MiR-208b-3p is an upstream regulator of redox-associated cardiomyocyte survival

Background Cardiac stress induces MYH6 -to- MYH7 remodeling and activates redox-defense programs, but the regulatory mechanisms that distinguish adaptive from maladaptive stress responses remain incompletely defined. We investigated the role of miR-208b-3p, an intronic MYH7 microRNA, in cardiac stress adaptation. Methods and Results We integrated myocardial transcriptomic and small RNA sequencing from stress-adapted Mlp −/− mice and human cardiomyopathy to identify stress-adaptive programs associated with preserved myocardial viability and complemented these analyses with in vivo miR-208b-3p inhibition and cellular gain-of-function experiments. Mlp −/− hearts exhibited marked Myh7 induction accompanied by an ≈20-fold increase in miR-208b-3p, whereas this coordinated response was blunted in human end-stage dilated and ischemic cardiomyopathies. In vivo inhibition of miR-208b-3p selectively reduced Myh7 , without altering Myh6 or baseline cardiac function. This reduction in Myh7 occurred without induction of established Myh7 transcriptional repressors, and miR-208b-3p gain-of-function similarly reduced MYH7 while suppressing several canonical repressors, indicating that its relationship with MYH7 extends beyond the established repressor pathway. miR-208b-3p inhibition activated oxidative stress, NRF2, autophagy, and cell-survival pathways. Oxidative stress transiently suppressed miR-208b-3p, with rebound induction after stress removal, whereas antioxidant treatment increased its expression. Pharmacological NRF2 activation did not alter miR-208b-3p, whereas miR-208b-3p gain-of-function reduced oxidative stress-associated apoptotic signaling and suppressed ATM, a predicted target and regulator of cellular stress responses, supporting an upstream role for miR-208b-3p in stress adaptation. Conclusions MiR-208b-3p is a dynamic component of cardiac stress adaptation that links myosin remodeling with redox and survival responses. Its regulation of ATM and association with NRF2-related stress responses support an upstream role in coordinating cellular adaptation to cardiac stress.