Effects Of HMG-CoA Reductase Inhibitors Research Articles

EXPRESS: Effectiveness of HMG-CoA reductase inhibitors on inflammation and metabolic markers in the US-Mexico border Hispanic population.

HMG-CoA reductase inhibitors (statins) are commonly used for dyslipidemia management to reduce the risk of cardiovascular disease (CVD). High-sensitivity C-reactive protein (hs-CRP) is an emerging systematic low-grade inflammatory marker associated with atherosclerotic CVD development. Despite racial/ethnic disparities in the use and response of statins and the anti-inflammatory effects of statins, the effectiveness of statins on inflammation and metabolic markers is unknown among Hispanics. We performed a retrospective cohort study using 150 adult patients scheduled for an annual physical exam at a family medicine clinic between January 1, 2021, and December 31, 2021. Effect size with a 95% confidence interval (CI) was estimated using adjusted regression analyses. Among 150 patients, 52 (34.67%) received statins. Patients who received statins had significantly reduced median hs-CRP (1.9 vs. 3.2, p=0.007), mean low-density lipoprotein (LDL-C) (101.18 vs. 124.6, p<0.001), and total cholesterol (172.6 vs. 194.5, p<0.001) concentrations compared to those who did not receive statins. In the propensity-scores matched analysis, lower concentrations of log-transformed hs-CRP (regression coefficient [RC], -0.48; 95%CI: -0.89, -0.07), LDL-C (RC, -19.57; 95%CI: -33.04, -6.1), and total cholesterol (RC, -23.47; 95%CI: -38.96, -7.98) were associated with statin use. In addition, hepatic steatosis (adjusted relative risk [aRR]=0.25; 95%CI: 0.08, 0.78, p= 0.017) was significantly lower among patients with the use of statins. Our study suggests that HMG-CoA reductase inhibitors may help reduce inflammation among Hispanic patients with dyslipidemia and hypertension. These findings have useful implications for preventing risk and disparities associated with cardiovascular and other inflammatory-induced diseases among the fastest-growing US Hispanic minorities.

Formulation of simvastatin within high density lipoprotein enables potent tumour radiosensitisation.

Preclinical, clinical and epidemiologic studies have established the potent anticancer and radiosensitisation effects of HMG-CoA reductase inhibitors (statins). However, the low bioavailability of oral statin formulations is a key barrier to achieving effective doses within tumour. To address this issue and ascertain the radiosensitisation potential of simvastatin, we developed a parenteral high density lipoprotein nanoparticle (HDL NP) formulation of this commonly used statin. A scalable method for the preparation of the simvastatin-HDL NPs was developed using a 3D printed microfluidic mixer. This enables the production of litre scale amounts of particles with minimal batch to batch variation. Simvastatin-HDL NPs enhanced the radiobiological response in 2D/3D head and neck squamous cell carcinoma (HNSCC) in vitro models. The simvastatin-HDL NPs radiosensitisation was comparable to that of 10 and 5 times higher doses of free drug in 2D and 3D cultures, respectively, which could be partially explained by more efficient cellular uptake of the statin in the nanoformulation as well as by the inherent biological activity of the HDL NPs on the cholesterol pathway. The radiosensitising potency of the simvastatin-HDL nanoformulation was validated in an immunocompetent MOC-1 HNSCC tumour bearing mouse model. This data supports the rationale of repurposing statins through reformulation within HDL NPs. Statins are safe and readily available molecules including as generic, and their use as radiosensitisers could lead to much needed effective and affordable approaches to improve treatment of solid tumours.

Examining the effects of HMG-CoA reductase inhibitors on anabolic and catabolic signaling pathway proteins associated with degenerative disc disease.

