cerivastatin and Inflammation

The main therapy needed most in the bone field is an anabolic agent for the treatment of osteoporosis. Current drugs on the market, which included bisphosphonates, calcitonin, estrogen and related compounds, vitamin D analogues trabecular microarchitecture. Therefore, it would be desirable to have a satisfactory and universally and iprifalvone, are essentially bone resorption inhibitors that mainly act to stabilize bone mass. Patients with established osteoporosis have lost more than 50% of their bone mass at critical sites in the skeleton, and more over have marked disruption of acceptable drug that would stimulate new bone formation and correct this disturbance of trabecular microarchitecture characteristic of established osteoporosis. Recently inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which controls the first step in the biosynthesis of cholesterol, have been shown to stimulate bone formation in rodents both in vitro and in vivo. The effect is associated with an increased expression of the bone morphogenetic protein-2 (BMP-2) gene in bone cells. These statins drugs are widely used agents for lowering cholesterol and reducing heart attacks, however they are also known to elicit numerous pleiotropic effects including inhibition of proliferation and migration of smooth muscle cells, inhibition of tumor growth and anti-inflammatory activity. Some of these effects have been attributed to not only to the reduction of cholesterol synthesis by inhibition of the HMG-CoA reductase enzyme but also by the concurrent reduction in downstream metabolites of the mevalonate pathway such as mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. The findings that statins are capable of increasing bone formation and bone mass in rodents suggests a potential new action for the statins, which may be beneficial in patients with established osteoporosis where marked bone loss has occurred. Recent clinical data suggests that they may reduce the risk of fracture in patients taking these drugs. However, their precise role can only be determined by appropriate randomized clinical trials, which demonstrate their efficacy in this regard in patients.

Topics: Animals; Bone Development; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lovastatin; Neoplasms; Nitric Oxide Synthase; Pyridines; Simvastatin

Angiotensin (Ang) II is capable of producing inflammatory changes by signals through its AT1 receptor. Reactive oxygen species production, adhesion molecule expression, chemokines, and other mediators are involved. Nuclear factor-kappaB (NK-kappaB) and activator protein 1 (AP-1) are two of the transcription factors activating the responsible genes. We have studied Ang II-independent modulating effects in a double transgenic rat model harboring the human renin and angiotensinogen genes. We have recently focused on the protective effects of HMG-CoA reductase inhibition and review these data here. We found that cerivastatin decreased mortality, lowered blood pressure, preserved renal function, decreased cardiac hypertrophy, and inhibited the entire chain of inflammatory events. Furthermore, NF-kappaB and AP-1 activation was sharply attenuated. We also observed that cerivastatin blocked ERK1/2 phosphorylation in vivo and in vitro. Cerivastatin also inhibited phorbol ester-transmitted events in vascular smooth muscle cells. Because Rho, a member of the Ras protein superfamily is important to Ang II-dependent and -independent vascular smooth muscle signaling events, we suggest that cerivastatin may act by inhibiting the prenylation, membrane anchoring, and subsequent activation of Ras proteins. These data may in part explain cholesterol-independent, HMG-CoA reductase-related, protective effects.

Topics: Angiotensin II; Animals; Heart; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Kidney; Pyridines

Hypercholesterolemia, a risk factor for cardiovascular disease, is associated with inflammation and hypercoagulability. Both can be mediated by the CD40 system. This study investigated whether the CD40 system is upregulated in patients with moderate hypercholesterolemia and whether it is influenced by therapy with a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.. Fifteen patients with moderate hypercholesterolemia and 15 healthy control subjects were investigated. CD154 and P-selectin were analyzed on platelets and CD40 was analyzed on monocytes before and under therapy with the statin cerivastatin by double-label flow cytometry. Blood concentrations of soluble CD154 and monocyte chemoattractant protein-1 (MCP-1) were evaluated. Our main findings were as follows. Patients with moderate hypercholesterolemia showed a significant increase of CD154 and P-selectin on platelets and CD40 on monocytes compared with healthy subjects. Soluble CD154 showed a nonsignificant trend for higher plasma levels in patients. A positive correlation was found for total or LDL cholesterol and CD154, but not for CD40 on monocytes. The latter was upregulated in vitro by C-reactive protein, which was found to be significantly elevated in patients with moderate hypercholesterolemia. CD154 on platelets proved to be biologically active because it enhanced the release of MCP-1, which was markedly elevated in an in vitro platelet-endothelial cell coculture model and in the serum of patients. Short-term therapy with a HMG-CoA reductase inhibitor significantly downregulated CD40 on monocytes and serum levels of MCP-1.. Patients with moderate hypercholesterolemia show upregulation of the CD40 system, which may contribute to the known proinflammatory, proatherogenic, and prothrombotic milieu found in these patients.

