Direct vascular effects of HMG-CoA reductase inhibitors

Bellosta, Stefano; Bernini, Franco; Ferri, Nicola; Quarato, P.; Canavesi, M.; Arnaboldi, Lorenzo; Fumagalli, R.; Paoletti, Rodolfo; Corsini, Alberto

doi:10.1016/s0021-9150(97)00319-5

Cited by 198 publications

(117 citation statements)

References 59 publications

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“…In a similar study using¯uvastatin sodium, another HMGCoA reductase, while the per cent areas of smooth muscle cells, collagen ®bres, and extracellular lipid deposits were decreased, the per cent area of macrophages was increased in the early atherosclerotic lesions of young WHHL rabbits (Shiomi et al, 1998). Both cerivastatin and¯uvastatin show inhibitory e ects on proliferation of smooth muscle cells in in vitro studies (Corsini et al, 1996;Negre-Aminou et al, 1997;Bellosta et al, 1998) and in vivo studies using normocholesterolaemic rabbits which had neointimal thickening of arteries caused by injury (Soma et al, 1993;Bandoh et al, 1996;Igarashi et al, 1997b). However, in our studies using young WHHL rabbits, uvastatin caused a decrease in the per cent area of smooth muscle cells in the atherosclerotic lesions whereas cerivastatin did not, despite the similar hypolipidemic e ects of the two drugs.…”

Section: Discussionmentioning

confidence: 44%

“…However, in our studies using young WHHL rabbits, uvastatin caused a decrease in the per cent area of smooth muscle cells in the atherosclerotic lesions whereas cerivastatin did not, despite the similar hypolipidemic e ects of the two drugs. On the other hand, pravastatin, which shows little inhibitory e ect on smooth muscle cell proliferation in vitro (Soma et al, 1993;Corsini et al, 1996;Bellosta et al, 1998) decreased the per cent area of macrophages and extracellular lipid deposits, but did not a ect smooth muscle cells in the established lesions of mature WHHL rabbits (Shiomi et al, 1995). These results suggest that the e ects of various HMGCoA reductase inhibitors on the composition of atherosclerotic lesions di er, despite the similar hypolipidemic e ects.…”

Section: Discussionmentioning

confidence: 99%

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Effect of cerivastatin sodium, a new inhibitor of HMG‐CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits

Shiomi

Ito

1999

British J Pharmacology

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1 The aim of this study was to examine whether cerivastatin sodium, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a ects the lesional composition of spontaneously developed atherosclerosis due to hypercholesterolaemia and delays progression of the lesions. 2 We administered cerivastatin to 2-month-old WHHL rabbits, a low-density lipoprotein receptorde®cient animal model, at a dose of 0.6 mg kg 71 day 71 for 32 weeks. We examined the plasma lipid levels, the severity of atherosclerosis, and composition of atherosclerotic lesions. Lesional composition was determined using immunohistostaining for macrophages and smooth muscle cells, and Azan-Mallory staining for collagen ®bres and extracellular lipid deposits. 3 Compared to the control group, the plasma cholesterol levels were decreased in the treated group by 39% (12.7+0.6 mmol L 71 versus 20.9+1.0 mmol L 71 , P50.001). Atherosclerosis was suppressed by about 37% as measured by the thickness of the aortic lesions (158+13 mm versus 250+15 mm, P50.001), and by 28% as measured by coronary stenosis (62.7+11.4 versus 86.9+12.2, P50.05). In the cerivastatin group, regarding the per cent areas of lesional components in the lesion area, the macrophages (21.0+1.5% versus 27.9+1.9%, P50.01) and extracellular lipid deposits (3.2+0.4% versus 5.1+0.4%, P50.001) were decreased in the aortic lesions, and the per cent area of macrophages in the coronary lesions was also decreased (4.9+1.4% versus, 11.6+2.4%, P50.05). The per cent area of smooth muscle cells and collagen ®bres did not signi®cantly decrease. 4 These results indicate that cerivastatin contributed to the plaque stabilization and delayed progression of early atherosclerosis in young WHHL rabbits, in addition to the potent hypolipidemic e ects.

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Section: Discussionmentioning

confidence: 44%

Section: Discussionmentioning

confidence: 99%

Effect of cerivastatin sodium, a new inhibitor of HMG‐CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits

Shiomi

Ito

1999

British J Pharmacology

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“…HMG-CoA reductase inhibitors have pleiotropic effects on many different cell types (31)(32)(33)(34) and can potently decrease cellular proliferation (17,33,(35)(36)(37)(38). Inhibition of HMG-CoA reductase leads to the cellular depletion of mevalonate, which is a key intermediary in the production of dolichyl phosphate (39,40).…”

Section: Discussionmentioning

confidence: 99%

Apposite Insulin-like Growth Factor (IGF) Receptor Glycosylation Is Critical to the Maintenance of Vascular Smooth Muscle Phenotype in the Presence of Factors Promoting Osteogenic Differentiation and Mineralization

