BRD4770 inhibits vascular smooth muscle cell proliferation via SUV39H2, but not EHMT2 to protect against neointima formation.

The behavior of vascular smooth muscle cells (VSMCs) contributes to the formation of neointima. We previously found that EHMT2 suppressed autophagy activation in VSMCs. BRD4770, an inhibitor of EHMT2/G9a, plays a critical role in several kinds of cancers. However, whether and how BRD4770 regulates the behavior of VSMCs remain unknown. In this study, we evaluate the cellular effect of BRD4770 on VSMCs by series of experiments in vivo and ex vivo. We demonstrated that BRD4770 inhibited VSMCs' growth by blockage in G2/M phase in VSMCs. Moreover, our results demonstrated that the inhibition of proliferation was independent on autophagy or EHMT2 suppression which we previous reported. Mechanistically, BRD4770 exhibited an off-target effect from EHMT2 and our further study reveal that the proliferation inhibitory effect by BRD4770 was associated with suppressing on SUV39H2/KTM1B. In vivo, BRD4770 was also verified to rescue VIH. Thus, BRD4770 function as a crucial negative regulator of VSMC proliferation via SUV39H2 and G2/M cell cycle arrest and BRD4770 could be a molecule for the therapy of vascular restenosis.

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation.

Although EHMT2 (also known as G9a) plays a critical role in several kinds of cancers and cardiac remodeling, its function in vascular smooth muscle cells (VSMCs) remains unknown. In the present study, we revealed a novel function of EHMT2 in regulating autophagic cell death (ACD) of VSMC. Inhibition of EHMT2 by BIX01294 or knockdown of EHMT2 resulted in reduced VSMC numbers which were independent of proliferation and apoptosis. Interestingly, EHMT2 protein levels were significantly decreased in VSMCs treated with autophagic inducers. Moreover, more autophagic vacuoles and accumulated LC3II were detected in VSMCs treated with BIX01294 or lenti-shEHMT2 than their counterparts. Furthermore, we found that EHMT2 inhibited the ACD of VSMCs by suppressing autophagosome formation. Mechanistically, the pro-autophagic effect elicited by EHMT2 inhibition was associated with SQSTM1 and BECN1 overexpression. Moreover, these detrimental effects were largely nullified by SQSTM1 or BECN1 knockdown. More importantly, similar results were observed in primary human aortic VSMCs. Overall, these findings suggest that EHMT2 functions as a crucial negative regulator of ACD via decreasing SQSTM1 or BECN1 expression and that EHMT2 could be a potent therapeutic target for cardiovascular diseases (e.g., aortic dissection).

Melatonin protects circulatory death heart from ischemia/reperfusion injury via the JAK2/STAT3 signalling pathway.

AIMS: The shortage of donor hearts could be alleviated with the use of the allografts from donation after circulatory death (DCD). Here, we evaluated the protective effect of melatonin on myocardial ischemia/reperfusion (MI/R) injury in a DCD heart model after ex vivo perfusion. MAIN METHODS: Donor hearts were harvested from DCD model rats pre-treated with or without melatonin and subjected to 30 min of ex vivo perfusion, followed by transplantation. Tissue samples were obtained at 3, 12, and 24 h after heart transplantation. Myocardial oedema was evaluated based on the water content and wet/dry ratio, while inflammation was examined with hematoxylin & eosin staining. The expression levels of matrix metalloproteinase-9, interleukin-6, and tumour necrosis factor-α were evaluated. Oxidative stress level was determined from the content of malondialdehyde, activities of superoxide dismutase and glutathione peroxidase, and expression of Nrf2, NQO1 and cytochrome-C. Myocardial apoptosis was detected with TUNEL assay and measurement of the expression levels of Bax, Bcl-2, caspase-3, and cleaved caspase-3. The activation of the JAK2/STAT3 signalling pathway was evaluated by determining the levels of p-JAK2 and p-STAT3. KEY FINDINGS: Melatonin pre-treatment protected the heart from MI/R by reducing myocardial oedema and inflammation, attenuating oxidative stress, and decreasing myocardial apoptosis. Furthermore, the JAK2/STAT3 signalling pathway was activated after melatonin treatment during MI/R. The protective effects of melatonin were abolished by AG490. SIGNIFICANCE: Melatonin pre-treatment protected the heart from MI/R in a DCD heart model after ex vivo perfusion. Melatonin exerted cardioprotective effects through the activation of the JAK2/STAT3 signalling pathway.

Design of Helically Double-Leveled Gaps for Stretchable Fiber Strain Sensor with Ultralow Detection Limit, Broad Sensing Range, and High Repeatability.

Flexible strain sensors have attracted extensive attention in electronic skins and health monitoring systems. To date, it remains a great challenge for the development of a multifunctional strain sensor with simultaneous ultralow detection limit, broad sensing range, and high repeatability. In this paper, we report a new carbon nanotube/flexible fiber-shaped strain sensor. The fiber substrate has a novel microstructure where a highly elastic rubber fiber core is tightly wound by a continuous spring-like polypropylene fiber as the shell. Our sensor offers combined sensing performances of ultralow detection limit of 0.01% strain, wide sensing range of 200% strain, and high repeatability of 20 000 cycles by designing double-leveled helical gaps. This strain sensor shows a rapid response time of 70 ms under both stretching and releasing. In addition, it is available for a variety of other deformations such as bending and torsion. Due to the unique fiber structure, it can extend the torsion detection range to 1000 rad m-1. On the basis of the superior sensing performances, our sensor demonstrates to efficiently work for both subtle physiological activities and vigorous human motions. This work provides a general and effective strategy for designing smart wearable devices with high performance.

Acute Type I aortic dissection: a propensity-matched comparison of elephant trunk and arch debranching repairs.

OBJECTIVES: Our goal was to compare the performance of the frozen elephant trunk (FET) and the hybrid aortic arch debranching procedures for acute Type I aortic dissection. METHODS: From January 2013 to December 2015, 168 patients with Type I aortic disease underwent ascending aorta and total aortic arch replacement with FET implantation (the FET group, n = 132) or arch debranching with 1-stage aortic arch exclusion using an endovascular stent in a retrograde manner (the debranching group, n = 36). A propensity score-matched subgroup of 26 pairs was identified. Perioperative data and mid-term follow-up results were assessed. RESULTS: In the FET and the debranching groups, the 30-day mortality rates were 14.4% and 5.6% (P = 0.254) and the incidence of stroke was 5.3% and 5.6% (P > 0.999). Cardiopulmonary bypass time was significantly shortened, and the circulatory arrest was exempted in the debranching group. Cardiopulmonary bypass time was identified as a predictor for 30-day mortality (P = 0.027, odds ratio 1.01). Body mass index ≥ 25 kg/m2 was associated with multiorgan dysfunction syndrome (P = 0.016, odds ratio 3.51). Surgical modality did not significantly affect early outcomes. The 3-year survival rate was 76.1% (95% confidence interval, 63.0-81.9%) in the FET group and 82.5% (95% confidence interval, 65.2-91.8%) in the debranching group (P = 0.330). CONCLUSIONS: The hybrid aortic arch procedure without circulatory arrest can be safely performed on patients with acute Type I aortic dissection. Irrespective of cost-effectiveness, arch debranching was a promising alternative for patients who were unfit for the FET procedure.