The molecular biology and pathophysiology of vascular calcification.

Vascular calcification (VC), commonly encountered in renal failure, diabetes, and aging, is associated with a large increase in the risk for cardiovascular events and mortality. Calcification of the arterial media and of heart valves clearly plays a mediating role in this regard, whereas it is less clear how calcification of plaque influences atherogenesis and risk for plaque rupture. Vascular calcification is an active process in which vascular smooth muscle cells (VSMCs) adopt an osteoblastic phenotype and deposit hydroxyapatite crystals; apoptosis of VSMCs also promotes this deposition. Drivers of this phenotypic transition, which include elevated serum phosphate, advanced glycation end-products, bone morphogenetic proteins, inflammatory cytokines, and leptin, invariably induce oxidative stress in VSMCs, which appears to be a necessary and sufficient condition for induction of the runt-related transcription factor 2 gene (RUNX2) and the shift to osteoblastic behavior. Magnesium antagonizes the impact of phosphate on VSMC osteoblastic transition, both by a direct effect within VSMCs and by suppressing absorption of dietary phosphate. Antioxidants that suppress reduced nicotinamide adenine dinucleotide phosphate oxidase activity may have the potential to block the osteoblastic transition of VSMCs. Minimizing the absorption of dietary phosphate may also be helpful in this regard, particularly in renal failure, and it can be achieved with plant-based dietary choices, avoidance of phosphate additives, and administration of pharmaceutical phosphate binders, supplemental magnesium, and niacin. Good vitamin K status opposes VC by optimizing the γ-carboxylation of matrix Gla protein, a physiological antagonist of VC. Adequate but not excessive vitamin D status also appears to discourage VC. Etidronate, a structural analogue of pyrophosphate, has shown potential for blocking VC.

Vascular remodeling and media calcification increases arterial stiffness in chronic kidney disease.

BACKGROUND: Cardiovascular disease is the most common cause of death in patients with chronic kidney disease (CKD). Arterial stiffness and calcification are non-traditional risk factors of cardiovascular disease in CKD. In CKD rats, we investigated the involvement of smooth muscle cells differentiation to osteoblast-like cells and blood vessel wall remodeling, associated with media calcification, in arterial stiffness. METHOD: CKD with vascular calcification was induced by subtotal nephrectomy followed by treatment with a high calcium and phosphate diet, and vitamin D supplementation (Ca/P/VitD). At week 3-6, hemodynamic parameters and pulse wave velocity (PWV) were assessed. Vascular media calcification and remodeling were determined by histological von Kossa staining and confocal immunofluorescence analysis of osteocalcin, elastin, α-smooth muscle actin (α-SMA) and collagen-1. RESULTS: Treatment of CKD rats with Ca/P/VitD, but not normal animals, induced a significant increase in pulse pressure and PWV (p < 0.05) and marked calcification in the media. In calcification areas, de novo expression of osteocalcin was observed, whereas α-SMA immunofluorescence levels were reduced (p < 0.01). The immunofluorescence levels of elastin were also reduced, which was related to disruption of elastic lamella. In contrast, collagen-1 immunofluorescence levels in areas of calcification were increased (p < 0.01). Changes in both α-SMA and elastin inversely correlated with the PWV. CONCLUSION: This study indicate that smooth muscle cells differentiation to osteoblast-like cells and the associated media remodeling, which includes disruption of elastic lamellas and deposition of collagen are, at least in part, associated with the increased arterial stiffness observed in CKD rats with vascular calcification.

Morphometric analysis of the influence of selenium over vasospastic femoral artery in rats.