Topics: Adult; Arteriosclerosis; Blood Platelets; CD40 Antigens; CD40 Ligand; Cells, Cultured; Chemokine CCL2; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Inflammation; Male; Monocytes; P-Selectin; Pyridines; Thrombosis; Up-Regulation

Periprosthetic osteolysis precipitates aseptic loosening of components, increases the risk of periprosthetic fracture and, through massive bone loss, complicates revision surgery and ultimately is the primary cause for failure of joint arthroplasty. The anti-inflammatory properties of HMG-CoA reductase inhibitors belonging to the statin family are well recognized. We investigated a possible role for status in initiating the first stage of the osteolytic cycle, namely monocytic activation.. We used an in vitro model of the human monocyte/macrophage inflammatory response to poly-methylmethacrylate (PMMA) particles after pretreat-ing cells with cerivastatin, a potent member of the statin family. Cell activation based upon production of TNF-alpha and MCP-1 cytokines was analyzed and the intracellular Raf-MEK-ERK signal transduction pathway was evaluated using western blot analysis, to identify its role in cell activation and in any cerivastatin effects observed.. We found that pretreatment with cerivastatin significantly abrogates the production of inflammatory cytokines TNF-alpha and MCP-1 by human monocytes in response to polymethylmethacrylate particle activation. This inflammatory activation and attenuation appear to be mediated through the intracellular Raf-MEK-ERK pathway.. We propose that by intervening at the upstream activation stage, subsequent osteoclast activation and osteolysis can be suppressed. We believe that the anti-inflammatory properties of statins may potentially play a prophylactic role in the setting of aseptic loosening, and in so doing increase implant longevity.

Topics: Anti-Inflammatory Agents; Arthroplasty, Replacement; Cytokines; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Models, Biological; Monocytes; Osteolysis; Polymethyl Methacrylate; Prosthesis Failure; Pyridines

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.

Topics: Alkaline Phosphatase; Atorvastatin; Calcinosis; Dose-Response Relationship, Drug; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Mevalonic Acid; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Polyisoprenyl Phosphates; Pyridines; Pyrroles; Sesquiterpenes

Recent clinical studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert protective effects against nonhemorrhagic stroke. In a murine cerebral ischemia model produced by occlusion of the middle cerebral artery, statins were shown to reduce infarct size. However, the effect of statins on hypertension-based stroke is unknown. The purpose of this study is to clarify the effect of a statin on stroke in stroke-prone spontaneously hypertensive rats (SHR-SP), in which both cerebral hemorrhage and infarction occur.. We treated SHR-SP chronically from 4 weeks of age with cerivastatin (2 mg/kg per day by gavage) or vehicle. The physiological parameters, the incidence of stroke-associated symptoms, and mortality were assessed.. At 14 weeks of age, the incidence (13+/-3% versus 37+/-8%; P<0.01) and the size of stroke (1.6+/-0.2 versus 2.2+/-0.1 arbitrary units; P<0.01) were significantly decreased by cerivastatin, although blood pressure and plasma cholesterol levels were not different. Moreover, stroke-associated symptoms and early mortality of SHR-SP were markedly reduced in the statin-treated group (mortality at the age of 15 weeks: 15% versus 50%; P<0.05). Statin treatment significantly reduced superoxide production from nonstroke parenchyma of brain and infiltration of inflammatory cells to the stroke lesions.. Our data show that a high dose of statin exerts protection against hypertension-based stroke and ameliorates the disease severity via inhibition of superoxide production and modulation of inflammation in brain.

