via changes in miRNA expression. Thus, we hypothesized that minocycline could prevent adverse cardiac remodeling induced by the β-AR agonist isoproterenol, involving miRNA-mRNA transcriptome alterations. Male C57BL/6J mice received isoproterenol (30 mg/kg/day sc) or vehicle via osmotic minipump for 21 days, along with daily minocycline (50 mg/kg ip) or sterile saline. Isoproterenol induced cardiac hypertrophy without altering cardiac function, which minocycline prevented. Total mRNA sequencing revealed isoproterenol altering gene networks associated with inflammation and metabolism, with fibrosis activation predicted by integrated miRNA-mRNA sequencing, involving miR-21, miR-30a, miR-34a, miR-92a, and miR-150, among others. Conversely, the cardiac miRNA-mRNA transcriptome predicted fibrosis inhibition in minocycline-treated mice, involving antifibrotic shifts in Atf3 and Itgb6 gene expression associated with miR-194 upregulation. Picrosirius red staining confirmed isoproterenol-induced cardiac fibrosis, prevented by minocycline. These results demonstrate minocycline's therapeutic potential in attenuating adverse cardiac remodeling through miRNA-mRNA-dependent mechanisms, especially in reducing cardiac fibrosis. We demonstrate that minocycline treatment prevents cardiac hypertrophy and fibrotic remodeling induced by chronic β-adrenergic stimulation by inducing antifibrotic shifts in the cardiac miRNA-mRNA transcriptome.