Siddals

Allen

Sinha

et al. 2011

Journal of Biological Chemistry

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The importance of vascular calcification in the development and progression of cardiovascular disease is well established (1, 2), and it is known to be a predictor of future cardiovascular events (3). Vascular calcification is an active cell-mediated process, involving the osteoblastic conversion of vascular smooth muscle cells (VSMCs), 2 calcifying vascular cells, pericytes, and adventitial myofibroblasts (4 -9). In vivo, vascular calcification has been shown to result from an endochondral ossification-like process, resulting in the formation of bone as well as both marrow and cartilage (10 -12).A previous study from Demer and co-workers (13) has shown that insulin-like growth factor-I (IGF-I) prevents the osteoblastic conversion of calcifying vascular cells. The role of IGF-I in the terminal differentiation of multiple cell types is well known (14 -16), but its role in phenotype maintenance is less well understood. We have previously shown that IGF signaling can be attenuated in 3T3-L1 cells using HMG-CoA reductase inhibitors through their effects on IGF receptor (IGFR) glycosylation and Ras prenylation (17). Therefore, by removing this protective pathway, we hypothesized that HMG-CoA reductase inhibitors would also render vascular cells more vulnerable to osteogenic differentiation and subsequent mineralization. This hypothesis is consistent with a recent study showing that atorvastatin promotes osteogenic differentiation and calcium deposition by VSMCs (18) and osteoblast cell lines (19,20) in vitro. However, there are also reports that HMG-CoA reductase inhibitors inhibit the osteoblastic conversion of human VSMCs (21, 22) and TGF␤-induced calcific nodule formation by valvular interstitial cells (23,24). The reason for these discrepancies is not clear but may reflect differences in the factors used to stimulate differentiation in these studies.Therefore, the purpose of this study was (i) to determine the importance of IGF signaling in promoting the proliferation and preventing the osteogenic differentiation of VSMCs, (ii) to determine whether HMG-CoA reductase inhibitors modulate the inhibitory effect of IGF-I on the osteogenic differentiation of VSMCs, and (iii) to elucidate the mechanism by which this modulation occurs. Our data show that cerivastatin, through alterations in IGFR glycosylation, attenuates the protective effect of IGF-I on VSMCs by preventing IGFR processing and cell-surface localization.

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“…The available clinical data for HMG-CoA reductase inhibitors demonstrate their efficacy and safety in treating hypercholesterolemia and improving long term morbidity and mortality related to coronary heart disease (76,77). The association between elevated plasma cholesterol and coronary heart disease, in particular atherosclerosis, has long been recognized.…”

Section: Discussionmentioning

confidence: 99%

The Prostacyclin Receptor Is Isoprenylated

et al. 1999

Journal of Biological Chemistry

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The prostacyclin receptor (IP), a G protein-coupled receptor, mediates the actions of the prostanoid prostacyclin and its mimetics. IPs from a number of species each contain identically conserved putative isoprenylation CAAX motifs, each with the sequence CSLC. Prostacyclin (prostaglandin (PG)1 I 2 ) is a labile metabolite of arachidonic acid, which is synthesized by the sequential actions of PGH 2 endoperoxide synthases 1 and 2 and prostacyclin synthase (1). The actions of prostacyclin generally counteract those of thromboxane A 2 , and thus the relative level of these two prostanoids in the circulation are important in the local control of vascular tone and platelet aggregation (2, 3). The main physiologic roles of thromboxane A 2 and prostacyclin are their contribution to the maintenance of vascular hemostasis: thromboxane A 2 , synthesized primarily by platelets, induces platelet shape change and aggregation and constriction of bronchial and vascular smooth muscle, whereas prostacyclin, mainly synthesized by the vascular endothelium, is a potent inhibitor of platelet aggregation and induces vasodilation (4 -7). Moreover, prostacyclin has been reported to confer a cytoprotective effect against tissue injury in acute myocardial ischemia or following hypoxic exposure of vascular endothelial cells (8). Imbalances in thromboxane A 2 or prostacyclin have been reported to be a major contributing factor in the development of a number of cardiovascular disorders including thrombosis, myocardial infarction, unstable angina, stroke, and atherosclerosis (9 -13). In addition to its central role in the cardiovascular system, prostacyclin may be important in the regulation of renal blood flow (14); it also acts as a negative feedback regulator of histamine secretion from mast cells (15) and acts as a lipolytic agent, antagonizing the antilipolytic effect of PGE 2 , in adipocytes (16).The actions of prostacyclin are mediated via interaction with a specific cell surface receptor, termed the prostacyclin receptor or IP (17). The major intracellular signaling pathway used is stimulation of adenylyl cyclase leading to increases in intracellular cAMP (18,19), a pathway thought to be relevant to inhibition of platelet aggregation and vascular smooth muscle relaxation (3). However, recent evidence indicates that IP agonists may couple to multiple signaling pathways including activation and inhibition of adenylyl cyclase, via G s and G i , respectively, stimulation of phosphoinositide metabolism, and changes in [Ca 2ϩ ] i concentrations (20,21). Evidence also exists to indicate that iloprost, a stable carbacyclin analogue of prostacyclin, can stimulate opening of ATP sensitive K ϩ channels resulting in hyperpolarization and relaxation of canine carotid artery (22).Molecular cloning of the human (23, 24), mouse (25), and rat

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Direct vascular effects of HMG-CoA reductase inhibitors

Cited by 198 publications

References 59 publications

Effect of cerivastatin sodium, a new inhibitor of HMG‐CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits

Effect of cerivastatin sodium, a new inhibitor of HMG‐CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits

Apposite Insulin-like Growth Factor (IGF) Receptor Glycosylation Is Critical to the Maintenance of Vascular Smooth Muscle Phenotype in the Presence of Factors Promoting Osteogenic Differentiation and Mineralization

The Prostacyclin Receptor Is Isoprenylated

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