443INTROduCTION Endothelial dysfunction, characterized by the loss of nitric oxide bioavailability, is the key element in the pathogenesis of atherosclerosis. The significance of endothelial dysfunction has been demonstrated by numerous animal model studies 1 and has been confirmed in clinical studies showing that it precedes clinical and morphological atherosclerotic changes. 2 Numerous studies have described associations between endothelial dysfunction and risk factors for cardiovascular diseases.3-5 Impaired endothelial function is a feature of aging and is present in patients with high levels of low-density lipoproteins, arterial hypertension, diabetes, acute coronary syndromes, autoimmune diseases, and in smokers. [3][4][5][6] Moreover, the number of atherosclerotic risk factors has been linked to the degree of endothelial dysfunction. AbsTRACTINTROduCTION Endothelial dysfunction, characterized by the loss of nitric oxide bioavailability, is a key element in the pathogenesis of atherosclerosis and an important prognostic factor in cardiovascular diseases. Therefore, the development of reliable, safe, and noninvasive methods of endothelial function assessment is important for their use in cardiovascular risk stratification. Brachial artery flow-mediated dilation (FMD) is widely used in research but technical difficulties and problems with calibration between laboratories limit its clinical use. Reactive hyperemia-peripheral artery tonometry (RH-PAT, EndoPAT) has been developed as a simpler, cheaper, and potentially more reproducible method.
Increased production of reactive oxygen species and loss of endothelial NO bioactivity are key features of vascular disease states such as diabetes mellitus. Tetrahydrobiopterin (BH4) is a required cofactor for eNOS activity; pharmacologic studies suggest that BH4 may mediate some of the adverse effects of diabetes on eNOS function. We have now investigated the importance and mechanisms of BH4 availability in vivo using a novel transgenic mouse model with endothelial-targeted overexpression of the rate-limiting enzyme in BH4 synthesis, guanosine triphosphate–cyclohydrolase I (GTPCH). Transgenic (GCH-Tg) mice demonstrated selective augmentation of endothelial BH4 levels. In WT mice, induction of diabetes with streptozotocin (STZ) increased vascular oxidative stress, resulting in oxidative loss of BH4, forming BH2 and biopterin. Endothelial cell superoxide production in diabetes was increased, and NO-mediated endothelium-dependent vasodilatation was impaired. In diabetic GCH-Tg mice, superoxide production from the endothelium was markedly reduced compared with that of WT mice, endothelial BH4 levels were maintained despite some oxidative loss of BH4, and NO-mediated vasodilatation was preserved. These findings indicate that BH4 is an important mediator of eNOS regulation in diabetes and is a rational therapeutic target to restore NO-mediated endothelial function in diabetes and other vascular disease states
While immunopathogenesis of atherosclerosis is well defined, immunological mechanisms of hypertension (HTN) and its link to atherosclerosis remain unclear. We hypothesized, that primary HTN is associated with a pro-inflammatory and pro-atherogenic phenotype of circulating monocytes, characterized by co-expression of the Fc-gamma receptor (CD16+) and LPS receptor (CD14+high). Methods: 132 subjects (74M and 58F) with typical clinical risk factors of atherosclerosis were studied. HTN (85%) was diagnosed based on blood pressure monitoring and use of anti-HTN drugs. Monocyte characteristics in the peripheral blood were determined by flow cytometry and plasma cytokine levels by ELISA. Results: CD16+CD14+ cells were more prevalent in subjects with HTN and were highest in subjects whose blood pressure was poorly controlled (Figure ). A significant correlation between blood pressure levels at the time of study (JNC7) and prevalence of CD14+CD16+ monocytes was found (Figure ). These relationships remained significant in multi-variate analysis (p = 0.01; type 3 sum of squares ANOVA) taking into account other major risk factors for atherosclerosis or treatments. Further analysis of subpopulations showed that levels of CD16 +CD14+ (high) monocytes, rather than CD16 + CD14(dim) revealed a strong relationship to hypertension. These monocytes showed significantly higher expression of activation markers HLA-DR and CD45RA and TNF-α production(p<0.05). These results provide a novel marker of inflammation in hypertension and may provide a link between hypertension and the development of atherosclerosis, which has been clinically well defined, but mechanistically unclear.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.