Role of Interferon Regulatory Factor 4 in the Regulation of Pathological Cardiac Hypertrophy

Abstract

IRF4, a member of the interferon regulatory factor (IRF) family, was previously shown to be restricted in the immune system and involved in the differentiation of immune cells. However, we interestingly observed that IRF4 was also highly expressed in both human and animal hearts. Given that several transcription factors have been shown to regulate the pathological cardiac hypertrophy, we then ask whether IRF4, as a new transcription factor, plays a critical role in pressure overload–elicited cardiac remodeling. A transgenic mouse model with cardiac-specific overexpression of IRF4 was generated and subjected to an aortic banding for 4 to 8 weeks. Our results demonstrated that overexpression of IRF4 aggravated pressure overload–triggered cardiac hypertrophy, fibrosis, and dysfunction. Conversely, IRF4 knockout mice showed an attenuated hypertrophic response to chronic pressure overload. Mechanistically, we discovered that the expression and activation of cAMP response element–binding protein (CREB) were significantly increased in IRF4-overexpressing hearts, while being greatly reduced in IRF4-KO hearts on aortic banding, compared with control hearts, respectively. Similar results were observed in ex vivo cultured neonatal rat cardiomyocytes on the treatment with angiotensin II. Inactivation of CREB by dominant-negative mutation (dnCREB) offset the IRF4-mediated hypertrophic response in angiotensin II–treated myocytes. Furthermore, we identified that the promoter region of CREB contains 3 IRF4 binding sites. Altogether, these data indicate that IRF4 functions as a necessary modulator of hypertrophic response by activating the transcription of CREB in hearts. Thus, our study suggests that IRF4 might be a novel target for the treatment of pathological cardiac hypertrophy and failure.

Novel Role for Caspase-Activated DNase in the Regulation of Pathological Cardiac Hypertrophy

“…Given that the mitogen-activated protein kinase (MAPK) signaling pathway has been previously shown to play an important role in cardiac hypertrophy, we first examined whether CAD affected the AB-induced MAPK signaling response. 27,28 As expected, we observed that MEK1/2, ERK1/2, c-Jun N-terminal kinase 1/2 (JNK1/2), and p38 were significantly phosphorylated in AB mice. However, the phosphorylation of MEK1/2 and ERK1/2 was almost completely inhibited in the CAD−/− hearts compared with the CAD+/+ hearts, whereas JNK1/2 and p38 were not significantly affected ( Figure 5A).…”

Interferon Regulatory Factor 9 Protects Against Cardiac Hypertrophy by Targeting Myocardin

“…An expanded Methods section is available in the online-only Data Supplement, including Reagents, Animal Models and Procedures, 3,[14][15][16][17] Echocardiography and Hemodynamic Measurements, 14,18,19 Histological Analysis, Cultured NRCMs and Recombinant Adenoviral Vectors, 14,16 Immunofluorescence Analysis, Western Blotting, and Quantitative Real-Time PCR, Plasmid Constructs, 13 Immunoprecipitation and the GST Pull-down Assay, Luciferase Reporter Assays, 20 EMSA, 17,21,22 and Statistical Analysis.…”

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

“…In human and mouse hypertrophic heart samples, the expression of IRF4 is significantly decreased, which is accompanied by the reactivation of fetal genes. 91 In mice carrying an IRF4 gene deletion, pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction were dramatically ameliorated in a manner that depended on the decreased expression and activation of cAMP response element-binding protein, a required activator of the fetal gene program.…”