Atorvastatin regulates vascular smooth muscle cell phenotypic transformation by epigenetically modulating contractile proteins and mediating Akt/FOXO4 axis.

Atherosclerosis (AS) is a prevalent cardiovascular disease with severe morbidity and high mortality. Phenotypic regulation of vascular smooth muscle cells (VSMCs) from the contractile and quiescent phenotype to the synthetic type is a critical step for the vascular remodeling of AS. Atorvastatin, as a 3­hydroxy­3­methyl­glutaryl coenzyme A reductase inhibitor, presents an anti­inflammatory effect to improve vascular endothelial functions. The aim of the present study was to examine the effect of atorvastatin on VSMCs phenotypic transformation and the underlying mechanism. The rat primary VSMCs were isolated and identified. The protein expression of contractile proteins, such as α­SMA, SM­MHC, and SM22α, was reduced by angiotensin II (AngII) and enhanced by atorvastatin, in which atorvastatin could reverse the effect of AngII in the VSMCs. The treatment of HDAC inhibitor trichostatin A was able to enhance AngII­inhibited expression of α­SMA and SM­MHC. Atorvastatin regulated AngII­associated VSMCs phenotypic transformation by epigenetically regulating contractile proteins. Moreover, atorvastatin modulated platelet­derived growth factor­BB (PDGF­BB)­induced VSMC phenotypic transformation by modulating the Akt/forkhead Box O4 (FOXO4) axis. Immunofluorescence analysis revealed that PDGF­BB enhanced the accumulation of FOXO4 in the VSMCs, while the treatment of atorvastatin was able to attenuate this effect and the co­treatment of Akt inhibitor LY294002 could further inhibit the phenotype. The treatment of PDGF­BB enhanced the interaction of SRF with FOXO4 and myocardin in the VSMCs, in which the co­treatment of atorvastatin and LY294002 could reverse the effect of PDGF­BB in the system. Thus, atorvastatin regulates VSMCs phenotypic transformation by epigenetically modulating contractile proteins and mediating the Akt/FOXO4 axis. Findings of the present study provide new insights into the mechanism by which atorvastatin modulates VSMCs, providing valuable evidence for the application of atorvastatin in the treatment of AS.

The geriatric nutritional risk index mediated the relationship between serum uric acid and hypertension: a mediation analysis.

BACKGROUND: The elevated serum uric acid (SUA) is associated with an increased risk of hypertension and nutritional status. Malnutrition might modify the association of SUA with hypertension. Therefore, the aims of this study were to examine the mediation effect of malnutrition on the association of SUA with the risk of hypertension in Chinese population. METHODS: The study was based on the China Health and Nutrition Survey in 2009. Participants aged ≥ 60 years with complete analyzed data were eligible. The Geriatric Nutritional Risk Index (GNRI) was calculated by serum albumin (ALB) and BMI. Participants were identified as hypertension if systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg or receiving antihypertensive drug. RESULTS: There were 2371 participants included in the final analysis. In total, there was a significant mediation effect of the GNRI on the relationship between SUA level with hypertension (P < 0.001; OR: 1.096; and 95 % CI: 1.048-1.146). And the proportion mediated was 17.77 %. The results stratified by sex were consistent with those of total population. The significant mediation effects of the GNRI were found in the 60-69 years and 70-79 years groups (P = 0.002 and 0.032; OR: 1.099 and 1.075; and 95 % CI: 1.036-1.165 and 1.006-1.148, respectively) but not in the 80-99 years group (P = 0.303). The proportions mediated were16.22 % and 18.36 %, respectively. CONCLUSIONS: The GNRI can mediate and account for approximately 17.77 % of the relationship between SUA level and the risk of hypertension. And this mediation effect was fully observed in both males and females, especially in the 60-79 years population.

Early invasive strategy for non-ST elevation acute coronary syndrome: a meta-analysis of randomized, controlled trials.

