Abstract-Epidemiological studies have demonstrated that the Mediterranean diet, which is rich in resveratrol, is associated with a significantly reduced risk of cardiovascular disease. However, the molecular mechanisms that underlie the beneficial effects of resveratrol on cardiovascular function remain incompletely understood. Therefore, we set out to identify the molecular target(s) mediating the protective action of resveratrol on vascular function. To this end, we performed vascular reactivity studies to evaluate the effects of resveratrol on superior thyroid artery obtained from 59 patients with hypertension and dyslipidemia. We found that resveratrol evoked vasorelaxation and reduced endothelial dysfunction through the modulation of NO metabolism via (1) an 5′ adenosine monophosphate-activated protein kinase-mediated increase in endothelial NO synthase activity; (2) a rise in tetrahydrobiopterin levels, which also increases endothelial NO synthase activity; and (3) attenuation of vascular oxidative stress, brought about by overexpression of manganese superoxide dismutase via an nuclear factor erythroid-derived 2-like 2-dependent mechanism. The effects of resveratrol on acetylcholine vasorelaxation were also tested in vessels from patients with nonhypertensive nondyslipidemia undergoing thyroid surgery. In this setting, resveratrol failed to exert any effect. Thus, our finding that resveratrol reduces endothelial dysfunction, an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular disease, supports the concept that the risk of vascular events could be further reduced by adherence to a set of dietary and behavioral guidelines. MethodsFor detailed methodology, please see the online-only Data Supplement. In brief, we collected superior thyroid artery (STA) from patients with HD (Table). Each vessel was divided into rings for use in different experimental series. Some rings were treated with resveratrol at 37°C, and then proteins were rapidly extracted for molecular studies to evaluate total and phosphorylated endothelial NO synthase (eNOS) protein levels, eNOS dimerization, GTP cyclohydrolase 1, copper-zinc superoxide dismutase (Cu-ZnSOD) and MnSOD expression, and NRF2 translocation; other rings were kept in 4°C Krebs solution for vascular reactivity studies; some were used for highperformance liquid chromatography (HPLC) dosage of BH 4 ; and others were rapidly used for measurement of O 2 − . Studies were also performed on vessels removed from patients with nonhypertensive, nondyslipidemia (nHD) undergoing thyroid surgery. Results Resveratrol Exerts a Vasorelaxant Effect by Modulating the Phosphorylation Status of eNOS and NO ReleaseEvaluation of the vascular reactivity of ex vivo STA from patients with HD revealed that endothelially mediated (acetylcholine-evoked) vasorelaxation was significantly blunted compared with relaxation induced by nitroglycerin ( Figure 1A). However, when HD STA rings were preconstricted with phenylephrine, resveratrol was ca...

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Partial least squares path modeling (PLS-PM) has become very popular in recent years, for measuring concepts that depend on different aspects and that are based on different types of relationships. PLS-PM represents a useful tool to explore relationships and to analyze the influence of the different aspects on the complex phenomenon analyzed. In particular, the use of higher-order constructs has allowed researchers to extend the application of PLS-PM to more advanced and complex models. In this work, our attention is focused on higher-order constructs that include reflective or formative relationships. Even if the dispute between formative models and reflective models is not exactly recent, it is still alive in current literature, for the most part within the context of structural equation models. This paper focuses attention on theoretical and mathematical differences between formative and reflective measurement models within the context of the PLS-PM approach. A simulation study is proposed in order to show how these approaches fit well in different modeling situations. The approaches have been compared using empirical application in a sustainability context. The findings from the simulation and the empirical application can help researchers to estimate and to use the higher-order PLS-PM approach in reflective and formative type models.

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Objectives-The purpose of this study was to evaluate the role of genetic variants within the coagulation factor II receptor (F2R) in the occurrence of coronary heart disease (CHD). Methods and Results-Four SNPs (Ϫ1738 G/A, 2860 G/A, 2930 T/C, and 9113 C/A) and an ins/del polymorphism Ϫ506-/GGCCGCGGGAAGC (D/I), replicating a consensus sequence for Ets-1 transcription factor, and their related haplotypes were tested for association to CHD in 1600 hypertensive patients divided in 2 groups according to presence (cases, nϭ559) and absence (controls, nϭ1041) of CHD. Allele I at Ϫ506 locus was associated with increased risk of CHD under additive, dominant, and recessive models of inheritance (all PϽ0.01). Three haplotypes carrying I allele were consistently associated with an increased risk of CHD (all PϽ0.05). Patients homozygous for the C allele at the 2930 locus also showed an increased risk of CHD (PϽ0.05). To test the functionality of Ϫ506 locus, nuclear extracts were incubated with Ϫ506D and Ϫ506I sequences by EMSA and F2R promoter activity (F2R-A) were assessed in HUVECs transfected with vectors carrying Ϫ506D and Ϫ506I sequences and exposed to hypoxia. Presence of the Ϫ506I sequence was associated with a 26% reduction of affinity binding to nuclear proteins and to blunted F2R-A in response to hypoxia as compared with the Ϫ506D sequence (all PϽ0.05). Key Words: coronary heart disease Ⅲ hypertension Ⅲ F2R Ⅲ haplotype Ⅲ hypoxia C oronary Heart Disease (CHD), a complex and heterogeneous disease with a heritability exceeding 50%, 1,2 represents the leading cause of death among cardiovascular diseases, and almost half of the patients experiencing a first heart attack have high blood pressure levels. 3 Individual susceptibility to CHD depends on multiple genetic and environmental factors that influence coronary artery lesion morphology and metabolism and therefore clinical presentation. Identification of genetic variants predisposing to CHD is essential to improve our knowledge of the mechanisms underlying CHD and, on a broader level, to ameliorate cardiovascular disease prevention and pharmacological treatment. Conclusions-F2RRecently, the Coagulation Factor II Receptor (F2R), the thrombin receptor expressed on human platelets and endothelial cells, has been identified as a powerful modulator of endothelial lining, and more generally, of vascular wall integrity and stability. 4,5 In aortic 6 and coronary artery rings 7 thrombin-activated F2R promotes endothelial-dependent vasodilatation through a nitric oxide-dependent mechanism and infusion of an F2R agonist in mice results in rapid hypotension followed by sustained hypertension. 8 In cultured endothelial cells prolonged F2R stimulation induces an inflammatory and angiogenic response through the enhanced expression of proinflammatory cytokines, 9 vascular endothelial growth factor (VEGF) and VEGF receptors expression. 10 Finally, experiments performed in animal model of vascular injury have suggested that inhibition of this receptor might be of clinical relevanc...