Recent evidence suggests that statins, among lipid-lowering drugs, can be used to lower serum cholesterol levels for reducing the risk of cardiovascular disease in individuals with high cholesterol, as well as reducing DNA damage and having anti-ageing and pleiotropic effects. Additionally, nuclear factor kappa B (NF-κB) is reported to be suppressed in statin-administered nucleus pulposus (NP) cells for the prevention of interleukin (IL) -1 beta (IL-1β)-induced apoptosis and extracellular matrix (ECM) degradation. The purpose of this study is the examine whether it is possible for pharmacological synthetic statin agents added into primary cell cultures obtained from human intervertebral disc tissue (IVD) to stop and eliminate tissue degeneration through the anabolic/catabolic signaling pathways associated with inflammation. Pitavastatin and rosuvastatin were added to monolayer grown human primary annulus fibrosus (AF)/NP cells. Cytotoxicity and proliferation analyses were carried out. AF/NP cells and ECM structure were also examined microscopically. In addition, changes in transcription factors and protein expressions of proinflammatory cytokines, which play important roles in anabolic and catabolic pathways associated with inflammation, were analyzed. Decreased proliferation and cell necrosis were observed at the end of 72 hours in the samples, in which statins were added, compared to the samples in the control group to which no pharmacological agent was administered. In addition to this, changes were observed in the expressions of proteins. All results were statistically significant (p<0.05). To better understand the regenerative effects of these two pharmacological agents on degenerated AF/NP cells, there is an urgent need for prospective studies in which different signaling pathways and receptors on these pathways are investigated, apart from IL-1β; NF-κB signaling pathway and SOX9.

Comparison of Efficacy and Safety of Statin-Ezetimibe Combination Therapy with Statin Monotherapy in Patients with Diabetes: A Meta-Analysis of Randomized Controlled Studies.

Dyslipidemia in diabetes mellitus is characterized by hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C). Additionally, the potentially increased risk of morbidity and mortality following atherosclerotic cardiovascular diseases should be considered in the treatment of dyslipidemia in patients with diabetes. We performed a meta-analysis of the published data to compare the effects of HMG-CoA reductase inhibitor (statin)-ezetimibe combination therapy and statin monotherapy on lipid and glucose parameters in patients with diabetes. We also compared safety based on the adverse events reported for the two groups. In total, 17 articles were included in this meta-analysis. In the efficacy assessment, the combination treatment afforded a significantly greater reduction in LDL-C than did statin monotherapy (standard difference in means 0.691; 95% confidence interval 0.534-0.847). A significantly greater improvement effect was observed in the levels of HDL-C, total cholesterol, triglyceride, and apolipoprotein B, but not apolipoprotein A1, with combination therapy than with statin monotherapy. Additionally, combination therapy reduced fasting blood glucose levels more significantly than did statin monotherapy. In terms of safety, there were no significant differences in treatment-related adverse events between the two treatments. Statin-ezetimibe combination therapy enhances levels of LDL-C and other lipids without increasing the risk of adverse events compared with statin monotherapy. The present meta-analysis presents valid evidence for appropriate drug regimens to treat dyslipidemia in patients with diabetes. PROSPERO Identifier Number CRD42021244578.

The effects of HMG-CoA reductase inhibitors on disease activity in multiple sclerosis: A systematic review and meta-analysis

ObjectiveTo assess whether statins (3‑hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) exert disease-modifying effects in multiple sclerosis (MS). ApproachA systematic review and meta-analysis was performed including randomized-controlled clinical trials (RCTs) on statin use in MS. A random-effects model was applied to calculate pooled estimates and odds ratios (ORs) with corresponding 95% confidence intervals (CIs), when comparing patients treated with statins alone or adjunct to disease modifying treatment (DMT) to non-statin-treated patients. ResultsWe identified 7 RCTs including 789 patients with relapsing-remitting MS (RRMS), all of whom received additional DMT with IFN-β. Single identified RCTs in secondary-progressive MS (SPMS), clinically isolated syndrome (CIS) and optic neuritis (ON) were not meta-analyzed. In RRMS, add-on statin use was not associated with the risk of clinical relapse (OR=1.30, 95%CI: 0.901.87) or EDSS-progression from baseline, neither appeared related to the risk of new contrast-enhancing or T2 lesions (OR=1.28, 95%CI: 0.364.58), and the risk of whole-brain volume reduction on MRI. Add-on statins to IFN-β were safe and well-tolerated. In SPMS, stand-alone simvastatin led to significantly reduced annualized rate of whole-brain volume reduction. In CIS and ON, statins were associated with reduced risk for new T2 lesions and improved visual recovery, respectively. ConclusionsWe detected no benefit from statin treatment as add-on to IFN-β in RRMS. However, a potential beneficial effect in SPMS, CIS and ON deserves independent confirmation and further evaluation within adequately powered RCTs.

