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.

Effects of neuregulin-1 on autonomic nervous system remodeling post-myocardial infarction in a rat model.

Sympathetic nerve and vagus nerve remodeling play an important part in cardiac function post-myocardial infarction (MI). Increasing evidence indicates that neuregulin-1 (NRG-1) improves cardiac function following heart failure. Since its impact on cardiac function and neural remodeling post-MI is poorly understood, we aimed to investigate the role of NRG-1 in autonomic nervous system remodeling post-MI. Forty-five Sprague-Dawley rats were equally randomized into three groups: sham (with the left anterior descending coronary artery exposed but without ligation), MI (left anterior descending coronary artery ligation), and MI plus NRG-1 (left anterior descending coronary artery ligation followed by intraperitoneal injection of NRG-1 (10 µg/kg, once daily for 7 days)). At 4 weeks after MI, echocardiography was used to detect the rat cardiac function by measuring the left ventricular end-systolic inner diameter, left ventricular diastolic diameter, left ventricular end-systolic volume, left ventricular end-diastolic volume, left ventricular ejection fraction, and left ventricular fractional shortening. mRNA and protein expression levels of tyrosine hydroxylase, growth associated protein-43 (neuronal specific protein), nerve growth factor, choline acetyltransferase (vagus nerve marker), and vesicular acetylcholine transporter (cardiac vagal nerve fiber marker) in ischemic myocardia were detected by real-time PCR and western blot assay to assess autonomous nervous remodeling. After MI, the rat cardiac function deteriorated significantly, and it was significantly improved after NRG-1 injection. Compared with the MI group, mRNA and protein levels of tyrosine hydroxylase and growth associated protein-43, as well as choline acetyltransferase mRNA level significantly decreased in the MI plus NRG-1 group, while mRNA and protein levels of nerve growth factor and vesicular acetylcholine transporters, as well as choline acetyltransferase protein level slightly decreased. Our results indicate that NRG-1 can improve cardiac function and regulate sympathetic and vagus nerve remodeling post-MI, thus reaching a new balance of the autonomic nervous system to protect the heart from injury.

Paclitaxel-coated balloons for the treatment of patients with in-stent restenosis: A meta-analysis of angiographic and clinical data.

Paclitaxel-coated balloons (PCBs) have become attractive alternative treatment options for patients with in-stent restenosis (ISR); however, the safety and efficacy of PCBs in comparison with those of conventional therapies are less well defined. The aim of this meta-analysis was to systematically review the efficacy and safety of PCBs for patients with ISR using comparisons with control groups. Electronic databases, such as MEDLINE, Embase and the Cochrane Central Register of Controlled Trials, were searched, and eligible studies that compared PCBs with uncoated balloons (UCBs) or drug-eluting stents (DESs) in patients with ISR were considered. Subgroup analyses were performed with different control groups. Nine studies (1,488 patients, 1,608 lesions) were included in the meta-analysis. Compared with patients who underwent UCB angioplasty, those who underwent PCB angioplasty exhibited a clear superiority in late lumen loss (LLL) [weighted mean difference (WMD), -0.46; 95% confidence interval (CI), (-0.59)-(-0.34); P<0.00001] and major adverse cardiac events (MACEs) [odds ratio (OR), 0.21; 95% CI, 0.13-0.33; P<0.00001]. The OR for myocardial infarction (MI) (OR, 0.46; 95% CI, 0.15-1.47; P=0.19) did not reach statistical significance. PCBs were associated with similar outcomes when compared with DESs with regard to LLL (WMD, -0.04; 95% CI, -0.18-0.10; P=0.57), MACEs (OR, 0.74; 95% CI, 0.36-1.53; P=0.42) and the ORs for all endpoints, including total mortality, target lesion revascularization, MI, stent thrombosis and binary restenosis, and no statistically significant differences were found. This meta-analysis showed that PCBs are associated with superior outcomes when compared with UCBs in the management of ISR, and are at least as efficacious and as well tolerated as DESs.

Changes of naturally occurring CD4(+)CD25(+) FOXP3(+) regulatory T cells in patients with acute coronary syndrome and the beneficial effects of atorvastatin treatment.

To determine the number and function of naturally occurring CD4(+)CD25(+)FOXP3(+) regulatory T cells (nTregs) in patients with acute coronary syndrome (ACS) and to determine the effects of a low dose of atorvastatin treatment (20 mg/day) on nTregs.Patients with ACS were randomly divided into a group receiving conventional therapy (n = 60) or conventional therapy supplemented with atorvastatin (20 mg/day) (n = 60). A group of healthy volunteers that did not suffer from ACS was used as controls (n = 60). T lymphocytes were isolated from ACS patients, both before and 4 weeks after treatment, or control patients and the percentage of nTregs was determined by flow cytometry. Serum levels of cytokines were determined by enzyme-linked immunosorbent assays. A mixed lymphocyte reaction was used to determine the ability of nTregs to inhibit proliferation of effector T cells. Quantitative PCR and Western blot were used to analyze (forkhead box P3) FOXP3 mRNA transcript levels and the expression of FOXP3 protein.In ACS patients, the percentage and inhibitory properties of nTregs were reduced, IFN-γ and hsCRP levels were increased, and IL-10 and TGF-ß1 levels were lowered. Atorvastatin treatment increased the percentage and inhibitory ability of nTregs, decreased serum IFN-γ and hsCRP levels, and decreased IL-10 and TGF-ß1 levels, as compared with the non-atorvastatin group.Our findings suggest that nTregs play an atheroprotective role in atherosclerosis. The inhibitory effects of atorvastatin on inflammation in ACS may be due to its beneficial effects on nTregs and restoration of immune homeostasis.

Mesenchymal stem cells alleviate atherosclerosis by elevating number and function of CD4(+)CD25 (+)FOXP3 (+) regulatory T-cells and inhibiting macrophage foam cell formation.

Atherosclerosis is a chronic inflammatory disease characterized by the formation of plaques inside arteries, leading to narrowing and blockage. Potential therapeutic strategies include expanding the population of regulatory T-cells (Tregs) to enhance atheroprotective immunity, and inhibiting the formation of macrophage foam cells. Here, we studied the effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) on atherosclerotic plaque formation in Apolipoprotein E(-/-) (ApoE-KO) mice, and elucidated the underlying mechanism. BM-MSCs isolated from 4 week-old ApoE-KO mice were evaluated by flow cytometry for expression of MSC-specific markers. Thirty eight week-old ApoE-KO mice were randomly divided into three experimental groups (n = 10 per group): 1. MSC group-received BM-MSCs intravenously; 2. Vehicle group-received DMEM; 3. Control group-did not receive any treatment. Administration of MSCs resulted in a marked decrease in the size of atherosclerotic plaques 3 months after treatment. In addition, the number and function of CD4(+)CD25(+)FOXP3(+) regulatory T-cells (Tregs) in cultured splenocytes, and the expression of FOXP3 at both mRNA and protein levels, was significantly increased in the MSC group. In vitro experiments further indicated that the formation of macrophage foam cells was inhibited by treatment with MSCs, accompanied by a significant downregulation in CD36 and scavenger receptor A (SRA). Our findings suggest that MSCs play an atheroprotective role by enhancing the number and function of Tregs and inhibiting the formation of macrophage foam cells. Hence, administration of MSCs to atherosclerotic patients might have significant clinical benefits.