Description: Nebivolol is a selective β1-blocker with nitric oxide–enhancing effects. MicroRNAs are small noncoding RNA molecules that downregulate gene expression. We compared the effects of nebivolol and atenolol, a first generation β1-selective blocker, on left ventricular hypertrophy, fibrosis, and function and microRNA expression in a rodent model of hypertension. Dahl salt-sensitive rats received either low-salt chow (control) or AIN-76A high-salt (8% NaCl) diet and randomized to vehicle (high-salt), nebivolol (20 mg/kg per day), or atenolol (50 mg/kg per day) for 8 weeks. High-salt induced left ventricular hypertrophy and fibrosis and decreased the expression of miR-27a, -29a, and -133a. Nebovolol attenuated deterioration of left ventricular systolic function, remodeling, and fibrosis more than atenolol, despite similar effects on heart rate and blood pressure. Nebivolol, but not atenolol, prevented the decrease in miR-27a and -29a induced by high-salt. Nebivolol and atenolol equally attenuated the decrease in miR-133a. In vitro overexpression of miR-27a,-29a, and -133a inhibited cardiomyocyte hypertrophy and reduced collagen expression. Both miR-27a and -29a target Sp1, and miR-133a targets Cdc42. Pharmacological inhibition of Sp1 and Cdc42 decreased myocardial fibrosis and hypertrophy. Our data support a differential microRNAs expression profile in salt-induced hypertension. Nebivolol substantially attenuated cardiac remodeling, hypertrophy, and fibrosis more than atenolol. These effects are related to attenuation of the hypertension-induced decrease in miR-27a and -29a (with a subsequent decrease in Sp1 expression) and miR-133a (with a subsequent decrease in Cdc42).

Description: Interferon regulatory factor 1 (IRF1), a critical member of the IRF family, was previously shown to be associated with the immune system and to be involved in apoptosis and tumor suppression. However, the role of IRF1 in pressure overload–induced cardiac remodeling has remained unclear. Using genetic approaches, we established a central role for the IRF1 transcription factor in the regulation of cardiac remodeling both in vivo and in vitro, and we determined the mechanism underlying this process. The expression level of IRF1 was remarkably altered in both failing human hearts and hypertrophic murine hearts. Transgenic mice with cardiac-specific IRF1 overexpression exacerbated aortic banding–induced cardiac hypertrophy, ventricular dilation, fibrosis, and dysfunction, whereas IRF1-deficient (knockout) mice exhibited a significant reduction in the hypertrophic response. Similar results were observed in a global IRF1-knockout rat model. Mechanistically, the prohypertrophic effects elicited by IRF1 in response to pathological stimuli were associated with the direct activation of inducible nitric oxide synthase (iNOS). Furthermore, we identified 1 IRF1-binding site in the promoter region of the iNOS gene, which was essential for its transcription. To examine the IRF1-iNOS axis in vivo, we generated IRF1-transgenic/iNOS-knockout mice. IRF1 exerted profoundly detrimental effects in these mice; however, these effects were nullified by iNOS ablation. These data suggest the IRF1–iNOS axis as a crucial regulator of cardiac remodeling and that IRF1 could be a potent therapeutic target for cardiac remodeling.