BACKGROUND: Cerebral vasospasm (CV) is the leading cause of morbidity and mortality occurring after subarachnoid hemorrhage (SAH). Etiopathogenesis of CV is multifactorial. Selenium is the cofactor of the glutathione peroxidase (GSH-Px) enzyme which is a very important defense mechanism against antioxidants. According to the literature, oxidants are known to play a remarkable role in the pathogenesis of vasospasm occurring after SAH. Therefore, many studies have been conducted with antioxidant agents, based on the theory that elevated activity of GSH-Px enzyme might prevent the development of CV after SAH. Majority of those studies reported positive results. However, as a result of our literature review, we came across no study which involves the investigation of the role of selenium alone in the prevention of CV after SAH. In our study, we aim to find the answer to the following question: "Can selenium alone prevent cerebral vasospasm following SAH at early stage?" METHODS: We used the "rat femoral artery vasospasm model" of Okada et al. as the vasospasm model of our study. First, rats were divided into three groups: group 1 (n = 8), control group; group 2 (n = 8), vasospasm group; and group 3 (n = 8), vasospasm + selenium group. Statistical comparison of groups 1 and 2 revealed significant thickening in the vascular wall and a decrease in the lumen diameter in group 2, compared with group 1. Statistical comparison of the vascular lumen diameters of groups 1 and 3 showed no significant difference, whereas the comparison of mean vascular wall thickness displayed a significant increase in group 3. Moreover, statistical comparison of groups 2 and 3 regarding vascular lumen diameters showed a significant decrease in group 2, whereas group 3 displayed a significant decrease in terms of vascular wall thickness. CONCLUSION: According to the results of our study, selenium morphometrically prevents the development of peripheral vasospasms.

Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study.

OBJECTIVES: Our aim was to determine the effects of high-dose (2 g) nicotinic acid (NA) on progression of atherosclerosis and measures of vascular function. BACKGROUND: NA raises high-density lipoprotein cholesterol (HDL-C) and reduces low-density lipoprotein cholesterol and is widely used as an adjunct to statin therapy in patients with coronary artery disease. Although changes in plasma lipoproteins suggest potential benefit, there is limited evidence of the effects of NA on disease progression when added to contemporary statin treatment. METHODS: We performed a double-blind, randomized, placebo-controlled study of 2 g daily modified-release NA added to statin therapy in 71 patients with low HDL-C (<40 mg/dl) and either: 1) type 2 diabetes with coronary heart disease; or 2) carotid/peripheral atherosclerosis. The primary end point was the change in carotid artery wall area, quantified by magnetic resonance imaging, after 1 year. RESULTS: NA increased HDL-C by 23% and decreased low-density lipoprotein cholesterol by 19%. At 12 months, NA significantly reduced carotid wall area compared with placebo (adjusted treatment difference: -1.64 mm(2) [95% confidence interval: -3.12 to -0.16]; p = 0.03). Mean change in carotid wall area was -1.1 +/- 2.6 mm(2) for NA versus +1.2 +/- 3.0 mm(2) for placebo. In both the treatment and placebo groups, larger plaques were more prone to changes in size (r = 0.4, p = 0.04 for placebo, and r = -0.5, p = 0.02 for NA). CONCLUSIONS: In statin-treated patients with low HDL-C, high-dose modified-release NA, compared with placebo, significantly reduces carotid atherosclerosis within 12 months. (Oxford Niaspan Study: Effects of Niaspan on Atherosclerosis and Endothelial Function; NCT00232531).

Effect of alpha lipoic acid on oxidative stress and vascular wall of diabetic rats.

UNLABELLED: PREMISES AND OBJECTIVES: Antioxidant plays an important role in preventing the progression of diabetes mellitus (DM) complications. The aim of the present study was to investigate the effect of alpha lipoic acid (ALA) supplementation on plasma lipid, oxidative stress and vascular changes in diabetic rats. MATERIAL AND METHODS: Diabetes was induced by a single intravenous injection of streptozotocin (STZ) (50 mg/kg). The diabetic rats were divided into two groups: (i) supplemented group with ALA (100 mg/kg/day) and (ii) non-supplemented group without ALA. Non-diabetic rats (NDM) formed the control group, which received saline injection. RESULTS: Following eight weeks of supplementation, fasting blood glucose (FBG) and glycosylated hemoglobin (HBA1c) in ALA-supplemented rats was found to be significantly lower than the non-supplemented group. ALA-supplementation also improved dyslipidemia that occurred in diabetic rats. ALA-supplementation also significantly increased plasma superoxide dismutase (SOD) activity and vitamin C level as compared to the No Suppl group. The increase in plasma and aorta malondealdehyde + 4-hydroxynonenal (MDA + 4-HNE) levels were also inhibited and the levels of oxidative DNA damage of peripheral lymphocytes were significantly reduced. Electron microscopic examination of thoracic aorta revealed that normal tissue organization was disrupted in STZ-diabetic rats with ALA-supplementation reducing the changes in the vascular morphology. CONCLUSIONS: It is concluded that ALA has the potential in preventing the alteration of vascular morphology in diabetic rats probably through the improvement of glycemic status and dyslipidemia as well as its antioxidant activities.

