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Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine.

ABSTRACT: The role of vitamin D deficiency in coronary artery disease (CAD) progression is uncertain. Chronic inflammation in epicardial adipose tissue (EAT) has been implicated in the pathogenesis of CAD. However, the molecular mechanism underlying vitamin D deficiency-enhanced inflammation in the EAT of diseased coronary arteries remains unknown. We examined a mechanistic link between 1,25-dihydroxyvitamin D-mediated suppression of nuclear factor-?B (NF-?B) transporter, karyopherin ?4 (KPNA4) expression and NF-?B activation in preadipocytes. Furthermore, we determined whether vitamin D deficiency accelerates CAD progression by increasing KPNA4 and nuclear NF-?B levels in EAT.Nuclear protein levels were detected by immunofluorescence and Western blot. Exogenous KPNA4 was transported into cells by a transfection approach and constituted lentiviral vector. Swine were administered vitamin D-deficient or vitamin D-sufficient hypercholesterolemic diet. After 1 year, the histopathology of coronary arteries and nuclear protein expression of EAT were assessed. 1,25-dihydroxyvitamin D inhibited NF-?B activation and reduced KPNA4 levels through increased vitamin D receptor expression. Exogenous KPNA4 rescued 1,25-dihydroxyvitamin D-dependent suppression of NF-?B nuclear translocation and activation. Vitamin D deficiency caused extensive CAD progression and advanced atherosclerotic plaques, which are linked to increased KPNA4 and nuclear NF-?B levels in the EAT.1,25-dihydroxyvitamin D attenuates NF-?B activation by targeting KPNA4. Vitamin D deficiency accelerates CAD progression at least, in part, through enhanced chronic inflammation of EAT by upregulation of KPNA4, which enhances NF-?B activation. These novel findings provide mechanistic evidence that vitamin D supplementation could be beneficial for the prevention and treatment of CAD.

SUBMITTER: Chen S

PROVIDER: S-EPMC4965317 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine.

Chen Songcang S Swier Vicki J VJ Boosani Chandra S CS Radwan Mohamed M MM Agrawal Devendra K DK

Arteriosclerosis, thrombosis, and vascular biology 20160602 8

<h4>Objective</h4>The role of vitamin D deficiency in coronary artery disease (CAD) progression is uncertain. Chronic inflammation in epicardial adipose tissue (EAT) has been implicated in the pathogenesis of CAD. However, the molecular mechanism underlying vitamin D deficiency-enhanced inflammation in the EAT of diseased coronary arteries remains unknown. We examined a mechanistic link between 1,25-dihydroxyvitamin D-mediated suppression of nuclear factor-κB (NF-κB) transporter, karyopherin α4 ...[more]

PMID: 27255724

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Project description:Homocysteine (Hcy) elevation and vitamin D deficiency have emerged as potential markers of coronary artery disease (CAD). However, even tough hypovitaminosis D has been suggested to interfere with Hcy catabolism, no study has so far addressed the interaction of vitamin D and Hcy and their impact on CAD, that was the aim of present study. A cohort of consecutive patients undergoing coronary angiography in a single center were included and analyzed within the year 2019. Significant CAD was defined as at least 1 vessel stenosis > 50%, while severe CAD as left main and/or three-vessel disease. Hcy and vitamin D levels were assesssed at admission. We included 3150 patients undergoing coronary angiography at our centre, who were divided according to the quartiles values of vitamin D. Patients with lower levels of Vitamin D displayed a higher cardiovascular risk profile and a higher prevalence of CAD. We observed an inverse linear relationship between lower levels of vitamin D and higher Hcy (r = - 0.092, p < 0.001) and a higher prevalence of hyperhomocysteinemia in patients with lower quartiles values of vitamin D (p < 0.001). By forward conditional regression model, low vitamin D appeared as independent predictors of Homocysteine levels above the median (OR[95%CI] = 1.79[1.37-2.33], p < 0.001). In addition, patients with low vitamin D (below the median) and increased Hcy displayed a non-significantly higher rate of CAD (81% vs 77.7%, p = 0.13, adjusted OR[95%CI] = 1.16[0.88-1.54], p = 0.29) but a significant increase in the rate of severe left main/3-vessel CAD (37.4% vs 30.5%, p = 0.005, adjusted OR[95%CI] = 1.29[1.02-1.67], p = 0.04). Among patients with vitamin D levels above the median, Hcy levels did not impact on the prevalence and extent of CAD (77.7 vs 77.2%, p = 0.81, adjusted OR[95%CI] = 0.94[0.73-1.20], p = 0.60 for CAD and 31.8% vs 27.7%, p = 0.08, adjusted OR[95%CI] = 0.97[0.75-1.25], p = 0.81 for severe left main/3-vessel CAD). No significant interaction between Hcy and vitamin D with CAD or severe CAD was observed. The present study shows an independent inverse linear relationship between vitamin D and Hcy values. Moreover, the association of Hcy with the extent of CAD was significant only among patients with hypovitaminosis D, and not in the cohort of subjects with vitamin D levels above the median, suggesting that a normal vitamin D status can prevent the deleterious effects of hyperhomocysteinemia on coronary atherosclerosis, a hypothesis that certainly needs further confirmation in larger randomized trials.

Project description:BackgroundFamilial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.ObjectivesThe study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.MethodsWe assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.ResultsThe 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).ConclusionsANGPTL3 deficiency is associated with protection from CAD.

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Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine.

Publications

Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine.

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