cholecalciferol and Arteriosclerosis

Pronounced vascular calcium overload, especially of compliance arteries, is an important aspect of aging, and of various age-related vascular diseases such as hypertension and atherosclerosis. The development of new drugs specifically aimed at attenuating the evolution and/or pathological consequences of vascular calcium overload is hindered by the paucity of animal models available. Although several laboratory animals exhibit vascular calcium overload, this evolves slowly and is far less marked than in man. Nevertheless, Fleckenstein and associates (1989) suggested a suitable animal model involving the treatment of young rats with vitamin D3 and nicotine; such treatment produces pronounced vascular calcium overload within a few weeks. This paper describes the cardiovascular effects of such treatment, and our preliminary attempts to pharmacologically modify vascular calcium overload and its cardiovascular consequences.

Topics: Animals; Arteriosclerosis; Blood Vessels; Calcium; Cholecalciferol; Hemodynamics; Hypertension; Nicotine; Rats; Tissue Distribution

Topics: Arteriosclerosis; Cholecalciferol; Chronic Disease; Growth Hormone; Humans; Vitamin D

Imbalancing nutritionally adequate diets with an excessive amount of fat calories and cholesterol has obscured the fact that intimal thickening occurs spontaneously in time on low-fat cholesterol-free diets during the aging process, and that intimal thickening can be accelerated by dietary angiotoxic "risk factors." Electron microscopy of arterial tissue from animal models identified degenerated smooth muscle cells in the fetus from sows kept on low-fat cholesterol-free diets. After birth, the degenerated smooth muscle cells increased in number with age. The presence of angiotoxic "risk factors" such as oxidized cholesterol and vitamin D3 (cholecalciferol) in the diet of such animal models increased the frequency of smooth muscle cell death in their arteries. Two types of pathology could be developed in the thoracic aorta by continuous or short term feeding of 12.5 times more vitamin D than normally present in commercial rations: 1) a diffuse fibroelastic intimal thickening in the thoracic aorta (arteriosclerosis) with no evidence of lipid deposition by continuous feeding of vitamin D or 2) an initimal thickening in the thoracic aorta and intimal thickening with foam cells and extracellular lipid deposits (atherosclerosis) in the coronary arteries after a short period of supplemental vitamin D followed by 3 to 4 months of supplement-free diets. These two types of arterial damage were identical to that in the plugs of thoracic aorta obtained as a by-product of elective coronary bypass surgery. Although all of the possible sources of oxidized cholesterol in the diet have as yet not been identified, laboratory studies have identified oxidized cholesterol as an angiotoxic factor. Since population groups that consume less vitamin D-supplemented foods, less deep fat fried cholesterol-containing foods, and less hydrogenated fats have a lower incidence of coronary heart disease than Americans, it seems judicious for food processors to reduce these previously unconsidered risk factors to a minimum. This could be done by eliminating vitamin D2 and D3 from all vitamin supplements, from all food and cereal products and from the diet of livestock 1 month before they were killed so that the intake of vitamin D is no larger than the 400 IU/quart in milk which is necessary to prevent rickets in children. Deep fat fryers, which are kept at almost 200 C for 24 hr/day, could perhaps be replaced with microwave ovens in fast food chain outlets. Processors could hydrogenate ve

Topics: Aging; Animals; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Cell Survival; Cholecalciferol; Cholesterol; Cholesterol, Dietary; Coronary Disease; Diet; Dietary Fats; Dietary Proteins; Energy Intake; Fats, Unsaturated; Female; Humans; Lipoproteins, LDL; Myocardium; Oxidation-Reduction; Pregnancy; Risk

Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low vitamin D status. To date, randomized clinical trials of vitamin D supplementation have not found an effect, possibly because of using too low a dose of vitamin D.. To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population.. The Vitamin D Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants retracted consent, and all others (n = 5108) were included in the primary analysis.. Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years).. The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with vitamin D deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis.. Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being vitamin D deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the vitamin D group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes.. Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study.. clinicaltrials.gov Identifier: ACTRN12611000402943.