Topics: Animals; Blood Pressure; Blood Vessels; Brain; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Inflammation; Kinetics; Lipids; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Superoxides; Survival Analysis

Despite the development of effective immunosuppressive therapy, transplant graft arterial disease (GAD) remains the major limitation to long-term graft survival. The interplay between host inflammatory cells and donor vascular wall cells results in an intimal hyperplastic lesion, which leads to ischemia and graft failure. HMG-CoA reductase inhibitors (statins) reduce GAD in human cardiac allografts, although it is unclear whether this is secondary to cholesterol lowering or other mechanisms. This study tested the hypothesis that statins can suppress GAD by cholesterol-independent pathways.. We performed heterotopic murine cardiac transplants in total allogeneic or major histocompatibility complex class II-mismatched combinations. Transplanted animals received either control chow, chow containing 25 ppm cerivastatin (low dose), or chow containing 125 ppm cerivastatin (high dose). Mean plasma cerivastatin concentrations were 0.0 (control), 10.1 (low dose), and 21.9 (high dose) nmol/L, respectively. Plasma cholesterol levels were the same in all groups. GAD scores decreased in low-dose (P<0.05) and high-dose (P<0.0001) cerivastatin groups compared with controls, with concomitant reduction in graft-infiltrating cells and significantly decreased intragraft RANTES and monocyte chemotactic protein-1 mRNA expression. Cerivastatin, as well as other statins, also reduced RANTES and monocyte chemotactic protein-1 production in mouse endothelial cells stimulated with interferon-gamma and tumor necrosis factor-alpha in vitro.. Clinically achievable levels of an HMG-CoA reductase inhibitor attenuate GAD in murine heart transplants, diminish host inflammatory cell recruitment, and do not alter cholesterol levels. These results indicate that statins can affect arterial biology and inflammation independently of their effects on cholesterol metabolism.

Topics: Animals; Arteriosclerosis; Cells, Cultured; Chemokine CCL2; Chemokine CCL5; Chemokines; Cholesterol; Dose-Response Relationship, Drug; Endothelium, Vascular; Gene Expression; Graft Survival; Heart Transplantation; Histocompatibility Antigens Class II; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lymphocyte Culture Test, Mixed; Macrophages; Mice; Mice, Inbred Strains; Pyridines; RNA, Messenger; T-Lymphocytes; Transplantation, Heterotopic; Transplantation, Homologous

The terminal complement complex C5b-9 is known to participate in inflammatory processes including atherosclerosis. Inflammation appears to be a direct consequence of C5b-9-mediated cell stimulation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors may exert anti-inflammatory effects on vascular cells independent of lowering plasma cholesterol. Thus, we studied activation of vascular smooth muscle cells (VSMCs) by C5b-9 focusing on whether inhibition of the HMG-CoA reductase can reduce the proinflammatory effects of C5b-9.C5b-9 in sublytic concentrations increased the proliferation of human VSMCs and induced a time-dependent activation of the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK). Proliferation and ERK1/2 activation could be inhibited by the specific ERK inhibitor PD98059. HMG-CoA inhibition with cerivastatin-reduced VSMC proliferation and C5b-9-induced ERK1/2 activation. Cerivastatin also reduced the C5b-9-induced synthesis of the proinflammatory interleukin-6 (IL-6). Furthermore, C5b-9 induced activation of the transcription factors activator protein- 1 (AP-1) and nuclear factor-kappaB (NF-kappaB), which could be inhibited by pretreatment of VSMCs with cerivastatin. L-mevalonate and geranylgeranylpyrophosphate reversed the inhibitory effects of cerivastatin. The present study in VSMCs shows that cerivastatin inhibits IL-6 synthesis and cell proliferation induced by the terminal complement complex C5b-9. This may be an important mechanism contributing to the beneficial effects of HMG-CoA reductase inhibitors beyond lowering of plasma cholesterol.

