Resveratrol Induces Vascular Smooth Muscle Cell Differentiation through Stimulation of SirT1 and AMPK

Phenotypic plasticity in vascular smooth muscle cells (VSMC) is necessary for vessel maintenance, repair and adaptation to vascular changes associated with aging. De-differentiated VSMC contribute to pathologies including atherosclerosis and intimal hyperplasia. As resveratrol has been reported to have cardio- protective effects, we investigated its role in VSMC phenotypic modulation. We demonstrated the novel finding that resveratrol promoted VSMC differentiation as measured by contractile protein expression, contractile morphology and contraction in collagen gels. Resveratrol induced VSMC differentiation through stimulation of SirT1 and AMPK. We made the novel finding that low or high dose resveratrol had an initially different mechanism on induction of differentiation. We found that low dose resveratrol stimulated differentiation through SirT1-mediated activation of AKT, whereas high dose resveratrol stimulated differentiation through AMPK-mediated inhibition of the mTORC1 pathway, allowing activation of AKT. The health effects of resveratrol in cardiovascular diseases, cancer and longevity are an area of active research. We have demonstrated a supplemental avenue where-by resveratrol may promote health by maintaining and enhancing plasticity of the vasculature

Regulation of vascular smooth muscle cell differentiation

Vascular smooth muscle cell (VSMC) differentiation is an essential component of vascular development. These cells perform biosynthetic, proliferative, and contractile roles in the vessel wall. VSMCs are not terminally differentiated and are able to modulate their phenotype in response to changing local environmental cues. There is clear evidence that alterations in the differentiated state of the VSMC play a critical role in the pathogenesis of atherosclerosis and intimal hyperplasia, as well as in a variety of other major human diseases, including hypertension, asthma, and vascular aneurysms. The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms involved in controlling phenotypic switching of SMCs, with particular focus on examination of signaling pathway that regulate this process

Variation in thromboembolic complications among patients undergoing commonly performed cancer operations

ObjectiveThere is widespread evidence that cancer confers an increased risk of deep venous thrombosis (DVT). This risk is thought to vary among different cancer types. The purpose of this study is to better define the incidence of thrombotic complications among patients undergoing surgical treatment for a spectrum of prevalent cancer diagnoses in contemporary practice.MethodsAll patients undergoing one of 11 cancer surgical operations (breast resection, hysterectomy, prostatectomy, colectomy, gastrectomy, lung resection, hepatectomy, pancreatectomy, cystectomy, esophagectomy, and nephrectomy) were identified by Current Procedural Terminology and International Classification of Diseases, Ninth Revision codes using the American College of Surgeons National Surgical Quality Improvement Program database (2007-2009). The study endpoints were DVT, pulmonary embolism (PE), and overall postoperative venous thromboembolic events (VTE) within 1 month of the index procedure. Multivariate logistic regression was utilized to calculate adjusted odds ratios for each endpoint.ResultsOver the study interval, 43,808 of the selected cancer operations were performed. The incidence of DVT, PE, and total VTE within 1 month following surgery varied widely across a spectrum of cancer diagnoses, ranging from 0.19%, 0.12%, and 0.28% for breast resection to 6.1%, 2.4%, and 7.3%, respectively, for esophagectomy. Compared with breast cancer, the incidence of VTE ranged from a 1.31-fold increase in VTE associated with gastrectomy (95% confidence interval, 0.73-2.37; P = .4) to a 2.68-fold increase associated with hysterectomy (95% confidence interval, 1.43-5.01; P = .002). Multivariate logistic regression revealed that inpatient status, steroid use, advanced age (≥60 years), morbid obesity (body mass index ≥35), blood transfusion, reintubation, cardiac arrest, postoperative infectious complications, and prolonged hospitalization were independently associated with increased risk of VTE.ConclusionsThe incidence of VTE and thromboembolic complications associated with cancer surgery varies substantially. These findings suggest that both tumor type and resection magnitude may impact VTE risk. Accordingly, such data support diagnosis and procedural-specific guidelines for perioperative VTE prophylaxis and can be used to anticipate the risk of potentially preventable morbidity

