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      Beneficial Effects of Calcitriol on Hypertension, Glucose Intolerance, Impairment of Endothelium-Dependent Vascular Relaxation, and Visceral Adiposity in Fructose-Fed Hypertensive Rats

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          Abstract

          Besides regulating calcium homeostasis, the effects of vitamin D on vascular tone and metabolic disturbances remain scarce in the literature despite an increase intake with high-fructose corn syrup worldwide. We investigated the effects of calcitriol, an active form of vitamin D, on vascular relaxation, glucose tolerance, and visceral fat pads in fructose-fed rats. Male Wistar-Kyoto rats were divided into 4 groups (n = 6 per group). Group Con: standard chow diet for 8 weeks; Group Fru: high-fructose diet (60% fructose) for 8 weeks; Group Fru-HVD: high-fructose diet as Group Fru, high-dose calcitriol treatment (20 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding; and Group Fru-LVD: high-fructose diet as Group Fru, low-dose calcitriol treatment (10 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding. Systolic blood pressure was measured twice a week by the tail-cuff method. Blood was examined for serum ionized calcium, phosphate, creatinine, glucose, triglycerides, and total cholesterol. Intra-peritoneal glucose intolerance test, aortic vascular reactivity, the weight of visceral fat pads, adipose size, and adipose angiotensin II levels were analyzed at the end of the study. The results showed that the fructose-fed rats significantly developed hypertension, impaired glucose tolerance, heavier weight and larger adipose size of visceral fat pads, and raised adipose angiotensin II expressions compared with the control rats. High- and low-dose calcitriol reduced modestly systolic blood pressure, increased endothelium-dependent aortic relaxation, ameliorated glucose intolerance, reduced the weight and adipose size of visceral fat pads, and lowered adipose angiotensin II expressions in the fructose-fed rats. However, high-dose calcitriol treatment mildly increased serum ionized calcium levels (1.44 ± 0.05 mmol/L). These results suggest a protective role of calcitriol treatment on endothelial function, glucose tolerance, and visceral adiposity in fructose-fed rats.

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          Most cited references 54

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          Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease.

          Currently, we are experiencing an epidemic of cardiorenal disease characterized by increasing rates of obesity, hypertension, the metabolic syndrome, type 2 diabetes, and kidney disease. Whereas excessive caloric intake and physical inactivity are likely important factors driving the obesity epidemic, it is important to consider additional mechanisms. We revisit an old hypothesis that sugar, particularly excessive fructose intake, has a critical role in the epidemic of cardiorenal disease. We also present evidence that the unique ability of fructose to induce an increase in uric acid may be a major mechanism by which fructose can cause cardiorenal disease. Finally, we suggest that high intakes of fructose in African Americans may explain their greater predisposition to develop cardiorenal disease, and we provide a list of testable predictions to evaluate this hypothesis.
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            A causal role for uric acid in fructose-induced metabolic syndrome.

            The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.
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              25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study.

              Vitamin D deficiency may be involved in the development of atherosclerosis and coronary heart disease in humans. We assessed prospectively whether plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with risk of coronary heart disease. A nested case-control study was conducted in 18,225 men in the Health Professionals Follow-up Study; the men were aged 40 to 75 years and were free of diagnosed cardiovascular disease at blood collection. The blood samples were returned between April 1, 1993, and November 30, 1999; 99% were received between April 1, 1993, and November 30, 1995. During 10 years of follow-up, 454 men developed nonfatal myocardial infarction or fatal coronary heart disease. Using risk set sampling, controls (n = 900) were selected in a 2:1 ratio and matched for age, date of blood collection, and smoking status. After adjustment for matched variables, men deficient in 25(OH)D ( or=30 ng/mL) (relative risk [RR], 2.42; 95% confidence interval [CI], 1.53-3.84; P < .001 for trend). After additional adjustment for family history of myocardial infarction, body mass index, alcohol consumption, physical activity, history of diabetes mellitus and hypertension, ethnicity, region, marine omega-3 intake, low- and high-density lipoprotein cholesterol levels, and triglyceride levels, this relationship remained significant (RR, 2.09; 95% CI, 1.24-3.54; P = .02 for trend). Even men with intermediate 25(OH)D levels were at elevated risk relative to those with sufficient 25(OH)D levels (22.6-29.9 ng/mL: RR, 1.60 [95% CI, 1.10-2.32]; and 15.0-22.5 ng/mL: RR, 1.43 [95% CI, 0.96-2.13], respectively). Low levels of 25(OH)D are associated with higher risk of myocardial infarction in a graded manner, even after controlling for factors known to be associated with coronary artery disease.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 March 2015
                2015
                : 10
                : 3
                Affiliations
                [1 ]Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
                [2 ]Institutes of Life Sciences, Pharmacology & Toxicology, and Medical Sciences, Tzu Chi University, Hualien, Taiwan
                [3 ]Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
                [4 ]Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
                [5 ]Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
                Institut National de la Santé et de la Recherche Médicale, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CLC TCF. Performed the experiments: CLC TCF. Analyzed the data: CLC TCF. Contributed reagents/materials/analysis tools: CYP TJFL TCF. Wrote the paper: CLC TCF.

                Article
                PONE-D-14-26679
                10.1371/journal.pone.0119843
                4361671
                25774877

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 7, Tables: 1, Pages: 19
                Product
                Funding
                This study was supported by a grant from Tzu Chi General Hospital (TCRD 102-50), Hualien, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
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                All relevant data are within the paper and its Supporting Information files.

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