Translating the effects of statins: From redox regulation to suppression of vascular wall inflammation

2012 ◽  
Vol 108 (11) ◽  
pp. 840-848 ◽  
Author(s):  
Alexios Antonopoulos ◽  
Marios Margaritis ◽  
Cheerag Shirodaria ◽  
Charalambos Antoniades
Keyword(s):  
Nitric Oxide ◽  
Redox Regulation ◽  
Mevalonate Pathway ◽  
Vascular Wall ◽  
Statin Treatment ◽  
Lipid Lowering ◽  
Redox Signalling ◽  
Beneficial Effects ◽  
Reductase Inhibitors ◽  
Coa Reductase

SummaryVascular oxidative stress is a key feature of atherogenesis, and targeting vascular redox signalling is a rational therapeutic goal in vascular disease pathogenesis. 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors or statins are potent lipid-lowering drugs that improve cardiovascular outcomes. It is now widely accepted that cardiovascular disease prevention by statins is dependent not only on their lipid lowering effects, but also on their beneficial effects on vascular redox signalling. Cell culture and animal models have provided important findings on the effects of statins on vascular redox and nitric oxide bioavailability. Recent evidence from studies on human vessels has further enhanced our understanding of the “pleiotropic” effects of statins on vascular wall. Reversal of endothelial dysfunction in human vessels by statins is dependent on the mevalonate pathway and Rac1 inhibition. These critical steps are responsible for reducing NADPH-oxidase activity and improving tetrahydrobiopterin bioavailability and nitric oxide synthase (NOS) coupling in human vessels. However, mevalonate pathway inhibition has been also held responsible for some of the side effects observed after statin treatment. In this review we summarise the existing knowledge on the effects of statins on vascular biology by discussing key findings from basic science as well as recent evidence from translational studies in humans. Finally, we discuss emerging aspects of statin pleiotropy, such as their effects on adipose tissue biology and adipokine synthesis that may light additional mechanistic links between statin treatment and improvement of clinical outcome in primary and secondary prevention.

scholarly journals Comparison Between Atorvastatin and Rosuvastatin on Anti- Thrombogenic Effect in Patients with Hyperlipidemia

2018 ◽  
Vol 8 (3) ◽  
pp. 153-158
Author(s):  
Samia Haque Tonu ◽  
Jesmine Fauzia Dewan ◽  
Fahmida Hasnat ◽  
Begum Rudaba Jahan
Keyword(s):  
Platelet Count ◽  
Serum Lipid ◽  
Thrombus Formation ◽  
Lipid Lowering ◽  
Atorvastatin Group ◽  
Beneficial Effects ◽  
Reductase Inhibitors ◽  
Significant Difference ◽  
Rosuvastatin Group ◽  
Coa Reductase

Background: Atorvastatin and rosuvastatin are two widely used HMG-CoA reductase inhibitors (statins). These are used as lipid-lowering drugs to reduce atherosclerosis-induced cardiovascular events. The beneficial effects of statins also involve some lipid-independent mechanisms which include modification of thrombus formation and degradation, alteration in inflammatory response, plaque stabilization and improvement of endothelial function.Objective: To compare antithrombogenic effect of atorvastatin and rosuvastatin in patients with hyperlipidemia.Materials and Methods: A prospective, open-labeled, interventional, randomized and single-center study was carried out in Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from March, 2016 to August, 2017 on 52 hyperlipidemic patients. After randomization patients were assigned to atorvastatin 10 mg or rosuvastatin 5 mg daily for 8 weeks. Blood was collected at baseline and after intervention to measure platelet count, prothrombin time (PT) and serum lipid profile.Results: The baseline characteristics of patients treated with atorvastatin and rosuvastatin were almost identical. The platelet count in atorvastatin group was reduced after intervention (2.30%, p=0.463) which was not significant but in rosuvastatin group platelet count reduced significantly (12.33%, p=0.021) after intervention. There was no statistically significant difference (p=0.187) between the two statin treated groups. PT was increased significantly after intervention in both atorvastatin group (31.44%, p<0.001) and in rosuvastatin group (31.93%, p=0.003), which was statistically significant. No significant difference was observed between the two groups (p=0.573). Both atorvastatin and rosuvastatin significantly improved serum lipid profile.Conclusion: The present study reveals that rosuvastatin reduced thrombogenesis more effectively than atorvastatin in hyperlipidemic patients.J Enam Med Col 2018; 8(3): 153-158

