Abstract Fri171: MiRNA-181a-mediated Downregulation of GRK2 as a Potential Therapeutic Strategy for Heart Failure

Background: G protein-coupled receptor kinase 2 (GRK2) is a key regulator of β-adrenergic receptor (β-AR) signaling and a promising therapeutic target for heart failure (HF). Pathological upregulation of GRK2 following cardiac injury contributes to β-AR desensitization and impaired cardiac function. Recent evidence suggests that miR-181a can target GRK2 expression in cardiomyocytes, however, the functional consequences of increasing miR-181a expression in the heart on GRK2 regulation remain unclear. We hypothesize that miR-181a overexpression can reduce GRK2 expression in cardiomyocytes, mitigating its maladaptive responses to stress. Methods&Results: Neonatal rat ventricular myocytes (NRVMs) were transfected with miR-181a mimic, scrambled control, or Kaposi sarcoma-associated herpesvirus (KSHV) miR-K12-3 (miR-K12) mimic. MiR-K12 is a miRNA known to directly target GRK2 to promote endothelial cell migration and invasion and was included as a positive control. After transfection, cells were stimulated with isoproterenol (ISO) to induce β-AR signaling. Prolonged ISO treatment increased GRK2 levels in control and scrambled miRNA groups, whereas miR-181a overexpression significantly attenuated this response (p<0.05). Additionally, ISO-induced upregulation of hypertrophic markers was significantly reduced with miR-181a overexpression (p<0.05). Conclusion: miR-181a overexpression reduces ISO-induced upregulation of GRK2 and hypertrophic markers in cardiomyocytes, suggesting a protective role in GRK2-mediated β-AR signaling and pathological remodeling. Ongoing studies aim to elucidate the molecular mechanisms underlying this regulation. In vivo studies utilizing AAV-mediated miR-181a delivery in a transverse aortic constriction (TAC) model, along with in vivo hemodynamic assessments, will further evaluate its therapeutic potential in HF.