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Epicatechin and catechin modulate endothelial activation induced by platelets of patients with peripheral artery disease.

ABSTRACT: Platelet activation contributes to the alteration of endothelial function, a critical initial step in atherogenesis through the production and release of prooxidant mediators. There is uncertainty about the precise role of polyphenols in interaction between platelets and endothelial cells (ECs). We aimed to investigate whether polyphenols are able to reduce endothelial activation induced by activated platelets. First, we compared platelet activation and flow-mediated dilation (FMD) in 10 healthy subjects (HS) and 10 patients with peripheral artery disease (PAD). Then, we evaluated the effect of epicatechin plus catechin on platelet-HUVEC interaction by measuring soluble cell adhesion molecules (CAMs), NOx production, and eNOS phosphorylation (p-eNOS) in HUVEC. Compared to HS, PAD patients had enhanced platelet activation. Conversely, PAD patients had lower FMD than HS. Supernatant of activated platelets from PAD patients induced an increase of sCAMs release and a decrease of p-eNOS and nitric oxide (NO) bioavailability compared to unstimulated HUVEC. Coincubation of HUVEC, with supernatant of PAD platelets patients, pretreated with a scalar dose of the polyphenols, resulted in a decrease of sCAMs release and in an increase of p-eNOS and NO bioavailability. This study demonstrates that epicatechin plus catechin reduces endothelial activation induced by activated platelets.

SUBMITTER: Carnevale R

PROVIDER: S-EPMC4142301 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Epicatechin and catechin modulate endothelial activation induced by platelets of patients with peripheral artery disease.

Carnevale R R Loffredo L L Nocella C C Bartimoccia S S Bucci T T De Falco E E Peruzzi M M Chimenti I I Biondi-Zoccai G G Pignatelli P P Violi F F Frati G G

Oxidative medicine and cellular longevity 20140807

Platelet activation contributes to the alteration of endothelial function, a critical initial step in atherogenesis through the production and release of prooxidant mediators. There is uncertainty about the precise role of polyphenols in interaction between platelets and endothelial cells (ECs). We aimed to investigate whether polyphenols are able to reduce endothelial activation induced by activated platelets. First, we compared platelet activation and flow-mediated dilation (FMD) in 10 healthy ...[more]

PMID: 25180068

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Project description:ObjectiveWe have previously shown that peripheral artery disease (PAD) is associated with marked impairment of endothelial function (EF). Given that poor EF is associated with functional status of PAD patients as well as with increased morbidity and mortality in patients undergoing vascular procedures, determination of factors associated with poor EF in a PAD cohort is important. We hypothesized that decreased kidney function is associated with impaired EF in patients with PAD.MethodsThis was a cross-sectional study of PAD patients presenting to a vascular surgery outpatient clinic at the San Francisco Veterans Affairs Medical Center including patients enrolled in the OMEGA-PAD I trial (NCT01310270) and the OMEGA-PAD Cohort. Brachial artery flow-mediated vasodilation was performed to assess EF. Kidney function was characterized by estimated glomerular filtration rate with the abbreviated Modification of Diet in Renal Disease formula. Linear regression was performed to assess the relationship between EF and kidney function in claudicants.ResultsNinety-seven patients with intermittent claudication participated in this study. Mean age was 69 ± 8 years, 97% were male, and 79% were white. Comorbidities included hypertension (91%), dyslipidemia (87%), coronary artery disease (42%), and diabetes mellitus (38%). Mean ankle-brachial index was 0.73 ± 0.14 and mean flow-mediated vasodilation was 7.0% ± 3.8%, indicating impaired EF. Linear regression showed an association between kidney function and EF (by 10 mL/min/1.73 m(2); β, 0.12; confidence interval, 0.05-0.20; P = .001). After multivariable regression adjusting for age, race, log tumor necrosis factor α, hypertension, dyslipidemia, and diabetes, estimated glomerular filtration rate remained significantly associated with EF (P = .033).ConclusionsIn patients with PAD, decreased kidney function is associated with endothelial dysfunction. Further longitudinal studies are needed to better understand the impact of kidney function on PAD progression and the role of endothelial dysfunction in this process.