Involvement of agmatine in antidepressant-like effect of HMG-CoA reductase inhibitors in mice

3-Hydroxy-3-methyl-glutaryl-co-enzyme–A (HMG-CoA) reductase inhibitors (statins) are popularly used for the treatment of obesity and hypercholesterolemia with established safety profile. Statins exhibits a wide range of neurobehavioral effects in addition to their peripheral actions, and may be beneficial in treatment of psychiatric conditions. Present study investigated the role of agmatine and imidazoline receptors in antidepressant-like effect of statins in mouse forced swimming test (FST). The antidepressant-like effect of atorvastatin (5 mg/kg, p.o.) and simvastatin (10 mg/kg, p.o.) was potentiated by pretreatment with agmatine (5 mg/kg, i.p.) as well as the drugs known to increase endogenous agmatine levels in brain viz., L-arginine (40 μg/mouse, i.c.v.), an agmatine biosynthetic precursor; arcaine (50 μg/mouse, i.c.v), agmatinase inhibitor; and aminoguanidine (6.5 μg/mouse, i.c.v.), a diamine oxidase inhibitor. Further, both the statins increased agmatine levels within hippocampus and prefrontal cortex. Conversely, prior administration of I1 receptor antagonist, efaroxan (1 mg/kg, i.p.) and I2 receptor antagonist, idazoxan (0.25 mg/kg, i.p.) blocked the antidepressant-like effect of statins and their synergistic combination with agmatine. These results demonstrate the involvement of agmatine and imidazoline receptors in antidepressant-like effect of statins and suggest as a potential therapeutic target for the treatment of depressive disorders.

Antihyperlipidemic Activity of Hydroxyl Methylglutaryl Coenzyme A Reductase Inhibitor on Lipid Profile in Secondary Hyperlipidemia

Objectives: To observe the variations in lipid profile in patients with secondary hyperlipidemia using HMG-CoA reductase inhibitor.Methods: This study was done at private hospital in patients predominantly suffering from secondary hyperlipidemia. The duration of study was about 4 months. Body weight, height and blood pressure of subjects were assessed. The subjects were asked to answer the related question on cigarette smoking, health related complaints, detailed history of family, drug usage, and nutritional habits. Subjects were requested to make up a permission form before starting the research study. This case control study was performed at local private Hospital, located at Karachi from 1st April 2017 to 30th July 2017. The aim of research was to analyze the effects of HMG-CoA reductase inhibitor on lipid profile in patients of secondary hyperlipidemia. Age between 35 to 65 years and secondary hyperlipidemicpatients were included in the inclusion criteria. Lactating/pregnant women, renal, liver and established coronary artery diseases were included in exclusion criteria.&#x0D; Results: Sixty patients having deteriorated lipid profile were included in this research (age 30-60 years). Subjects were prescribed simvastatin orally 20 mg/day (international product) for 04 months. The total cholesterol, triacylglycerol, LDL and HDL were analysed using simvastatin (20mg/day) of international standard in the serum of secondary hyperlipidemic patients.Conclusion: During this study it is observed that Simvastatin raises the HDL level and reduces LDL level and cholesterol level.

Role of simvastatin and allium sativum on lipid profile in diabetic dyslipidemic patients: a comparative study.

Objectives: To evaluate the changes in lipid profile in patients with diabetic dyslipidemia using lipid lowering drug, simvastatin and herbal product allium sativum. Study Design: Clinical trial. Setting: Surgeon Munawar Memorial Hospital, Karachi. Period: 1st January 2017 to 30th April 2017. Material &amp; Methods: The study was designed to assess the effects of hmg-coa reductase inhibitor (simvastatin) and allium sativum on lipid profile in patients with diabetic dysplipidemia. The exclusion criteria included lactating/pregnant women’s, renal, liver and established coronary artery disease. Results: Sixty patients with abnormal lipid profile were included in the study (age 30-60 years). Patients were divided into two groups (30 patients each). Group a was orally administered with product of simvastatin (20 mg)/day for 04 months and in group b, patients were orally administered with herbal product of allium sativum (300 mg)/day for 04 months. Conclusion: On the basis of this study it is observed that allium sativum as well as simvastatin tablets both reduce total cholesterol, low density lipoprotein cholesterol (ldl-c) and increase high density lipoprotein cholesterol (hdl-c).

Effects of HMG-CoA reductase inhibitors on P2Y&lt;sub&gt;1&lt;/sub&gt; receptor-mediated IL-8 release

Effects of HMG-CoA reductase inhibitors on P2Y&lt;sub&gt;1&lt;/sub&gt; receptor-mediated IL-8 release

Clinical effectiveness of HMG-CoA reductase inhibitors on operated aortic aneurysm in Taiwan: a population based cohort study

Clinical effectiveness of HMG-CoA reductase inhibitors on operated aortic aneurysm in Taiwan: a population based cohort study

Statins and inflammation in cardiovascular disease.

