Neopterin derivatives – a novel therapeutic target rather than biomarker for atherosclerosis and related diseases

VASA ◽  
2020 ◽  
pp. 1-9
Author(s):  
Takuya Watanabe
Keyword(s):  
Coronary Artery Disease ◽  
Endothelial Cells ◽  
Coronary Artery ◽  
Adhesion Molecule ◽  
Therapeutic Target ◽  
No Synthase ◽  
Foam Cell Formation ◽  
Atheromatous Plaques ◽  
Artery Disease ◽  
Novel Therapeutic

Summary: This review provides an updated overview of the emerging roles of neopterin derivatives in atherosclerosis. Neopterin, a metabolite of guanosine triphosphate, is produced by interferon-γ-activated macrophages and is expressed at high levels in atheromatous plaques within the human carotid and coronary arteries as well as in the aorta. Plasma concentrations of neopterin are higher in patients with carotid, cerebral, and coronary artery diseases as well as aortic aneurysm. The concentration of neopterin is positively correlated with the severity of coronary artery disease. However, a prospective cohort study showed that neopterin contributes to protection against plaque formation in carotid arteries in patients with atherosclerosis. Moreover, using both in vitro and in vivo experiments, a recent study has shown the atheroprotective effects of neopterin. Neopterin suppresses the expression of monocyte chemotactic protein-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in endothelial cells, and thereby suppresses the adhesion of monocytes to endothelial cells. It also suppresses the inflammatory phenotype of monocyte-derived macrophages. In addition, neopterin suppresses oxidized low-density lipoprotein-induced foam cell formation in macrophages and the migration and proliferation of vascular smooth muscle cells. Neopterin injection into apolipoprotein E-deficient ( Apoe-/-) mice suppresses the development of atherosclerotic lesions. A neopterin derivative tetrahydroneopterin (BH4), also known as a cofactor for nitric oxide (NO) synthases, suppresses atherosclerosis and vascular injury-induced neointimal hyperplasia in Apoe-/- mice. BH4 administration improves endothelial dysfunction in patients with coronary artery disease. These findings suggest that neopterin production may increase to counteract the progression of atherosclerosis, as neopterin contributes to atheroprotection. Otherwise, the increased neopterin levels in atherosclerosis may reflect a compensatory mechanism associated with inducible NO synthase upregulation in macrophages to supply BH4 for high output NO production caused by decreased endothelial NO synthase in atherosclerosis. Therefore, neopterin derivatives are a novel therapeutic target for atherosclerosis and related diseases.

Abstract 20478: Circulating Inflammatory Potential Measured by an Endothelial Biosensor Assay in Coronary Artery Disease Patients

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Heidi Cung ◽  
Joe Anderson ◽  
James Nawarskas ◽  
Matthew Campen
Keyword(s):  
Coronary Artery Disease ◽  
Endothelial Cells ◽  
Coronary Artery ◽  
Adhesion Molecule ◽  
Inflammatory Markers ◽  
Serum Samples ◽  
Control Subjects ◽  
Tnf Α ◽  
Healthy Control ◽  
Artery Disease

Introduction: Vascular disease is driven by systemic inflammation that can arise from sites distal to the affected coronary or cerebral vessels. The objective of this study is to characterize the inflammatory potential of serum from patients with coronary artery disease (CAD) using cultured endothelial cells as a biosensor of the circulating milieu. Methods: Serum samples from CAD patients (N=48) and healthy control subjects (N=50) were incubated with primary human coronary artery endothelial cells at a 1:10 dilution for 4h, following by isolation of the cellular RNA. Alteration of inflammation-responsive elements (adhesion molecules and cytokines) was assessed on a gene expression level. Specific indicators included intercellular adhesion molecule-1 (ICAM), vascular cell adhesion molecule-1 (VCAM), and interleukin-8 (IL-8). Additionally, the serum samples from the CAD patients and healthy individuals were quantitatively analyzed for IL-1β, IL-6, IL-8, and TNF-α using an electrochemical luminescence platform. Results: For the CAD subjects’ serum, the mean values of ICAM, VCAM, and IL-8 expression were all elevated compared to healthy control subjects (p<0.001 for each by Students T-test). Correlational analysis revealed the three indicators (ICAM, VCAM, and IL-8) to be independent of each other and also other inflammatory markers such as C-reactive protein. IL-8 expression was negatively correlated with serum HDL levels but positively correlated with body fat composition. Interestingly, serum levels of IL-1β, IL-6, IL-8, and TNF-α in CAD patients were not statistically different from healthy control subjects. Conclusions: As yet uncharacterized circulating factors in the serum of CAD patients appear to activate endothelial cells. This assay paradigm performed well in terms of discriminating patients with CAD compared to healthy subjects, with greater range and specificity than specific inflammatory markers.

