Permissions: Requests for permissions to reproduce figures, tables, or portions of articles origi... more Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at:
Abstract Vascular calcification is a significant component of atherosclerosis and has important c... more Abstract Vascular calcification is a significant component of atherosclerosis and has important clinical implications, such as being a marker of the atherosclerotic burden and predictor of future coronary events. There are two pathophysiological processes involved in the development of vascular calcification: apoptosis and phenotypic changes to chondrocytes or osteoblasts (chondro-/osteogenic differentiation). Vascular calcification associated with phenotypic changes of vascular smooth muscle cells are facilitated by inflammationinduced ALP expression or an inorganic phosphate signaling pathway via Pit-1. These mechanisms may operate to develop vascular calcification associated with atherosclerosis and chronic kidney disease (CKD). Moreover, the functional derangement of inhibitory molecules (inhibitors of vascular calcification) such as MGP, fetuin-A, and OPG may be involved in the progression of vascular calcification under various pathological conditions.
A close relationship has been reported between microalbuminuria and atherosclerosis in patients w... more A close relationship has been reported between microalbuminuria and atherosclerosis in patients with diabetes mellitus. The aim of this study was to determine which of the 2 aspects of atherosclerosis, arterial thickening or stiffness, has more effect on levels of microalbuminuria in type 2 diabetic patients. Twenty-four-hour urine samples of 167 Japanese type 2 diabetic patients (aged 58 +/- 12 years) without overt proteinuria were collected for quantitative analysis of urinary albumin excretion (UAE). Arterial stiffness was evaluated by measuring aortic pulse-wave velocity (PWV), and arterial thickness was measured by the intima-media thickness (IMT) of the carotid artery. The aortic PWV and carotid IMT were both significantly positively correlated with logarithmically transformed UAE (r=0.269, p<0.001; and r=0.188, p<0.05, respectively). Although there was a significant positive correlation between aortic PWV and carotid IMT (r=0.263, p<0.001), multiple regression analys...
Protein deficiency was proposed as one of the main causes of osteoporosis by Albright and Reifens... more Protein deficiency was proposed as one of the main causes of osteoporosis by Albright and Reifenstein [1]. Malnutrition, hypovitaminosis C, Cushing's syndrome and alarm reaction were included in the category of osteoporosis due to protein loss. Albright described some cases of idiopathic osteoporosis in which the effects of low and high protein intake as well as those of intravenous administration of albumin were observed. Fourman and Royer [22] also suggested that protein deficiency could be a cause of osteoporosis. On the other hand it has been reported that a high intake of protein may be a risk factor in the pathogenesis of osteoporosis, by inducing hypercalciuria [3]. In the present investigations the effects of a low albumin diet and bone changes in genetically albumin deficient rats were studied.
Although lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (... more Although lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decreases the progression of coronary artery and aortic valve calcification, the mechanism of action of these drugs to inhibit the calcification process remains unclear. In this study, we investigated the effect of statins such as cerivastatin and atorvastatin on vascular calcification by utilizing an in vitro model of inflammatory vascular calcification. Cerivastatin and atorvastatin dose-dependently inhibited in vitro calcification of human vascular smooth muscle cells (HVSMCs) induced by the following inflammatory mediators (IM): interferon-gamma, 1alpha,25-dihydroxyvitamin D3, tumor necrosis factor-alpha, and oncostatin M. These statins also depressed expression of alkaline phosphatase (ALP) in HVSMCs induced by these factors. Mevalonate and geranylgeranylpyrophosphate reversed the inhibitory effect of cerivastatin on ALP expression in HVSMCs, while farnesylpyrophosphate showed no effect on the ALP activities inhibited by this drug, suggesting that inhibition of Rho and its downstream target, Rho kinase may mediate the inhibitory effect of cerivastatin. Cerivastatin prevented RhoA activation in HVSMCs induced by the IM. A specific inhibitor of Rho kinase (Y-27632) inhibited in vitro calcification and induction of ALP in HVSMCs. These findings provide a possible mechanism of statins to prevent the progression of calcification in inflammatory vascular diseases such as atherosclerosis and cardiac valvular calcification.