Chronic inflammation and immune system activation underlie a variety of seemingly unrelated cardiac conditions including not only atherosclerosis and the subsequent coronary artery disease but also peripheral artery disease, hypertension with target organ damage and heart failure. The beneficial effects of HMG-CoA reductase inhibitors or statins are mainly attributed to their ability to inhibit hepatic cholesterol biosynthesis. Beyond their lipid lowering activity, ample evidence exists in support of their potent anti-inflammatory properties which initiate from the inhibition of GTPase isoprenylation, activating a cataract of secondary pathways and extend to the inhibition and blocking of immune cell activation and interaction. To summarize the anti-inflammatory mechanisms of statins in clinical and experimental settings in cardiovascular disease. A systematic search of PubMed and the Cochrane Database was conducted in order to identify the majority of trials, studies, current guidelines and novel articles related to the subject. In vitro, statins have immuno-modulatory and anti-inflammatory effects, and they can exert anti-atherosclerotic effects independently of their hypolipidemic actions. In addition, positive results have emerged from mechanistic and experimental studies on the active role of HMG-CoA reductase inhibitors in HF. By extrapolating those data in clinical setting, we further understand how HMG-CoA reductase inhibitors can beneficially affect not only systolic but also diastolic HF. In this review article, we present the basic pathophysiologic data supporting the anti-inflammatory actions of statins in clinical and experimental settings and we link these mechanisms with confirmatory clinical data on the potent non lipid lowering effects of HMG-CoA reductase inhibitors.

The beneficial effects of HMG-CoA reductase inhibitors in the processes of neurodegeneration.

Statins, cholesterol lowering drugs, have been demonstrated to exert beneficial effects in other conditions such as primary and progressing neurodegenerative diseases beyond their original role. Observation that statins ameliorate the neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS) and cerebral ischemic stroke, the neuroprotective effects of these drugs are thought to be linked to their anti-inflammatory, anti-oxidative, and anti-excitotoxic properties. Despite the voluminous literature on the clinical advantages of 3-hydroxy-3-methylglutaryl Co-enzyme A reductase (HMGCR) inhibitors (statins) in cardiovascular system, the neuroprotective effects and the underlying mechanisms are little understood. Hence, the present review tries to provide a critical overview on the statin-induced neuroprotection, which are presumed to be associated with the ability to reduce cholesterol, Amyloid-β and apolipoprotein E (ApoE) levels, decrease reactive oxygen and nitrogen species (ROS and RNS) formation, inhibit excitotoxicity, modulate matrix metalloproteinases (MMPs), stimulate endothelial nitric oxide synthase (eNOS), and increase cerebral blood perfusion. This review is also aimed to illustrate that statins protect neurons against the neuro-inflammatory processes through balancing pro-inflammatory/anti-inflammatory cytokines. Ultimately, the beneficial role of statins in ameliorating the development of PD, AD, MS and cerebral ischemic stroke has been separately reviewed.

Statins up-regulate SmgGDS through β1-integrin/Akt1 pathway in endothelial cells.

The pleiotropic effects of HMG-CoA reductase inhibitors (statins) independent of cholesterol-lowering effects have attracted much attention. We have recently demonstrated that the pleiotropic effects of statins are partly mediated through up-regulation of small GTP-binding protein dissociation stimulator (SmgGDS) with a resultant Rac1 degradation and reduced oxidative stress. However, it remains to be elucidated what molecular mechanisms are involved. To first determine in what tissue statins up-regulate SmgGDS expression, we examined the effects of two statins (atorvastatin 10 mg/kg per day and pravastatin 50 mg/kg per day for 1 week) on SmgGDS expression in mice in vivo. The two statins increased SmgGDS expression especially in the aorta. Atorvastatin also increased SmgGDS expression in cultured human umbilical venous endothelial cells (HUVEC) and human aortic endothelial cells, but not in human aortic vascular smooth muscle cells. Furthermore, Akt phosphorylation was transiently enhanced only in HUVEC in response to atorvastatin. Then, to examine whether Akt is involved for up-regulation of SmgGDS by statins, we knocked out Akt1 by its siRNA in HUVEC, which abolished the effects by atorvastatin to up-regulate SmgGDS. Furthermore, when we knocked down β1-integrin to elucidate the upstream molecule of Akt1, the effect of atorvastatin to up-regulate SmgGDS was abolished. Finally, we confirmed that Akt activator, SC79, significantly up-regulate SmgGDS in HUVEC. These results indicate that statins selectively up-regulate SmgGDS in endothelial cells, for which the β1-integrin/Akt1 pathway may be involved, demonstrating the novel aspects of the pleiotropic effects of statins.

