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.

Cathepsin B (CTSB), a member of the lysosomal cathepsin family that is expressed in both murine and human hearts, was previously shown to participate in apoptosis, autophagy, and the progression of certain types of cancers. Recently, CTSB has been linked to myocardial infarction. Given that cathepsin L, another member of the lysosomal cathepsin family, ameliorates pathological cardiac hypertrophy, we hypothesized that CTSB plays a role in pressure overload-induced cardiac remodeling. Here we report that CTSB was upregulated in cardiomyocytes in response to hypertrophic stimuli both in vivo and in vitro. Moreover, knockout of CTSB attenuated pressure overload-induced cardiac hypertrophy, fibrosis, dysfunction, and apoptosis. Furthermore, the aortic banding-induced activation of TNF-α, apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinases (JNK), c-Jun, and release of cytochrome c was blunted by CTSB deficiency, which was further confirmed in in vitro studies induced by angiotensin II. In cardiomyocytes pretreatment with SP600125, a JNK inhibitor, suppressed the cardiomyocytes hypertrophy by inhibiting the ASK1/JNK pathway. Altogether, these data indicate that the CTSB protein functions as a necessary modulator of hypertrophic response by regulating TNF-α/ASK1/JNK signaling pathway involved in cardiac remodeling.

The present study demonstrates for the first time that mindin serves as a novel mediator that protects against cardiac hypertrophy and the transition to heart failure by blocking AKT/GSK3β and TGF-β1-Smad signalling.