Inflammatory cells such as macrophages and T lymphocytes play an important role in vascular calci... more Inflammatory cells such as macrophages and T lymphocytes play an important role in vascular calcification associated with atherosclerosis and cardiac valvular disease. In particular, macrophages activated with cytokines derived from T lymphocytes such as interferon-γ (IFN-γ) may contribute to the development of vascular calcification. Moreover, we have shown the stimulatory effect of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) on in vitro calcification through increasing the expression of alkaline phosphatase (ALP), an ectoenzyme indispensable for bone mineralization, in vascular smooth muscle cells. Therefore, we hypothesized that macrophages may induce calcifying phenotype, especially the expression of ALP in human vascular smooth muscle cells (HVSMCs) in the presence of IFN-γ and 1,25(OH) 2 D 3 . To test this hypothesis, we used cocultures of HVSMCs with human monocytic cell line (THP-1) or peripheral blood monocytes (PBMCs) in the presence of IFN-γ and 1,25(OH) 2 D 3 . THP-1 ce...
Background—Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis f... more Background—Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family. OPG-deficient mice develop severe osteoporosis and medial arterial calcification of the aorta and renal arteries. OPG immunoreactivity was demonstrated in the normal blood vessels and in early atherosclerotic lesions. A recent clinical study suggests that there is a significant correlation between elevated serum OPG levels and cardiovascular mortality. We examined whether serum OPG levels are associated with the progression of coronary artery disease (CAD).Methods and Results—Serum OPG levels were examined in 201 patients who underwent coronary angiography because of stable chest pain. The number of diseased vessels was used to represent the severity of CAD. Serum OPG levels were measured by ELISA and were significantly greater in patients with significant stenosis of the coronary arteries than in those without stenosis. As the severity of CAD increased, there was ...
Background— Recent genetic animal models reveal important roles of platelet P-selectin on progres... more Background— Recent genetic animal models reveal important roles of platelet P-selectin on progression of atherosclerosis. In the present study, we examine the relation between platelet P-selectin expression and atherosclerotic parameters in 517 subjects. Methods and Results— Unrelated subjects (n=517; 235 male and 282 female), including 187 with type 2 diabetes, 184 with hypertension, and 366 with hyperlipidemia, were enrolled in the study. P-selectin expression was determined by whole-blood flow cytometry. Arterial stiffness (stiffness index β) and arterial wall thickness (intima-media thickness [IMT]) were determined by carotid ultrasound. P-selectin expression was significantly and positively correlated with carotid IMT and stiffness index β. Multiple regression analyses showed that the association of the percentage of P-selectin–positive platelets with carotid IMT was independent of other clinical factors. Moreover, the percentage of P-selectin–positive platelets was higher in s...
Background —A significant association between vascular calcification and osteoporosis has been no... more Background —A significant association between vascular calcification and osteoporosis has been noted, suggesting that calcium homeostasis is important in vascular calcification as well as in osteoporosis. Moreover, results of our previous studies suggest that calcium-regulating hormones such as parathyroid hormone–related peptide (PTHrP) may modulate vascular calcification. Therefore, we hypothesized that 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] may have a direct impact on the calcium-regulating system of vascular smooth muscle cells, resulting in deposition of calcium in vascular wall. Methods and Results —We investigated the effect of 1,25(OH) 2 D 3 on in vitro calcification by bovine vascular smooth muscle cells (BVSMCs). 1,25(OH) 2 D 3 dose dependently increased BVSMC calcification and alkaline phosphatase activity. 1,25(OH) 2 D 3 also decreased secretion of PTHrP by BVSMCs in a dose-dependent manner and depressed its gene expression. Furthermore, exogenous PTHrP (fragment 1...