Prevalence of dyslipidemia in Japanese patients with rheumatoid arthritis and effects of atorvastatin treatment.

Few studies have examined dyslipidemia in patients with rheumatoid arthritis (RA), especially in Japanese cohorts. The aims of this study were to investigate the lipid profiles of RA patients, to assess the relationships between lipid profiles and RA activity and treatment, and to elucidate the effects of HMG-CoA reductase inhibitors (statins) in Japanese patients with RA. A multicenter observational study was conducted in 488 patients with RA. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels, and RA activity as assessed by disease activity score 28 (DAS28), and treatment for RA were analyzed retrospectively. In statin-treated patients, drug efficacy was also analyzed. The prevalence of hyper LDL-C, hyper TG, and hypo HDL-C were 29.3, 24.2, and 10.2%, respectively, and the overall prevalence of dyslipidemia was 56.5%. The level of HDL-C was inversely correlated with DAS28. Patients treated with low-dose glucocorticoids showed significantly higher levels of HDL-C and lower TC/HDL-C ratios compared with patients not receiving glucocorticoid treatment. Conversely, patients treated with biologic agents showed significantly higher levels of LDL-C, lower levels of HDL-C, and higher TC/HDL-C ratios. Atorvastatin significantly improved lipid profiles after a few months of treatment. The prevalence of dyslipidemia in Japanese patients with RA is higher than that in the non-RA population. Our result suggests that controlling RA disease activity might improve lipid profiles and eventually lower cardiovascular risk. Low-dose atorvastatin was effective for treatment of dyslipidemia in RA patients but had no apparent effect on RA disease activity.

Coronary Plaque Burden at Coronary CT Angiography in Asymptomatic Men and Women.

Purpose To assess the relationship between total, calcified, and noncalcified coronary plaque burdens throughout the entire coronary vasculature at coronary computed tomographic (CT) angiography in relationship to cardiovascular risk factors in asymptomatic individuals with low-to-moderate risk. Materials and Methods This HIPAA-compliant study had institutional review board approval, and written informed consent was obtained. Two hundred two subjects were recruited to an ongoing prospective study designed to evaluate the effect of HMG-CoA reductase inhibitors on atherosclerosis. Eligible subjects were asymptomatic individuals older than 55 years who were eligible for statin therapy. Coronary CT angiography was performed by using a 320-detector row scanner. Coronary wall thickness and plaque were evaluated in all epicardial coronary arteries greater than 2 mm in diameter. Images were analyzed by using dedicated software involving an adaptive lumen attenuation algorithm. Total plaque index (calcified plus noncalcified plaque) was defined as plaque volume divided by vessel length. Multivariable regression analysis was performed to determine the relationship between risk factors and plaque indexes. Results The mean age of the subjects was 65.5 years ± 6.9 (standard deviation) (36% women), and the median coronary artery calcium (CAC) score was 73 (interquartile range, 1-434). The total coronary plaque index was higher in men than in women (42.06 mm(2) ± 9.22 vs 34.33 mm(2) ± 8.35; P < .001). In multivariable analysis controlling for all risk factors, total plaque index remained higher in men than in women (by 5.01 mm(2); P = .03) and in those with higher simvastatin doses (by 0.44 mm(2)/10 mg simvastatin dose equivalent; P = .02). Noncalcified plaque index was positively correlated with systolic blood pressure (β = 0.80 mm(2)/10 mm Hg; P = .03), diabetes (β = 4.47 mm(2); P = .03), and low-density lipoprotein (LDL) cholesterol level (β = 0.04 mm(2)/mg/dL; P = .02); the association with LDL cholesterol level remained significant (P = .02) after additional adjustment for the CAC score. Conclusion LDL cholesterol level, systolic blood pressure, and diabetes were associated with noncalcified plaque burden at coronary CT angiography in asymptomatic individuals with low-to-moderate risk. (©) RSNA, 2015 Online supplemental material is available for this article.

Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials.