OBJECTIVE: Patients with non-ST elevation acute coronary syndrome (NSTE-ACS) benefit from coronary intervention, but the optimal timing for an invasive strategy is not well defined. This study aimed to determine whether an early invasive strategy (<12 hours) is superior to a delayed invasive strategy. METHODS: Twelve studies of nine randomized, controlled trials of 8586 patients were included. RESULTS: There were no significant differences in all-cause death (risk ratio [95% confidence interval]) (0.90, [0.77-1.06), re-myocardial infarction (re-MI) (0.95 [0.70-1.29]), major bleeding (0.97 [0.77-1.23]), and refractory ischemia (0.74 [0.53-1.05]) when we compared use of early and delayed invasive strategies. Furthermore, analysis of the effect of the chosen strategy on high-risk patients showed that the rate of composite death or re-MI was significantly decreased in patients with either a Global Registry of Acute Coronary Events (GRACE) risk score >140 or with elevated troponin levels (risk ratio 0.82 [0.72-0.92]; risk ratio 0.84 [0.76-0.93], respectively). CONCLUSIONS: This meta-analysis shows that an early angiographic strategy does not improve clinical outcome in patients with NSTE-ACS. An early invasive strategy might reduce the rate of composite death or re-MI in high-risk patients with GRACE risk scores >140 or elevated cardiac markers.

Drug-eluting balloons in the treatment of de-novo coronary lesions: a meta-analysis of randomized-controlled trials.

AIM: The aim of this meta-analysis was to evaluate the efficacy of drug-eluting balloons (DEBs) plus bare-metal stents (BMS) for the treatment of de-novo coronary lesions. METHODS AND RESULTS: Eleven trials involving 1279 patients were included in this study. The main endpoints were as follows: late lumen loss (LLL), binary restenosis, stent thrombosis (ST), and major adverse cardiovascular events (MACEs). The definition of MACEs was a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR). Compared with BMS alone, DEB plus BMS showed a lower risk for LLL (P=0.007) and MACEs (P=0.010). There were no significant differences in binary restenosis (P=0.212), ST (P=0.199), death (P=0.141), MI (P=0.439), and TLR (P=0.340). Compared with drug-eluting stents (DES), DEB plus BMS could increase the risk of LLL (P=0.002) and MACEs (P=0.026). The risks of binary restenosis (P=0.113), ST (P=0.832), death (P=0.115), MI (P=0.831), and TLR (P=0.111) were similar between DEB plus BMS and DES. CONCLUSION: DEB plus BMS was better than BMS alone in reducing LLL and MACEs, especially when dilatation was performed after stenting for de-novo coronary lesions, but it was inferior to DES. Therefore, the treatment strategy with DEB plus BMS should not be recommended for de-novo coronary lesions, except for patients who have contraindications for DES.

Angiotensin II in atrial structural remodeling: the role of Ang II/JAK/STAT3 signaling pathway.

Ang II/JAK/STAT3 signaling pathway is known to be involved in atrial remodeling associated with development and progression of atrial fibrillation. In the present study, we used in vivo animal model and human atrial specimens to further characterize the role of this pathway in the atrial structural remodeling. We observed an elevated level of Ang II in the atrial samples of AF patients. This increase in Ang II was accompanied by increased expression of collagens I and III, MMP1, MMP2 and elevated phosphorylation of STAT3. Using rat models, we demonstrated that Ang II infusion induced profound changes in the level of apoptosis, expression of collagen subtypes I and III, caspase-3, caspase-8, MMP1, MMP2 and redistribution of cytochrome C. The data further support the key role of Ang II in the development of AF and highlight the specific mechanisms and changes associated with this process.

Effects of tirofiban on platelet activation and endothelial function in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention.

This pilot study examined, for the first time, the effect of intracoronary administration of tirofiban, an inhibitor of platelet aggregation, on platelet activation and endothelial dysfunction in patients with ST-segment-elevated myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). A total of 119 STEMI patients were randomized into either tirofiban group (n = 72, intracoronary injection of 10 µg/kg tirofiban prior to PCI, followed by intravenous infusion at 0.15 µg/kg min) or a control group (n = 47), which did not receive tirofiban. Periprocedural administration of tirofiban was associated with significantly reduced levels of platelet activation (lower levels of CD62P and PAC-1) and endothelial dysfunction (reduced levels of endothelial microparticles, VCAM-1, and ICAM-1) 48 h after PCI. At 10 days after PCI, patients in the tirofiban group had a higher incidence of complete STR (78.7 vs. 65.0%) and higher left ventricular ejection fractions (47.8 vs. 44.2) compared to those in the control group. The clinical outcomes between two groups did not differ significantly two weeks after treatment. The results demonstrated that periprocedural administration of tirofiban is associated with significantly attenuated platelet activation and endothelial dysfunction in STEMI patients undergoing PCI. This may have contributed to the improved myocardial reperfusion and preservation of left ventricular systolic function in these patients.