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles origi... more Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at:
Abstract Vascular calcification is a significant component of atherosclerosis and has important c... more Abstract Vascular calcification is a significant component of atherosclerosis and has important clinical implications, such as being a marker of the atherosclerotic burden and predictor of future coronary events. There are two pathophysiological processes involved in the development of vascular calcification: apoptosis and phenotypic changes to chondrocytes or osteoblasts (chondro-/osteogenic differentiation). Vascular calcification associated with phenotypic changes of vascular smooth muscle cells are facilitated by inflammationinduced ALP expression or an inorganic phosphate signaling pathway via Pit-1. These mechanisms may operate to develop vascular calcification associated with atherosclerosis and chronic kidney disease (CKD). Moreover, the functional derangement of inhibitory molecules (inhibitors of vascular calcification) such as MGP, fetuin-A, and OPG may be involved in the progression of vascular calcification under various pathological conditions.
A close relationship has been reported between microalbuminuria and atherosclerosis in patients w... more A close relationship has been reported between microalbuminuria and atherosclerosis in patients with diabetes mellitus. The aim of this study was to determine which of the 2 aspects of atherosclerosis, arterial thickening or stiffness, has more effect on levels of microalbuminuria in type 2 diabetic patients. Twenty-four-hour urine samples of 167 Japanese type 2 diabetic patients (aged 58 +/- 12 years) without overt proteinuria were collected for quantitative analysis of urinary albumin excretion (UAE). Arterial stiffness was evaluated by measuring aortic pulse-wave velocity (PWV), and arterial thickness was measured by the intima-media thickness (IMT) of the carotid artery. The aortic PWV and carotid IMT were both significantly positively correlated with logarithmically transformed UAE (r=0.269, p<0.001; and r=0.188, p<0.05, respectively). Although there was a significant positive correlation between aortic PWV and carotid IMT (r=0.263, p<0.001), multiple regression analys...
Protein deficiency was proposed as one of the main causes of osteoporosis by Albright and Reifens... more Protein deficiency was proposed as one of the main causes of osteoporosis by Albright and Reifenstein [1]. Malnutrition, hypovitaminosis C, Cushing's syndrome and alarm reaction were included in the category of osteoporosis due to protein loss. Albright described some cases of idiopathic osteoporosis in which the effects of low and high protein intake as well as those of intravenous administration of albumin were observed. Fourman and Royer [22] also suggested that protein deficiency could be a cause of osteoporosis. On the other hand it has been reported that a high intake of protein may be a risk factor in the pathogenesis of osteoporosis, by inducing hypercalciuria [3]. In the present investigations the effects of a low albumin diet and bone changes in genetically albumin deficient rats were studied.
Although lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (... more Although lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decreases the progression of coronary artery and aortic valve calcification, the mechanism of action of these drugs to inhibit the calcification process remains unclear. In this study, we investigated the effect of statins such as cerivastatin and atorvastatin on vascular calcification by utilizing an in vitro model of inflammatory vascular calcification. Cerivastatin and atorvastatin dose-dependently inhibited in vitro calcification of human vascular smooth muscle cells (HVSMCs) induced by the following inflammatory mediators (IM): interferon-gamma, 1alpha,25-dihydroxyvitamin D3, tumor necrosis factor-alpha, and oncostatin M. These statins also depressed expression of alkaline phosphatase (ALP) in HVSMCs induced by these factors. Mevalonate and geranylgeranylpyrophosphate reversed the inhibitory effect of cerivastatin on ALP expression in HVSMCs, while farnesylpyrophosphate showed no effect on the ALP activities inhibited by this drug, suggesting that inhibition of Rho and its downstream target, Rho kinase may mediate the inhibitory effect of cerivastatin. Cerivastatin prevented RhoA activation in HVSMCs induced by the IM. A specific inhibitor of Rho kinase (Y-27632) inhibited in vitro calcification and induction of ALP in HVSMCs. These findings provide a possible mechanism of statins to prevent the progression of calcification in inflammatory vascular diseases such as atherosclerosis and cardiac valvular calcification.