In 2012, the United States Food and Drug Administration (FDA) issued a warning regarding potential adverse effects of HMG-CoA reductase inhibitors (statins) on cognition, based on the Adverse Events Reporting System and a review of the medical literature. We aimed to synthesize randomized clinical trial (RCTs) evidence on the association between statin therapy and cognitive outcomes. We searched MEDLINE, EMBASE, and Cochrane CENTRAL through December 2012, and reviewed published systematic reviews of statin treatment. We sought RCTs that compared statin treatment versus placebo or standard care, and reported at least one cognitive outcome (frequency of adverse cognitive events or measurements using standard neuropsychological cognitive test scores). Studies reporting sufficient information to calculate effect sizes were included in meta-analyses. Standardized and unstandardized mean differences were calculated for continuous outcomes for global cognition and for pre-specified cognitive domains. The main outcome was change in cognition measured by neuropsychological tests; an outcome of secondary interest was the frequency of adverse cognitive events observed during follow-up. We identified 25 RCTs (all placebo-controlled) reporting cognitive outcomes in 46,836 subjects, of which 23 RCTs reported cognitive test results in 29,012 participants. Adverse cognitive outcomes attributable to statins were rarely reported in trials involving cognitively normal or impaired subjects. Furthermore, meta-analysis of cognitive test data (14 studies; 27,643 participants) failed to show significant adverse effects of statins on all tests of cognition in either cognitively normal subjects (standardized mean difference 0.01, 95% confidence interval, CI, -0.01 to 0.03, p = 0.42) or Alzheimer's disease subjects (standardized mean difference -0.05, 95% CI -0.19 to 0.10, p = 0.38). Statin therapy was not associated with cognitive impairment in RCTs. These results raise questions regarding the continued merit of the FDA warning about potential adverse effects of statins on cognition.

Abstract 12523: Crucial Role of SmgGDS in the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis in Mice

Introduction: We have previously demonstrated that small GTP-binding protein dissociation stimulator (SmgGDS) plays a crucial role in the pleiotropic effects of HMG-CoA reductase inhibitors (statins) in mice and humans. In the present study, we tested our hypothesis that SmgGDS plays a crucial role in the inhibitory effects of statins on the development of cardiac hypertrophy and fibrosis. Methods &amp; Results: We administered angiotensin II (AngII, 2 mg/kg/day, 2 weeks) to SmgGDS-deficient ( SmgGDS +/- ) mice and littermate controls ( SmgGDS +/+ ), which were orally treated with either statins (atorvastatin 10 mg/kg/day or pravastatin 50 mg/kg/day, n=10 each group) or vehicle. AngII equally elevated systolic blood pressure and promoted cardiac hypertrophy and fibrosis in SmgGDS +/+ and SmgGDS +/- . Both statins significantly reduced LV wall thickness, cardiac myocyte cross-sectional area, and fibrotic area in AngII-infused SmgGDS +/+ mice (all P&lt;0.01). In contrast, the inhibitory effects of statins were absent in AngII-infused SmgGDS +/- mice. Additionally, statins significantly improved LV diastolic function (E/A) in SmgGDS +/+ mice (P&lt;0.01) but not in SmgGDS +/- mice. Interestingly, immunostaining revealed that SmgGDS was highly expressed in cardiac fibroblasts (CFs) in the heart of AngII-infused SmgGDS +/+ mice. Then, we harvested CFs from SmgGDS +/+ and SmgGDS +/- mice and stimulated them with AngII with or without statins. At baseline, SmgGDS +/- CFs showed significant increase in Rac1 expression (1.8-fold), ERK1/2 activity (4.0-fold), Rho-kinase activity (phospho-MYPT/total-MYPT, 1.4-fold) compared to SmgGDS +/+ CFs, whereas Akt activity was significantly less in SmgGDS +/- CFs compared to SmgGDS +/+ CFs (n=4, all P&lt;0.05). Statin treatment significantly reduced Rac1 expression in SmgGDS +/+ CFs (-30%, n=4, P&lt;0.05), which was not observed in SmgGDS +/- CFs, suggesting that SmgGDS mediates the inhibitory effects of statins on Rac1 signaling. Conclusions: These results indicate that SmgGDS plays a crucial role in the inhibitory effects of statins on cardiac hypertrophy and fibrosis, partly through inhibition of Rac1, Rho-kinase, and ERK1/2 pathways.

Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: Possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors

BackgroundThis study aimed to investigate the effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats. MethodsWe determined the pharmacokinetic parameters of nifedipine and dehydronifedipine in rats after oral and intravenous administration of nifedipine without and with HMG-CoA reductase inhibitors.We evaluated the effect of HMG-CoA reductase inhibitors on the activity of P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4. ResultsAtorvastatin, fluvastatin, pravastatin and simvastatin inhibited CYP3A4 activities; inhibitory concentration (IC50) values were 47.0, 5.2, 15.0 and 3.3μM, respectively. Simvastatin and fluvastatin increased the cellular uptake of rhodamine-123.The area under the plasma concentration–time curve (AUC0–∞) and the peak plasma concentration (Cmax) of oral nifedipine were significantly increased by fluvastatin and simvastatin, respectively, compared to control group. The total body clearance (CL/F) of nifedipine after oral administration with fluvastatin and simvastatin were significantly decreased compared to those of control. The metabolite–parent AUC ratio (MR) of nifedipine with fluvastatin and simvastatin were significantly decreased, which suggested that fluvastatin and simvastatin inhibited metabolism of nifedipine, respectively. The AUC0–∞ of intravenouse nifedipine with fluvastatin and simvastatin was significantly higher than that of the control group. ConclusionThe increased bioavailability of nifedipine may be mainly due to inhibition of both P-gp in the small intestine and CYP3A subfamily-mediated metabolism of nifedipine in the small intestine and/or in the liver and to the reduction of the CL/F of nifedipine by fluvastatin and simvastatin.

Abstract 180: Synergistic Salutary Effects of HMG-CoA Reductase Inhibitor and Angiotensin II Receptor Blocker on Load-induced Heart Failure

We have shown previously that combined HMG-CoA reductase inhibitor (statin) and angiotensin II receptor blocker (ARB) therapy significantly improves both symptoms and left ventricular (LV) function over time in patients with heart failure (HF) by a clinical study [ HF-COSTAR Trial]. We elucidated the mechanisms of combination therapy with the ARB (losartan, LOS) and long-acting and statin (simvastatin, SIM) for the treatment of load-induced heart failure. Salt-loaded Dahl salt-sensitive (DS) rats were treated with vehicle, LOS (5mg/kg/day), SIM (2mg/kg/day) and LOS + SIM for 16 weeks. LOS and SIM in combination improved LV dysfunction (ΔLV fractional shortening; LOS = 60%, SIM = 42%, LOS + SIM = 24%, p &lt;0.05), limited LV hypertrophy (ΔLV septal thickness; LOS = −21%, SIM = −18%, LOS + SIM = −13%, p &lt;0.05) and reduced cardiac fibrosis (ΔLV collagen density; LOS = −26%, SIM = −16%, LOS + SIM = −28%, p &lt;0.05) more than LOS or SIM alone. Both Rho and matrix metalloprotease-9 (MMP-9) activity in LV tissue were increased in untreated DS rats, and LOS and SIM in combination decreased these changes more than did LOS and SIM monotherapies. We confirmed that the plasma level of Exp-3174 (E3174), a LOS metabolite and a potent inverse agonist of angiotensin II receptor type 1, was higher in rats treated with LOS and SIM in combination than in those treated with LOS alone (E3174/LOS ratio; LOS = 2.6 ± 0.3 vs. LOS + SIM = 3.2 ± 0.2, p &lt;0.05). Next, to mimic the response of volume-overload heart failure in vitro , cultured neonatal rat cardiomyocytes (CMs) were cyclically stretched. Stretch-induced increased CM hypertrophy was suppressed by pretreatment with both SIM and E3174 more than by pretreatment with LOS, E3174, SIM, or LOS and SIM in combination. Mechanical stretch also induced activation of extracellular signal regulated kinase (ERK) and the stretch-induced ERK activation of CMs was also significantly suppressed by SIM + E3174. In conclusion, LOS and SIM had beneficial myocardial effects in rats with salt-sensitive hypertension, partly through promoting the accumulation of plasma E3174. SIM enhanced the myocardial protective effects of LOS through suppression of Rho and MMP-9 activity. Thus, a combination of ARB with statin has a promising potential as a therapeutic strategy for HF.

The effects of HMG-CoA reductase inhibitor on lipopolysaccharide induced activation of pancreatic stellate cells

The effects of HMG-CoA reductase inhibitor on lipopolysaccharide induced activation of pancreatic stellate cells