Treating Dyslipidemia for the Primary and Secondary Prevention of Stroke

2017 ◽  
Vol 37 (03) ◽  
pp. 286-293
Author(s):  
Fotios Barkas ◽  
Haralampos Milionis
Keyword(s):  
Ischemic Stroke ◽  
Secondary Prevention ◽  
Stroke Risk ◽  
Therapeutic Interventions ◽  
Lipid Lowering ◽  
Prevention Measures ◽  
Primary And Secondary Prevention ◽  
Beneficial Effects ◽  
Reductase Inhibitors ◽  
Coa Reductase

AbstractStroke is associated with a heavy burden of mortality and disability, underscoring the importance of effective primary and secondary prevention measures. Dyslipidemia as a risk factor for ischemic stroke has long been disputed. Nevertheless, accumulating epidemiological evidence supports a role of lipid abnormalities in increasing ischemic stroke risk and representing a potential target for therapeutic interventions. 3-hydroxy-3-methyl-glutaryl- (HMG-) CoA reductase inhibitors (i.e., statins) are currently the mainstay of therapy for the management of hypercholesterolemia in patients with cardiovascular disease and stroke. Although their beneficial effects on stroke risk have been attributed chiefly to their lipid-lowering capacity, they also have pleiotropic effects. Other lipid lowering modalities have been shown to reduce the risk of ischemic stroke in individuals at high cardiovascular risk, but data regarding their use in secondary stroke prevention are lacking.

Statins and Inflammation in Cardiovascular Disease

2018 ◽  
Vol 23 (46) ◽  
pp. 7027-7039 ◽  
Author(s):  
Georgia Vogiatzi ◽  
Evangelos Oikonomou ◽  
Gerasimos Siasos ◽  
Sotiris Tsalamandris ◽  
Alexandros Briasoulis ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Lipid Lowering ◽  
Hmg Coa Reductase ◽  
Ample Evidence ◽  
Reductase Inhibitors ◽  
Immune System Activation ◽  
Hmg Coa Reductase Inhibitors ◽  
Anti Inflammatory ◽  
Artery Disease ◽  
Coa Reductase

Background: 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. </P><P> Objective: To summarize the anti-inflammatory mechanisms of statins in clinical and experimental settings in cardiovascular disease. </P><P> Methods: 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. </P><P> Results: In vitro, statins have immuno-modulatory and anti-inflammatory effects, and they can exert antiatherosclerotic 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. </P><P> Conclusion: 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.

Short telomere subtelomeric hypomethylation is associated with telomere attrition in elderly diabetic patients

2019 ◽  
Vol 97 (4) ◽  
pp. 335-339 ◽  
Author(s):  
Naoki Makino ◽  
Toyoki Maeda ◽  
Nobuyuki Abe
Keyword(s):  
Methylation Status ◽  
Statin Treatment ◽  
Diabetic Patients ◽  
Short Telomere ◽  
Telomere Shortening ◽  
Telomere Attrition ◽  
Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase

Telomere shortening is well known to be associated with the aging process and aging-associated diseases, including diabetes. The telomere length and subtelomeric methylation status in peripheral leucocytes (LTL) were compared in elderly type 2 diabetes (T2D) patients and diabetes-free controls (C). The methylation status was analyzed between MspI-TRF lengths and HpaII-TRF lengths by using methylation-sensitive and -insensitive restriction enzyme isoschizomers, MspI and HpaII, respectively. The mean telomere lengths, MspI-TRF or HpaII-TRF, were not significantly different between C and T2D patients. The percentage of fractionated densitometry showed that long and middle telomeres (>9.4 kb, 4.4–9.4 kb) were unaltered but short telomeres (<4.4 kb) in T2D patients were increased compared with C group. The methylation status revealed subtelomeric hypomethylation in short telomeres of T2D patients. When some patients with T2D were treated with 3-hydroxy-3-methylglutaril coenzyme A (HMG-CoA) reductase inhibitors (statin), results seen in short telomere of T2D patients were not observed and were not different from C. This suggested that this altered subtelomeric hypomethylation may be associated with the accelerated telomere shortening in elderly diabetic patients. These results also mean that the subtelomeric hypomethylation can also be influenced by statin treatment in T2D.