Topics: Aged; Aged, 80 and over; Angina Pectoris; Arrhythmias, Cardiac; Arteriosclerosis; Cardiovascular Diseases; Cholecalciferol; Dietary Supplements; Double-Blind Method; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; New Zealand; Proportional Hazards Models; Stroke; Venous Thrombosis; Vitamin D Deficiency; Vitamins

The aim of this study was to develop a rat model that shares the similarities of calcification in diabetes.. Male Wistar rats received a high-fat diet during 8 weeks followed by a low dose of streptozotocin. Half of them were treated with vitamin D3 and nicotine (VDN) 1 week after streptozotocin injection (DM) (DM+VDN). The others were treated with vehicle (DM). Arterial calcification was facilitated by vitamin D3 and nicotine in age-matched rats (VDN). Measurements of metabolic parameters, aortic calcium content, von Kossa staining, alkaline phosphatase activity and immunohistochemistry for osteopontin were performed. The expression of genes and proteins associated with calcification were also examined.. Treatment with VDN alone resulted in a small but not significant elevation of calcium content in aorta. However, in DM+VDN, aortic calcium content increased significantly as compared to the VDN. This calcification had also dramatically increased, as shown by von Kossa staining. Mechanistic studies revealed that addition of VDN treatment in diabetic rats enhanced both activity and mRNA expression of alkaline phosphatase. This treatment in diabetic- rats also enhanced the expression of core binding factor α 1 and its downstream protein osteopontin. In aorta, strong immunostaining for osteopontin was observed in DM+VDN. The result was also confirmed by Western blot analysis.. These results suggest that a model of accelerated arterial calcification in diabetes have been established and this model could be useful to investigate mechanisms related to vascular complication in diabetes.

Topics: Alkaline Phosphatase; Animals; Arteriosclerosis; Blotting, Western; Bone Density Conservation Agents; Calcium; Cholecalciferol; Diabetes Complications; Diabetes Mellitus, Experimental; Diet, High-Fat; Disease Models, Animal; Immunoenzyme Techniques; Male; Nicotine; Nicotinic Agonists; Osteopontin; Rats; Rats, Wistar; Vascular Calcification

Matrix Gla Protein (MGP) is a small protein which is thought to be an inhibitor of tissue calcification and a regulator of cell differentiation. In this study we have examined the transcriptional regulation of MGP within rat vascular smooth muscle cells (VSMCs). We found that MGP transcription is downregulated by retinoic acid and transforming growth factor beta (TGF beta) whereas it is upregulated by vitamin D3 and cyclic AMP.

Topics: Animals; Arteriosclerosis; Calcinosis; Calcium-Binding Proteins; Cholecalciferol; Cyclic AMP; Down-Regulation; Extracellular Matrix Proteins; Gene Expression Regulation; Humans; Matrix Gla Protein; Muscle, Smooth, Vascular; Rats; Transcription, Genetic; Transforming Growth Factor beta; Tretinoin; Up-Regulation

In man, i) arteries calcify with age and ii) age-linked arterial calcification is amplified by vascular pathology such as hypertension or arteriosclerosis. Age-linked arterial calcification has a bad prognosis but drugs to prevent it are lacking. This is partially due to the lack of appropriate animal models. This paper looks at the extent to which arteries calcify with age in the rat and whether hypertension or arteriosclerosis amplifies such calcification. Total calcium levels were determined by acid digestion and flame spectrophotometry and intracellular calcium levels ([Ca2+]i) by the intracellular calcium-sensitive dye, fura-2. Arteries contained up to 5 times more calcium than other soft tissues. Arteries progressively calcified with age whereas other soft tissues did not. Accumulation of calcium with age was essentially extracellular. Hypertension had no effect on age-related arterial calcification. Calcification of the same order as in man was produced in a rat model of arteriosclerosis (vitamin D plus nicotine treatment). In conclusion, as in man, age-linked, organ-specific arterial calcification does occur in rats but its intensity is far less. Arterial calcification of a similar degree to that observed in man can be obtained in rats by hypervitaminosis D plus nicotine.