Inflammatory cells such as macrophages and T lymphocytes play an important role in vascular calci... more Inflammatory cells such as macrophages and T lymphocytes play an important role in vascular calcification associated with atherosclerosis and cardiac valvular disease. In particular, macrophages activated with cytokines derived from T lymphocytes such as interferon-γ (IFN-γ) may contribute to the development of vascular calcification. Moreover, we have shown the stimulatory effect of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) on in vitro calcification through increasing the expression of alkaline phosphatase (ALP), an ectoenzyme indispensable for bone mineralization, in vascular smooth muscle cells. Therefore, we hypothesized that macrophages may induce calcifying phenotype, especially the expression of ALP in human vascular smooth muscle cells (HVSMCs) in the presence of IFN-γ and 1,25(OH) 2 D 3 . To test this hypothesis, we used cocultures of HVSMCs with human monocytic cell line (THP-1) or peripheral blood monocytes (PBMCs) in the presence of IFN-γ and 1,25(OH) 2 D 3 . THP-1 ce...
Background—Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis f... more Background—Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family. OPG-deficient mice develop severe osteoporosis and medial arterial calcification of the aorta and renal arteries. OPG immunoreactivity was demonstrated in the normal blood vessels and in early atherosclerotic lesions. A recent clinical study suggests that there is a significant correlation between elevated serum OPG levels and cardiovascular mortality. We examined whether serum OPG levels are associated with the progression of coronary artery disease (CAD).Methods and Results—Serum OPG levels were examined in 201 patients who underwent coronary angiography because of stable chest pain. The number of diseased vessels was used to represent the severity of CAD. Serum OPG levels were measured by ELISA and were significantly greater in patients with significant stenosis of the coronary arteries than in those without stenosis. As the severity of CAD increased, there was ...
Background— Recent genetic animal models reveal important roles of platelet P-selectin on progres... more Background— Recent genetic animal models reveal important roles of platelet P-selectin on progression of atherosclerosis. In the present study, we examine the relation between platelet P-selectin expression and atherosclerotic parameters in 517 subjects. Methods and Results— Unrelated subjects (n=517; 235 male and 282 female), including 187 with type 2 diabetes, 184 with hypertension, and 366 with hyperlipidemia, were enrolled in the study. P-selectin expression was determined by whole-blood flow cytometry. Arterial stiffness (stiffness index β) and arterial wall thickness (intima-media thickness [IMT]) were determined by carotid ultrasound. P-selectin expression was significantly and positively correlated with carotid IMT and stiffness index β. Multiple regression analyses showed that the association of the percentage of P-selectin–positive platelets with carotid IMT was independent of other clinical factors. Moreover, the percentage of P-selectin–positive platelets was higher in s...
Background —A significant association between vascular calcification and osteoporosis has been no... more Background —A significant association between vascular calcification and osteoporosis has been noted, suggesting that calcium homeostasis is important in vascular calcification as well as in osteoporosis. Moreover, results of our previous studies suggest that calcium-regulating hormones such as parathyroid hormone–related peptide (PTHrP) may modulate vascular calcification. Therefore, we hypothesized that 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] may have a direct impact on the calcium-regulating system of vascular smooth muscle cells, resulting in deposition of calcium in vascular wall. Methods and Results —We investigated the effect of 1,25(OH) 2 D 3 on in vitro calcification by bovine vascular smooth muscle cells (BVSMCs). 1,25(OH) 2 D 3 dose dependently increased BVSMC calcification and alkaline phosphatase activity. 1,25(OH) 2 D 3 also decreased secretion of PTHrP by BVSMCs in a dose-dependent manner and depressed its gene expression. Furthermore, exogenous PTHrP (fragment 1...
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