Topics: Cell Division; Cell Survival; Complement Membrane Attack Complex; Enzyme Activation; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interleukin-6; Lovastatin; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; NF-kappa B; Pyridines; Transcription Factor AP-1

To observe the anti-inflammatory effect of cerivastatin in a mouse model of vascular injury and its cholesterol-lowering effect.. We developed a mouse model of vascular remodeling induced by polyethylene cuff placement and determined the anti-inflammatory effects of cerivastatin in wild mice. Cerivastatin was given by Alzet micro-osmotic minipumps implanted intraperitoneally at the same time as cuff placement at doses of 0.1 mg/kg, 0.5 mg/kg and 1 mg/kg per day, respectively for 2 weeks after cuff placement. The insufficient doses of Cerivastatin to lower serum cholesterol and systolic blood pressure through the neointimal formation and BrdU index were investigated in mouse femoral injury artery induced by cuff-placement.. There was a little change in serum cholesterol by the treatment with cerivastatin, the cross-sectional area of intima of injured femoral artery was significantly increased, the neointima formation was significantly increased by the cuff-induced vascular injury at day 14. The neointimal formation and BrdU index were inhibited in the 1 mg/kg cerivastatin, but not in the 0.1 mg/kg and 0.5 mg/kg cerivastatin. Furthermore, 1 mg/kg of cerivastatin significantly inhibited the expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) without lowering serum cholesterol.. These results suggest that cerivastatin can inhibit vascular inflammation and the proliferation of vascular smooth muscle cells (VSMCs) through its lipid-lowering independent action. Such effects of cerivastatin may be an important mechanism, by which it prevents the development of atherosclerotic lesions.

Topics: Animals; Anti-Inflammatory Agents; Blood Pressure; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interleukin-1; Male; Mice; Mice, Inbred C57BL; Models, Anatomic; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pyridines; Tumor Necrosis Factor-alpha; Vascular Resistance

In patients with atherosclerosis, hepatic hydroxymethylglutaryl coenzyme A reductase (CSE) inhibitors may reduce the activation of inflammation. Because Chlamydia pneumoniae infection has been linked to coronary artery disease through the induction of plaque inflammation, we investigated whether cerivastatin affects the infection rate of human macrophages and endothelial cells (ECs) and their proinflammatory activation after chlamydial infection.. Macrophages were collected from the alveolar compartment of 6 volunteers and 10 patients with chronic bronchitis. ECs were obtained from 10 umbilical cords. The C. pneumoniae strain CWL was incubated with macrophages or ECs in the presence and absence of the CSE inhibitor cerivastatin. The infection rate was determined by immunofluorescence microscopy. The release of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), and tumor necrosis factor (TNF)-alpha was quantified by ELISA. The release of oxygen radicals was determined by ferricytochrome assay. Infection rates were tendentially lower after the preincubation of macrophages with CSE inhibitors (17.2% versus 9. 3% and 18.2% versus 10.4%, respectively; P=NS). The secretion of MCP-1, IL-8, and TNF-alpha by infected macrophages from volunteers increased. Coincubation with cerivastatin resulted in significantly lower MCP-1 and IL-8 production, whereas the release of TNF-alpha remained unaffected. Similar effects regarding chemokine release were observed in ECs.. CSE inhibitors modify the inflammatory response of human immune cells to C. pneumoniae. This finding could be relevant for the therapeutic potential of CSE statins in patients with atherosclerosis and C. pneumoniae infection.

Topics: Adult; Arteriosclerosis; Bronchitis; Cells, Cultured; Chlamydia Infections; Chlamydophila pneumoniae; Chronic Disease; Cytokines; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Macrophages, Alveolar; Male; Middle Aged; NF-kappa B; Pyridines; Statistics, Nonparametric; Superoxides