Topics: Aging; Animals; Aorta, Thoracic; Arteriosclerosis; Calcification, Physiologic; Calcium; Cholecalciferol; Hypertension; Male; Nicotine; Rats; Rats, Inbred F344; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar

Vitamin D3-induced mural calcification represents an animal model for investigating experimental calcium (Ca) overload and calcification of arterial walls. In this study, long-term progression of calcific degeneration in coronary arteries of rats after one intoxication with vitamin D3 was examined, as well as possible regression of preestablished mural Ca overload with the Ca antagonist verapamil. Sprague-Dawley rats were treated with one intramuscular (i.m.) overdose of vitamin D3 [300,000 IU/kg body weight (b.w.)]. Oral verapamil therapy (100 mg/kg/day b.w. for 24 weeks) was initiated 14 days after the vitamin D3 intoxication. Arteriosclerotic alterations were verified by microchemical analyses of tissue Ca and of cholesterol contents with atomic absorption spectroscopy (special graphite tube technique) and gas chromatography, respectively, and by standard histological techniques. Serum lipids were determined by sequential ultracentrifugation. Between week 3 and week 26 after the vitamin D3 injection, a progressive Ca incorporation from 448.8 +/- 110 to 1,310 +/- 166.3% of control values (i.e., coronary Ca content in 32-week-old untreated control rats = 100%) was observed, associated with calcific morphological lesions, and reactive intimal plaque formation. Verapamil prevented this progression and induced a regression of preestablished mural Ca overload. Therefore, the coronary Ca content after 24 weeks of verapamil treatment amounted to only 146.3 +/- 53.8% of controls. The data indicate that an initial calcific lesion of coronary arteries may serve as crystallization nucleus for advancing Ca overload and morphological alterations.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arteriosclerosis; Calcinosis; Calcium; Calcium Channel Blockers; Cholecalciferol; Coronary Vessels; Lipids; Male; Rats; Rats, Sprague-Dawley; Verapamil

According to chemical analyses, the development of conventional human coronary artery plaques from "fatty streaks" to "fibrous plaques" and "complicated lesions" is dominated by progressive mural calcium (Ca) incorporation. The atherogenic significance of Ca ions and arterial Ca overload was examined under the influence of nicotine, oxidatively modified low-density lipoproteins, spontaneous hypertension, and an elevated extracellular Ca concentration or vitamin D3. Experiments were carried out either in vitro on cultured medial cells of rats or in vivo on various types of experimental arteriosclerosis of rats. Suitable Ca antagonists (verapamil, diltiazem, nifedipine, or nitrendipine) prevented experimental Ca overload of arterial walls and transmembrane Ca uptake into cultured medial cells produced by risk factors. Thus they protected, in vivo and/or in vitro, against the atherogenic potential of Ca ions, i.e., migration, proliferation, matrix production and intracellular Ca overload of vascular smooth-muscle cells, as well as calcification of elastic fibers. The data indicate that various Ca-consuming processes demand a progressive uptake of Ca into arterial walls if Ca-dominated types of arteriosclerosis develop. Under experimental conditions, specific Ca antagonists inhibit Ca-mediated arteriosclerotic alterations by preventing progressive mural Ca incorporation.

Topics: Adult; Aged; Aged, 80 and over; Animals; Arteriosclerosis; Calcium; Calcium Channel Blockers; Cells, Cultured; Cholecalciferol; Cholesterol; Coronary Vessels; Diltiazem; Disease Models, Animal; Humans; Hypertension; Middle Aged; Muscle, Smooth, Vascular; Nicotine; Nifedipine; Nitrendipine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Risk Factors; Verapamil