Atorvastatin in the Treatment of Primary Hypercholesterolemia and Mixed Dyslipidemias

1998 ◽  
Vol 32 (10) ◽  
pp. 1030-1043 ◽  
Author(s):  
Helen S Yee ◽  
Nancy T Fong
Keyword(s):  
Clinical Trials ◽  
Clinical Studies ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Hmg Coa Reductase ◽  
Apo B ◽  
Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase ◽  
The Impact

OBJECTIVE: To review the efficacy and safety of atorvastatin in the treatment of dyslipidemias. DATA SOURCES: A MEDLINE search (January 1960–April 1998), Current Contents search, additional references listed in articles, and unpublished data obtained from the manufacturer were used to identify data from scientific literature. Studies evaluating atorvastatin (i.e., abstracts, clinical trials, proceedings, data on file with the manufacturer) were considered for inclusion. STUDY SELECTION: English-language literature was reviewed to evaluate the pharmacology, pharmacokinetics, therapeutic use, and adverse effects of atorvastatin. Additional relevant citations were used in the introductory material and discussion. DATA EXTRACTION: Open and controlled animal and human clinical studies published in the English-language literature were reviewed and evaluated. Clinical trials selected for inclusion were limited to those in human subjects and included data from animals if human data were not available. DATA SYNTHESIS: Atorvastatin is a recent hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase inhibitor for the treatment of primary hypercholesterolemia, mixed dyslipidemias, and homozygous familial hypercholesterolemia. In patients who have not met the low-density lipoprotein cholesterol (LDL-C) goal as recommended by the National Cholesterol Education Program Adult Treatment Panel II guidelines, atorvastatin 10–80 mg/d may be used as monotherapy or as an adjunct to other lipid-lowering agents and dietary modifications. In placebo-controlled clinical trials, atorvastatin 10–80 mg/d lowered LDL-C by 35–61% and triglyceride (TG) concentrations by 14–45%. In comparative trials, atorvastatin 10–80 mg/d showed a greater reduction of serum total cholesterol (TC), LDL-C, TG concentrations, and apolipoprotein B-100 (apo B) compared with pravastatin, simvastatin, or lovastatin. In comparison, currently available HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin) lower LDL-C concentrations by approximately 20–40% and TG concentrations by approximately 10–30%. In pooled placebo-controlled clinical trials of up to a duration of 52 weeks, atorvastatin in dosages up to 80 mg/d appeared to be well tolerated. The most common adverse effect of atorvastatin was gastrointestinal upset. The incidence of elevated serum hepatic transaminases may be greater at higher dosages of atorvastatin. The risk of myopathy and/or rhabdomyolysis is increased when an HMG-CoA reductase inhibitor is taken concomitantly with cyclosporine, gemfibrozil, niacin, erythromycin, or azole antifungals. CONCLUSIONS: Atorvastatin appears to reduce TC, LDL-C, TG concentrations, and apo B to a greater extent than do currently available HMG-CoA reductase inhibitors. Atorvastatin may be preferred in patients requiring greater than a 30% reduction in LDL-C or in patients with both elevated LDL-C and TG concentrations, which may obviate the need for combination lipid-lowering therapy. Adverse effects of atorvastatin appear to be similar to those of other HMG-CoA reductase inhibitors and should be routinely monitored. Long-term safety data (>1 y) on atorvastatin compared with other HMG-CoA reductase inhibitors are still needed. Cost-effectiveness studies comparing atorvastatin with other HMG-CoA reductase inhibitors remain a subject for further investigation. Published clinical studies evaluating the impact of atorvastatin on cardiovascular morbidity and mortality are still needed. Additionally, clinical studies evaluating the impact of lipid-lowering therapy in a larger number of women, the elderly (>70 y), and patients with diabetes for treatment of primary and secondary prevention of coronary heart disease are needed.

scholarly journals Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer

2021 ◽  
Author(s):  
Yoichi Morofuji ◽  
Shinsuke Nakagawa ◽  
Kenta Ujifuku ◽  
Takashi Fujimoto ◽  
Kaishi Otsuka ◽  
...  
Keyword(s):  
Cell Types ◽  
Pharmacological Action ◽  
Cerebrovascular Diseases ◽  
Lipid Lowering ◽  
Neuroprotective Effects ◽  
First Line Therapy ◽  
Reductase Inhibitors ◽  
Growth Inhibitory ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The preventive effect of statins on atherothrombotic stroke has been well established, but statins can influence other cerebrovascular diseases. This suggests that statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not been fully elucidated and are still controversial. This review discusses the recent evidence on the effects of statins on cardiovascular and cerebrovascular diseases and cancer. Additionally, this study describes the pharmacological action of statins, focusing on the aspect of &lsquo;beyond lipid-lowering.&rsquo;