The effect of long-term homocysteine-lowering on carotid intima-media thickness and flow-mediated vasodilation in stroke patients: a randomized controlled trial and meta-analysis.

BACKGROUND: Experimental and epidemiological evidence suggests that homocysteine (tHcy) may be a causal risk factor for atherosclerosis. B-vitamin supplements reduce tHcy and improve endothelial function in short term trials, but the long-term effects of the treatment on vascular structure and function are unknown. METHODS: We conducted a sub-study of VITATOPS, a randomised, double-blind, placebo-controlled intervention trial designed to test the efficacy of long term B-vitamin supplementation (folic acid 2 mg, vitamin B6 25 mg and vitamin B12 0.5 mg) in the prevention of vascular events in patients with a history of stroke. We measured carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) at least two years after randomisation in 162 VITATOPS participants. We also conducted a systematic review and meta-analysis of studies designed to test the effect of B-vitamin treatment on CIMT and FMD. RESULTS: After a mean treatment period of 3.9 +/- 0.9 years, the vitamin-treated group had a significantly lower mean plasma homocysteine concentration than the placebo-treated group (7.9 micromol/L, 95% CI 7.5 to 8.4 versus 11.8 micromol/L, 95% CI 10.9 to 12.8, p < 0.001). Post-treatment CIMT (0.84 +/- 0.17 mm vitamins versus 0.83 +/- 0.18 mm placebo, p = 0.74) and FMD (median of 4.0%, IQR 0.9 to 7.2 vitamins versus 3.0%, IQR 0.6 to 6.6 placebo, p = 0.48) did not differ significantly between groups. A meta-analysis of published randomised data, including those from the current study, suggested that B-vitamin supplements should reduce CIMT (-0.10 mm, 95% CI -0.20 to -0.01 mm) and increase FMD (1.4%, 95% CI 0.7 to 2.1%). However, the improvement in endothelial function associated with homocysteine-lowering treatment was significant in short-term studies but not in longer trials. CONCLUSION: Although short-term treatment with B-vitamins is associated with increased FMD, long-term homocysteine-lowering did not significantly improve FMD or CIMT in people with a history of stroke.

Global vasomotor dysfunction and accelerated vascular aging in beta-thalassemia major.

BACKGROUND: Patients with beta-thalassemia major (beta-TM) demonstrate an increased incidence of vascular complications, which are thought to result from a procoagulant/proinflammatory environment. We investigated the arterial vasorelaxing capacity and sought for early carotid atherosclerosis and underlying pathophysiological correlates in these transfusion-dependent patients. METHODS AND RESULTS: The vasodilatory properties of the brachial artery and the carotid intima-media thickness (IMT) were examined with ultrasonography in 35 non-diabetic young adults with beta-TM (patient group) and 35 control subjects (control group). Among thalassemic patients, both endothelium-dependent (FMD) and -independent dilatation (FID) as well as their ratio was impaired, whereas IMT was increased (p<0.01). Patients on optimal, as compared with those on non-optimal chelation treatment had a non-significantly lower IMT. Vasodilatory capacity in the patient group was inversely correlated with IMT and independently associated either with the quality of chelation therapy (FMD) or serum ferritin levels (FID). Plasma concentrations of D-dimers, circulating markers of endothelial activation, inflammation and apoptosis were higher, while plasma cholesterol and fibrinogen levels were lower-than-normal in the patient group. Independent predictors of IMT among thalassemic patients were tumor necrosis factor-alpha levels and age. CONCLUSIONS: Young adults with beta-TM exhibit both a global impairment of arterial vasorelaxation and early carotid atherosclerosis. A procoagulant/proinflammatory state in these transfusion-dependent patients may overwhelm atheroprotective mechanisms, including an optimal chelation regimen, and promote vascular injury and atherogenesis.