The therapeutic effects of calcium antagonist diltiazem on cerebrovascular smooth muscle of sclerotic and normal rats has been investigated. Arteriosclerosis was caused by treatment of the rats with a water soluble 1,25-dihydro-cholecalciferol in a dose of 97,000 IU. After 2-4 days, serum urea of the treated animals was increased from 56 +/- 8 to 78 +/- 17 mg/dl. Histological examinations of tissue probes from kidneys, heart, aorta and the major arteries by means of the staining method according to von Kossa clearly showed the picture of the Mönckeberg-type atherosclerosis. The calcified rats (N = 23) and the control group (N = 25) were anesthetized with ketamine/xylazine. Following craniotomy and tracheotomy for artificial ventilation, surface PO2 of the cerebro-cortex and cerebral blood flow via the inhalatory hydrogen clearance technique were measured. Surface PO2 frequency distribution of vitamin D3 treated animals showed a left shift (mean +/- SD = 29 +/- 8 compared with 34 +/- 6 mm Hg for controls) and a CBF decrease (1.36 +/- 0.51 compared to 1.50 +/- 0.60 ml/g.min for the controls). Diltiazem infusion of 2 ml/h corresponding to 5 micrograms/kg bw after 5 minutes caused a slight CBF decrease (1.50 +/- 0.60 to 1.43 +/- 0.78 ml/g.min) in controls and an insignificant CBF reduction in sclerotic rats. Mean arterial blood pressure was lowered by diltiazem infusion. The hypertensive sclerotic rats became almost normal (148 +/- 18 to 91 +/- 15 mm Hg) while the control animals decreased in MAP from 118 to 80 +/- 15 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arteriosclerosis; Cerebral Cortex; Cerebrovascular Circulation; Cholecalciferol; Creatine; Diltiazem; Female; Oxygen; Rats; Rats, Inbred Strains; Urea

Combined administration of vitamin D3 and nicotine produced severe myocardial and aortic calcinosis in mice within 4 days. Treatment of these mice with taurine increased the survival rate of the mice and reduced the elevation of calcium content in both aorta and myocardium as did diltiazem treatment. The present study suggests that taurine which is capable of regulating calcium flux may also prevent the progression of arteriosclerosis.

Topics: Animals; Aorta; Arteries; Arteriosclerosis; Calcinosis; Calcium; Cholecalciferol; Diltiazem; Male; Mice; Myocardium; Taurine

Atherosclerosis was induced in growing chickens by the administration of a diet containing elevated levels of cholesterol and vitamin D3. The effect of this diet on the accumulation of insoluble elastin and the synthesis of soluble and insoluble elastin in the thoracic aortas of these animals was measured. Although the diet resulted in significant increases in levels of cholesterol, 25-OH vitamin D3 and calcium in plasma, increased levels of cholesterol and calcium in aortic tissue, and histological evidence of aortic lipid deposition, there were no detectable differences between experimental and control animals in either the rate or the time course of accumulation of total insoluble elastin in the thoracic aorta, or in the rate and time course of synthesis of soluble and insoluble elastin. These data suggest that, at least in this model, any effect of atherosclerosis on aortic elastin production must be either small or so localized as to be not measurable by the methods used.

Topics: Animals; Animals, Newborn; Aorta; Arteriosclerosis; Calcifediol; Calcium; Chickens; Cholecalciferol; Cholesterol; Diet; Elastin; Female

The early fine structural changes in the arteries of rats induced by excess vitamin D3 perorally or parenterally were essentially similar, except the latter had a more prominent toxic effect to the vascular wall. The ultrastructural features, incidental to calcification, included the appearance of increased ground substance with a separation of collagenous and elastic fibrils, and degenerative changes in smooth muscle cells. Atherosclerosis was greatly accelerated at the sites of vascular injury when cholesterol, cholic acid and thiouracil were added to the basal diet. Calcification was initially observed in relation to elastic fibrils or degenerated cells in the upper and middle layers of the arteries, although there were few such deposits in the thickened intima of the coronary arteries. Calcium deposition could not be a direct effect of hypercalcemia, but the functional activity of smooth muscle cells did seem to promote the mineralization of calcium and phosphate. Furthermore, vitamin D-induced sclerosis did not prevent intimal thickening of the arteries when vitamin D3 was withdrawn.