Abstract 532: Effect of 3-hydroxy-3-methylglutaryl-CoA Reductase Inhibitors on Renal Function

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Rishi Sukhija ◽  
Zoran Bursac ◽  
Rajesh Sachdeva ◽  
Jawahar Mehta
Keyword(s):  
Renal Function ◽  
Kidney Disease ◽  
Lipid Lowering ◽  
Channel Blockers ◽  
Converting Enzyme Inhibitors ◽  
Cross Sectional ◽  
Renal Deterioration ◽  
Reductase Inhibitors ◽  
Cardiovascular Morbidity And Mortality ◽  
Coa Reductase

Background : 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) reduce serum cholesterol, and cardiovascular morbidity and mortality. The role of lipids in the progression of kidney disease and the potential beneficial effects of statins on renal function is unknown. Oxidative stress and inflammation may be the missing link between CAD and chronic kidney disease. Statins may protect the kidney through both lipid lowering properties and pleiotropic effects. Methods : We analyzed data in 197, 551 patients (mean age 64.8 ± 13.6 years, 95% males, 29.5% (58,332) statin users, and 70.5% (139, 219) non-statin users), who had baseline creatinine less than 3.5 mg/dl, from the cross-sectional data mined from the Veterans Affairs VISN 16 database. Deterioration of renal function was defined as doubling of the baseline or increase in creatinine of 0.5 mg/dl over at least 90 days. Results : Based on this definition, 3.4% of patients developed renal deterioration over 5 year of follow-up. After adjustment for demographics, diabetes mellitus, smoking, and other medications (especially use of angiotensin-converting enzyme inhibitors, calcium channel blockers and aspirin, all of which were confounders of the statin-renal deterioration relationship), use of statins reduced the odds of deterioration in renal function by 15% (OR 0.85, 95% CI = 0.80 – 0.89, p < 0.0001). This effect was independent of cholesterol lowering effect of statins. Impact of other variables was as follows: age (OR = 1.04, CI = 1.03–1.04, p < 0.0001), diabetes (OR = 1.76, CI = 1.67–1.85, p < 0.0001), and smoking (OR = 1.76, CI = 1.05–1.23, p = 0.0014). Conclusion : Statin use may retard the progression of renal disease. Although the precise mechanism is not known, lowering of LDL-cholesterol and improvement in endothelial function by statins may relate to reno-protective effect.

Statins restore ischemic limb blood flow in diabetic microangiopathy via eNOS/NO upregulation but not via PDGF-BB expression

2008 ◽  
Vol 294 (6) ◽  
pp. H2785-H2791 ◽  
Author(s):  
Takaaki Fujii ◽  
Mitsuho Onimaru ◽  
Yoshikazu Yonemitsu ◽  
Hiroyuki Kuwano ◽  
Katsuo Sueishi
Keyword(s):  
Statin Therapy ◽  
Vascular Complications ◽  
Lipid Lowering ◽  
Diabetic Microangiopathy ◽  
Diabetic Angiopathy ◽  
Hindlimb Ischemia ◽  
Reductase Inhibitors ◽  
Diabetic Vascular Complications ◽  
Foot Disease ◽  
Coa Reductase

3-Hydroxy-3-methyl-glutaryl CoA reductase inhibitors, or statins, have pleiotropic effects and can protect the vasculature in a manner independent of their lipid-lowering effect. The effectiveness of statins in reducing the risk of coronary events has been shown even in patients with diabetes, and their effects on diabetic complications have been reported. Using a model of severe hindlimb ischemia in streptozotocin-induced diabetic mice (STZ-DM), we investigated the effects and mechanisms of statin therapy in diabetic angiopathy in ischemic hindlimbs. As a result, STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Supplementation with statins significantly prevented autoamputation. We previously showed that diabetic vascular complications are caused by impaired expression of PDGF-BB, but statin therapy did not enhance PDGF-BB expression. Statins helped enhance endogenous endothelial nitric oxide (NO) synthase (eNOS) expression. Furthermore, the inhibition of NO synthesis by the administration of Nω-nitro-l-arginine methyl ester impaired the ability of statins to prevent STZ-DM mouse limb autoamputation, indicating that the therapeutic effect of statins in hindlimb ischemia in STZ-DM mice occurs via the eNOS/NO pathway. A combination therapy of statins and PDGF-BB gene supplementation was more effective for diabetic angiopathy than either therapy alone. In conclusion, these findings indicate that statin therapy might be useful for preventing intractable diabetic foot disease in patients with diabetic angiopathy.

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