Abstract-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. (Hypertension. 2017;69:249-258.

We used a bovine brain cDNA library to perform a yeast two-hybrid assay with bovine mature PrP C as bait. The screening result showed that aB-crystalline interacted with PrP C . The interaction was further evaluated both in vivo and in vitro with different methods, such as immunofluorescent colocalization, native polyacrylamide-gel electrophoresis, and IAsys biosensor assays. The results suggested that aB-crystalline may have the ability to refold denatured prion proteins, and provided first evidence that aB-crystalline is directly associated with prion protein.

BackgroundMaladaptive cardiac hypertrophy is a major risk factor for heart failure, which is the leading cause of death worldwide. C‐C motif chemokine receptor 9 (CCR9), a subfamily of the G protein–coupled receptor supergene family, has been highlighted as an immunologic regulator in the development and homing of immune cells and in immune‐related diseases. Recently, CCR9 was found to be involved in the pathogenesis of other diseases such as cardiovascular diseases; however, the effects that CCR9 exerts in cardiac hypertrophy remain elusive.Methods and ResultsWe observed significantly increased CCR9 protein levels in failing human hearts and in a mouse or cardiomyocyte hypertrophy model. In loss‐ and gain‐of‐function experiments, we found that pressure overload–induced hypertrophy was greatly attenuated by CCR9 deficiency in cardiac‐specific CCR9 knockout mice, whereas CCR9 overexpression in cardiac‐specific transgenic mice strikingly enhanced cardiac hypertrophy. The prohypertrophic effects of CCR9 were also tested in vitro, and a similar phenomenon was observed. Consequently, we identified a causal role for CCR9 in pathological cardiac hypertrophy. Mechanistically, we revealed a lack of difference in the expression levels of mitogen‐activated protein kinases between groups, whereas the phosphorylation of AKT/protein kinase B and downstream effectors significantly decreased in CCR9 knockout mice and increased in CCR9 transgenic mice after aortic binding surgery.ConclusionsThe prohypertrophic effects of CCR9 were not attributable to the mitogen‐activated protein kinase signaling pathway but rather to the AKT–mammalian target of rapamycin–glycogen synthase kinase 3β signaling cascade.

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