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Cardiac hypertrophy occurs in response to numerous stimuli like neurohumoral stress, pressure overload, infection, and injury, and leads to heart failure. Mfge8 (milk fat globule-EGF factor 8) is a secreted protein involved in various human diseases, but its regulation and function during cardiac hypertrophy remain unexplored. Here, we found that circulating MFGE8 levels declined significantly in failing hearts from patients with dilated cardiomyopathy. Correlation analyses revealed that circulating MFGE8 levels were negatively correlated with the severity of cardiac dysfunction and remodeling in affected patients. Deleting Mfge8 in mice maintained normal heart function at basal level but substantially exacerbated the hypertrophic enlargement of cardiomyocytes, reprogramming of pathological genes, contractile dysfunction, and myocardial fibrosis after aortic banding surgery. In contrast, cardiac-specific Mfge8 overexpression in transgenic mice significantly blunted aortic banding-induced cardiac hypertrophy. Whereas MAPK (mitogen-activated protein kinase) pathways were unaffected in either Mfge8-knockout or Mfge8-overexpressing mice, the activated Akt/PKB (protein kinase B)-Gsk-3β (glycogen synthase kinase-3β)/mTOR (mammalian target of rapamycin) pathway after aortic banding was significantly potentiated by Mfge8 deficiency but suppressed by Mfge8 overexpression. Inhibition of Akt with MK-2206 blocked the prohypertrophic effects of Mfge8 deficiency in angiotensin II-treated neonatal rat cardiomyocytes. Finally, administering a recombinant human MFGE8 in mice in vivo alleviated cardiac hypertrophy induced by aortic banding. Our findings indicate that Mfge8 is an endogenous negative regulator of pathological cardiac hypertrophy and may, thus, have potential both as a novel biomarker and as a therapeutic target for treatment of cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

The transcription factor NFAT1 (nuclear factor of activated T-cells 1), with the aid of transcriptional coactivators, has been recognized for its necessity and sufficiency to drive pathological cardiac hypertrophy. However, how the transcriptional activity of NFAT1 in terms of cardiac hypertrophy is controlled at the transcriptional level has not been well defined. Herein, we showed that a cardiac-enriched protein IRF2BP2 (interferon regulatory factor-2 binding protein 2) was further upregulated in both human and mouse hypertrophied myocardium and negatively regulated cardiomyocyte hypertrophic response in vitro. By generating cardiomyocyte-specific Irf2bp2 knockout and Irf2bp2-transgenic mouse strains, our in vivo experiments showed that, whereas IRF2BP2 loss-of-function exacerbated both aortic banding- and angiotensin II infusion-induced cardiac hypertrophic response, IRF2BP2 overexpression exerted a strong protective effect against these maladaptive processes. Particularly, IRF2BP2 directly interacted with the C-terminal transactivation domain of NFAT1 by competing with myocyte enhancer factor-2C and disturbing their transcriptional synergism, thereby impeding NFAT1-transactivated hypertrophic transcriptome. As a result, the devastating effect of Irf2bp2 deficiency on cardiac hypertrophy was largely rescued by NFAT1 blockage. Our study, thus, defined IRF2BP2 as a novel negative regulator in controlling pathological cardiac hypertrophy at the transcriptional level. [ABSTRACT FROM AUTHOR]

Tripartite motif (TRIM) 8 functions as an E3 ubiquitin ligase, interacting with and ubiquitinating diverse substrates, and is implicated in various pathological processes. However, the function of TRIM8 in the heart remains largely uncharacterized. This study aims to explore the role of TRIM8 in the development of pathological cardiac hypertrophy. Mice and isolated neonatal rat cardiomyocytes overexpressing or lacking TRIM8 were examined in several experiments. The effect of aortic banding-induced cardiac hypertrophy was analyzed by echocardiographic, pathological and molecular analyses. Our results indicated that the TRIM8 overexpression in hearts exacerbated the cardiac hypertrophy triggered by aortic banding. In contrast, the development of pathological cardiac hypertrophy was profoundly blocked in TRIM8-deficient hearts. Mechanistically, our study suggests that TRIM8 may elicit cardiodetrimental effects by promoting the activation of transforming growth factor β-activated kinase 1 (TAK1)-p38/JNK signaling pathways. Similar results were observed in cultured neonatal rat cardiomyocytes treated with angiotensin II. The rescue experiments using the TAK1-specific inhibitor 5z-7-ox confirmed the requirement of TAK1 activation in TRIM8-mediated pathological cardiac hypertrophy. Furthermore, TRIM8 contributed to TAK1 activation by binding to and promoting TAK1 ubiquitination. In conclusion, our study demonstrates that TRIM8 plays a deleterious role in pressure overload-induced cardiac hypertrophy by accelerating the activation of TAK1-dependent signaling pathways. [ABSTRACT FROM AUTHOR]

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