Long-term results of open and endovascular revascularization of superficial femoral artery occlusive disease

BackgroundFirst-line treatment for patients with superficial femoral arterial (SFA) occlusive disease has yet to be determined. This study compared long-term outcomes between primary SFA stent placement and primary femoral-popliteal bypass. Periprocedural patient factors were examined to determine their effect on these results.MethodsAll femoral-popliteal bypasses and SFA interventions performed in consecutive patients with symptoms Rutherford 3 to 6 between 2001 and 2008 were reviewed. Time-dependent outcomes were analyzed using the Kaplan-Meier method and log-rank test. Cox proportional hazards were performed to determine predictors of graft patency. Multivariate analysis was completed to identify patient covariates most often associated with the primary therapy.ResultsA total of 152 limbs in 141 patients (66% male; mean age, 66 ± 22 years) underwent femoral-popliteal bypass, and 233 limbs in 204 patients (49% male; mean age, 70 ± 11 years) underwent SFA interventions. Four-year primary, primary-assisted, and secondary patency rates were 69%, 78%, and 83%, respectively, for bypass patients and 66%, 91%, and 95%, respectively, for SFA interventions. Six-year limb salvage was 80% for bypass vs 92% for stenting (P = .04). Critical limb ischemia (CLI) and renal insufficiency were predictors of bypass failure. Claudication was a predictor of success for SFA stenting. Three-year limb salvage rates for CLI patients undergoing surgery and SFA stenting were 83%. Amputation-free survival at 3 years for CLI patients was 55% for bypass and 59% for SFA interventions. Multivariate predictors (odds ratios and 95% confidence intervals) of covariates most frequently associated with first-line SFA stenting were TransAtlantic Inter-Society Consensus II A and B lesions (5.9 [3.4-9.1], P < .001), age >70 years (2.1 [1.4-3.1], P < .001), and claudication (1.7 [1.1-2.7], P = .01). Regarding bypass as first-line therapy, claudicant patients were more likely to have nondiabetic status (5.6 [3.3-9.4], P < .001), creatinine <1.8 mg/dL (4.6 [1.5-14.9], P = .01), age <70 years (2.7 [CI, 1.6-8.3], P < .001), and presence of an above-knee popliteal artery target vessel (1.9 [CI, 1.1-3.4] P = .02).ConclusionIndication, patient-specific covariates, and anatomic lesion classification have significant association when determining surgeon selection of SFA stenting or femoral-popliteal bypass as first-line therapy. Patients with SFA disease can have comparable long-term results when treatment options are well matched to patient-specific and anatomic characteristics

Resveratrol Induced Differentiation in VSMC via SirT1-AKT Signaling.

<p>A, HuVSMC treated with increasing concentrations of resveratrol for 24 hours before western blot assessment with primary antibodies as indicated. Bar graphs represent densitometric quantification. N = 9 experiments. Probability values are indicated above bars: * p<0.05 versus control. B, HuVSMC were treated with 20 µM API-2 one hour prior to resveratrol or control treatment. Twenty-four hours following resveratrol treatment, cells were collected and assessed by western blot with primary antibodies as indicated. Bar graphs represent densitometric quantification. N = 4 experiments. Probability values are indicated above bars: * p<0.05, **p<0.01 versus control. C, HuVSMC were transfected with control siRNA or SirT1 siRNA for 24 hours, prior to treatment with 3 µM resveratrol or control. Twenty-four hours after treatment, cells were collected and assessed by western blot with primary antibodies as indicated. Bar graphs represent densitometric quantification. N = 3 experiments, in duplicate. Probability values are indicated above bars: * p<0.05, **p<0.01, *** p<0.001 versus control or </p