Abstract 426: Overexpression of Tissue-nonspecific Alkaline Phosphatase (TNAP) Accelerates Coronary Artery Disease in the Setting of Hypercholesterolemia in Mice

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Filippo Romanelli ◽  
AnthonyMarco Corbo ◽  
Maryam Salehi ◽  
Manisha C Yadav ◽  
Soha Salman ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Alkaline Phosphatase ◽  
Endothelial Cells ◽  
Coronary Artery ◽  
Vascular Calcification ◽  
Coronary Atherosclerosis ◽  
Atherogenic Diet ◽  
Arterial Calcification ◽  
Tissue Nonspecific Alkaline Phosphatase ◽  
Artery Disease

Objective: Vascular calcification in asymptomatic individuals is an independent predictor of coronary heart disease (CHD). It is therefore plausible that vascular calcification plays a direct pathophysiological role in atherosclerosis, an underlying cause of CHD. The purpose of this study was to examine the contribution that vascular calcification has on the development of coronary atherosclerosis in a mouse model of familial hypercholesterolemia. Approach and Results: Calcification was induced by overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells of mice harboring a point mutation in the low density lipoprotein receptor ( ldlr, wicked high cholesterol, WHC). Mice were fed an atherogenic diet; echocardiographic and biochemical data were collected longitudinally. Atherosclerosis and vascular calcification were analyzed histologically in the aorta, aortic sinus and coronary arteries. TNAP mice were also treated with a combination of an atherogenic diet and a specific inhibitor of TNAP (SBI-425). Combined with the ldlr mutation and an atherogenic diet, TNAP-driven arterial calcification led to severe atherosclerosis with 100% morbidity characterized by occlusive coronary artery disease, pathological cardiac hypertrophy with dilated LV and reduced ejection fraction (EF). We detected an interaction between vascular calcification and atherosclerosis in mice with endothelial TNAP overexpression. This interaction was particularly prominent in coronary circulation. Targeting TNAP activity therapeutically helped improve survival and heart function of endothelial TNAP overexpressor mice, however the incomplete inhibition of TNAP by SBI-425 was a limitation of this study. Conclusions: Vascular calcification via TNAP overexpression in endothelial cells promotes coronary atherosclerosis and is pathogenic under conditions of hypercholesterolemia.

scholarly journals JCAD , a Gene at the 10p11 Coronary Artery Disease Locus, Regulates Hippo Signaling in Endothelial Cells

2018 ◽  
Vol 38 (8) ◽  
pp. 1711-1722 ◽  
Author(s):  
Peter D. Jones ◽  
Michael A. Kaiser ◽  
Maryam Ghaderi Najafabadi ◽  
Simon Koplev ◽  
Yuqi Zhao ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Endothelial Cells ◽  
Coronary Artery ◽  
Disease Locus ◽  
Hippo Signaling ◽  
Artery Disease

scholarly journals CXCL12 Derived From Endothelial Cells Promotes Atherosclerosis to Drive Coronary Artery Disease

Circulation ◽  
2019 ◽  
Vol 139 (10) ◽  
pp. 1338-1340 ◽  
Author(s):  
Yvonne Döring ◽  
Emiel P.C. van der Vorst ◽  
Johan Duchene ◽  
Yvonne Jansen ◽  
Selin Gencer ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Endothelial Cells ◽  
Coronary Artery ◽  
Artery Disease

scholarly journals Expression of Cytokine and Adhesion Molecule mRNA in Atherectomy Specimens From Patients With Coronary Artery Disease

1999 ◽  
Vol 63 (4) ◽  
pp. 249-254 ◽  
Author(s):  
Toshiyuki Ishibashi ◽  
Mikihiro Kijima ◽  
Keiko Yokoyama ◽  
Joji Shindo ◽  
Kenji Nagata ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Adhesion Molecule ◽  
Artery Disease
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