Topics: Animals; Aorta; Arteries; Arteriosclerosis; Cholecalciferol; Cholesterol, Dietary; Coronary Vessels; Male; Rats

Coronary atherosclerosis developed in normolipemic swine fed a basal ration supplemented with 125,000 IU, 62,500 IU and 31,250 IU of vitamin D3/kg of diet for 3 months and subsequently only the basal ration for the following 3 months. Lesions consisted of intimal atheromata and calcified internal elastica and caused luminal narrowing. The incidence of atherosclerotic lesions was proportional to the vitamin D3 doses. The present experimentally induced lesions had many morphological features resembling those in coronary arteries from human subjects.

Topics: Adult; Aged; Animals; Arteries; Arteriosclerosis; Calcinosis; Calcium; Cholecalciferol; Cholesterol; Coronary Disease; Coronary Vessels; Disease Models, Animal; Humans; Middle Aged; Swine

Topics: Animals; Aorta; Arteriosclerosis; Cells, Cultured; Cholecalciferol; Cholesterol; Cholesterol, Dietary; Ergocalciferols; Haplorhini; Saimiri

Authors by a new combined diet consisting of cholesterol vitamin D3 and sour cream produced clinico-biochemical changes characteristic for atherosclerosis in a very short period in rabbits. This diet caused severe lipoproteinaemia, hypercholesterinaemia and microscopis and macroscopic changes in the aortic wall. Authors assume, that this diet is suitable for producin atherosclerosis in a short period.

Topics: Animals; Arteriosclerosis; Cholecalciferol; Cholesterol; Diet, Atherogenic; Hypercholesterolemia; Hyperlipidemias; Rabbits

The history, clinical signs and post mortem findings in a cow with metastatic pulmonary calcification and calcific arteriosclerosis after vitamin D3 treatment are described.

Topics: Animals; Arteriosclerosis; Calcinosis; Cattle; Cattle Diseases; Cholecalciferol; Female; Lung Diseases

The tissues of human subjects assayed for a higher level of vitamin D than the tissues of 6-month-old swine which had been fed a commercial ration containing 14 times more vitamin D3 than the National Research Council recommended requirement for growing swine. Bioassays of commercial livestock feeds indicate much higher vitamin D contents than the National Research Council recommendation. High levels of vitamin D activity are demonstrable in tissues from the animals on such livestock feeds. The grossly normal areas of the aorta of weanling swine fed 100,000 IU of vitamin D3/pound of basal ration during the initial 6 weeks had a higher frequency of degenerated smooth muscle cells than the grossly normal areas of the aorta of swine fed the commercial ration, or 7.43+/-0.45 and 5.60+/-0.27/100 cells, respectively, at the age of 3 months. Tbe addition of 13 pounds of hydrogenated fat and 200 g of cholesterol/100 pounds of the commercial ration further increased the frequency of degenerated smooth muscle cells by 0.53 (P less than 0.05) or to 7.96 +/- 0.39/100 cells in the grossly normal areas of the aorta of weanling swine fed this fat-supplemented ration to 3 months of age.

Topics: Adipose Tissue; Animal Feed; Animals; Aorta, Abdominal; Arteriosclerosis; Child; Cholecalciferol; Cholesterol, Dietary; Dietary Fats; Female; Humans; Infant; Liver; Muscles; Nutritional Requirements; Pregnancy; Species Specificity; Swine; United States; Vitamin D

Topics: Age Factors; Animals; Arteriosclerosis; Blood Vessels; Calcinosis; Calcium; Calcium Chloride; Cholecalciferol; Choline; Dihydrotachysterol; Female; Rats

Topics: Animals; Aorta; Aortic Diseases; Arteriosclerosis; Calciphylaxis; Calcium; Cholecalciferol; Cholesterol; Elastic Tissue; Esters; Female; Gluconates; Histocytochemistry; Lipids; Male; Microscopy, Polarization; Rabbits; Reticulin

Topics: Arteries; Arteriosclerosis; Cholecalciferol; Cholesterol; Chromatography; Coronary Disease; Desmosterol; Drug Therapy; Lipid Metabolism; Tissue Distribution; Triparanol

Topics: Animals; Aorta; Arteriosclerosis; Cholecalciferol; Pathology; Pharmacology; Research; Sheep; Sheep, Domestic; Toxicology