Interferon Regulatory Factor 1 Is Required for Cardiac Remodeling in Response to Pressure Overload

Abstract

Abstract-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

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

“…79 The ablation of iNOS largely abolished this exacerbation of cardiac remodeling in IRF1-TG mice, suggesting that the prohypertrophic regulation of IRF1 depends on the activation of iNOS. 79 A microarray-based miRNA screening assay reported by Li et al 158 indicated that a increased risk of hypertension was closely correlated with the plasma expression of hcmvmiR-UL112, a direct target of which is IRF1. Thus, IRF1 might be implicated in hypertension development.…”

“…Consistently, reduced IRF1 expression was observed in mice subjected to pressure overload-induced severe cardiac hypertrophy. 79 A loss-of-function experiment indicated that reduced IRF1 expression is associated with the retardation of AB-induced cardiac hypertrophy, whereas the cardiac-specific overexpression of IRF1 leads to accelerated hypertrophic response of ventricular dilation and cardiac dysfunction caused by the direct activation of iNOS. 79 The ablation of iNOS largely abolished this exacerbation of cardiac remodeling in IRF1-TG mice, suggesting that the prohypertrophic regulation of IRF1 depends on the activation of iNOS.…”

“…79 A loss-of-function experiment indicated that reduced IRF1 expression is associated with the retardation of AB-induced cardiac hypertrophy, whereas the cardiac-specific overexpression of IRF1 leads to accelerated hypertrophic response of ventricular dilation and cardiac dysfunction caused by the direct activation of iNOS. 79 The ablation of iNOS largely abolished this exacerbation of cardiac remodeling in IRF1-TG mice, suggesting that the prohypertrophic regulation of IRF1 depends on the activation of iNOS. 79 A microarray-based miRNA screening assay reported by Li et al 158 indicated that a increased risk of hypertension was closely correlated with the plasma expression of hcmvmiR-UL112, a direct target of which is IRF1.…”

Hesperetin protects against inflammatory response and cardiac fibrosis in postmyocardial infarction mice by inhibiting nuclear factor κB signaling pathway

“…Picrosirius red (PSR) staining for collagen deposition was performed as described previously (13)(14)(15)(16). In brief, hearts were fixed in 10% formalin after being excised from anesthetized mice.…”

Regulator of G-Protein Signaling 10 Negatively Regulates Cardiac Remodeling by Blocking Mitogen-Activated Protein Kinase–Extracellular Signal-Regulated Protein Kinase 1/2 Signaling

“…21,22 Briefly, the transgene vector of pCAG-loxP-CATloxP-RGS10 was constructed by replacing the lacZ gene in pCAGloxP-CAT-loxP-lacZ with the cDNA of full-length mouse RGS10. The construct was linearized and purified using the QIAquick Gel Extraction Kit (Qiagen, 28704), and was then used for pronuclear microinjection.…”