Project description:RationalePeripheral artery disease, common in metabolic syndrome and diabetes mellitus, responds poorly to medical interventions and is characterized by chronic vessel immaturity leading to lower extremity amputations.ObjectiveTo define the role of reversible palmitoylation at the endothelium in the maintenance of vascular maturity.Methods and resultsEndothelial knockout of the depalmitoylation enzyme APT-1 (acyl-protein thioesterase 1) in mice impaired recovery from chronic hindlimb ischemia, a model of peripheral artery disease. Endothelial APT-1 deficiency decreased fibronectin processing, disrupted adherens junctions, and inhibited in vitro lumen formation. In an unbiased palmitoylation proteomic screen of endothelial cells from genetically modified mice, R-Ras, known to promote vessel maturation, was preferentially affected by APT-1 deficiency. R-Ras was validated as an APT-1 substrate, and click chemistry analyses demonstrated increased R-Ras palmitoylation in cells with APT-1 deficiency. APT-1 enzyme activity was decreased in endothelial cells from db/db mice. Hyperglycemia decreased APT-1 activity in human umbilical vein endothelial cells, due, in part, to altered acetylation of the APT-1 protein. Click chemistry analyses demonstrated increased R-Ras palmitoylation in the setting of hyperglycemia. Altered R-Ras trafficking, increased R-Ras palmitoylation, and fibronectin retention were found in diabetes mellitus models. Loss of R-Ras depalmitoylation caused by APT-1 deficiency constrained R-Ras membrane trafficking, as shown by total internal reflection fluorescence imaging. To rescue cellular phenotypes, we generated an R-Ras molecule with an inserted hydrophilic domain to circumvent membrane rigidity caused by defective palmitoylation turnover. This modification corrected R-Ras membrane trafficking, restored fibronectin processing, increased adherens junctions, and rescued defective lumen formation induced by APT-1 deficiency.ConclusionsThese results suggest that endothelial depalmitoylation is regulated by the metabolic milieu and controls plasma membrane partitioning to maintain vascular homeostasis.

Project description:BackgroundAltered adipokine secretion in dysfunctional adipose tissue facilitates the development of atherosclerotic diseases including lower extremity peripheral artery disease (PAD). Asprosin is a recently identified adipokine and displays potent regulatory role in metabolism, but the relationship between asprosin and lower extremity PAD remains uninvestigated.Methods33 type 2 diabetes mellitus (T2DM) patients (DM), 51 T2DM patients with PAD (DM + PAD) and 30 healthy normal control (NC) volunteers were recruited and the blood samples were collected for detecting the circulatory asprosin level and metabolomic screening. RNA sequencing was performed using the aorta tissues from the type 2 diabetic db/db mice and human umbilical vein endothelial cells (HUVECs) were treated with asprosin to determine its impact on the endothelial-to-mesenchymal transition (EndMT).ResultsThe circulating levels of asprosin in DM + PAD group were significantly higher than that of NC group and the DM group. Circulating asprosin level was remarkably negatively correlated with ankle-brachial index (ABI), even after adjusting for age, sex, body mass index (BMI) and other traditional risk factors of PAD. Logistic regression analysis revealed that asprosin is an independent risk factor for PAD and receiver-operator characteristic (ROC) curve determined a good sensitivity (74.5%) and specificity (74.6%) of asprosin to distinguish PAD. Data from metabolomics displayed a typical characteristics of de novo amino acid synthesis in collagen protein production by myofibroblasts in patients with PAD and activation of TGF-β signaling pathway appeared in the aortic tissue of db/db mice. Asprosin directly induces EndMT in HUVECs in a TGF-β-dependent manner as TGF-β signaling pathway inhibitor SB431542 erased the promotional effect of asprosin on EndMT.ConclusionsElevated circulatory asprosin level is an independent risk factor of lower extremity PAD and might serve as a diagnostic marker. Mechanistically, asprosin directly induces EndMT that participates in vascular injury via activation of TGF-β signaling pathway. Trial registration This trial was registered at clinicaltrials.gov as NCT05068895.

Dataset Information

Epicatechin and catechin modulate endothelial activation induced by platelets of patients with peripheral artery disease.

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Epicatechin and catechin modulate endothelial activation induced by platelets of patients with peripheral artery disease.

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