darapladib and Atherosclerosis

Elevated levels of phospholipase A2 have been linked to atherosclerotic plaque progression, instability via promoting inflammation and subsequent acute coronary events. Epidemiological studies have demonstrated the correlation between elevated levels associated phospholipase A2 and cardiovascular events. Therefore, specific inhibition of lipoprotein-associated phospholipase A2 with darapladib has been tested as a therapeutic option for atherosclerosis. The aim of this profile is to review the physiologic aspects of lipoprotein-associated phospholipase A2 and to revisit the clinical evidence of darapladib as therapeutic option for atherosclerosis.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Atherosclerosis; Benzaldehydes; Humans; Inflammation; Oximes; Plaque, Atherosclerotic; Risk

Phospholipase A(2) (PLA(2)) are enzymes that hydrolyze the ester bond of glycerophospholipids releasing free fatty acids and lysophospholipids, including the arachidonic acid, the precursor of the eicosanoids and the inflammatory cascades. PLA(2) are present in the atherosclerotic plaques and their direct involvement in the proatherogenic inflammatory response is well documented. Epidemiological and genetic studies have demonstrated the correlation of the PLA(2) mass and enzymatic activity with the incidence of cardiovascular diseases. The potential pro-atherogenic role of PLA(2) led to the development of two small molecules, varespladib, a reversible sPLA(2) inhibitor, and darapladib, a selective Lp-PLA(2) inhibitor. Both molecules have demonstrated antiatherosclerotic properties in animal models, and positive effects on atherosclerotic plaque composition evaluated in phase 2 clinical trials. On these grounds, the results of three phase 3 studies have recently been published: the VISTA-16 study with varespladib in patients with acute coronary syndrome, and the STABILITY and SOLID-TIMI 52 studies with darapladib in patients with stable coronary heart disease and acute coronary syndrome, respectively. Unexpectedly, both studies did not demonstrate an additional protective action of PLA 2 inhibitors over the standard of care treatment with statins, antiplatelet drugs, and coronary revascularization. In the present article, the enzymatic properties and the involvement of sPLA(2) and Lp-PLA(2) in atherogenesis are reviewed, with a focus on the results of experimental studies and clinical studies with both varespladib and darapladib inhibitors.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Acute Coronary Syndrome; Atherosclerosis; Benzaldehydes; Clinical Trials, Phase III as Topic; Coronary Artery Disease; Humans; Indoles; Keto Acids; Lipoproteins; Oximes; Phospholipase A2 Inhibitors; Phospholipases A

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a vascular-specific inflammatory marker. It is so named because of its association with low-density lipoprotein in plasma. Atherosclerosis is an inflammatory disease. Lp-PLA2 is recognized as a risk marker in primary or secondary prevention of atherosclerosis. Elevated Lp-PLA2 levels are associated with the increased risk for cardiovascular events, even after multivariable adjustment for traditional risk factors. Patients with dyslipidemia are shown to benefit largely from the modification of Lp-PLA2. The degree of coronary artery disease (0-, 1-, 2-, or 3-vessel disease) and plasma low-density lipoprotein cholesterol significantly correlated to Lp-PLA2 levels. The low biologic fluctuation and high vascular specificity of Lp-PLA2 make it possible to use a single measurement in clinical decision making, and it also permits clinicians to follow the Lp-PLA2 marker serially. Simvastatin significantly reduces macrophage content, lipid retention, and the intima to media ratio but increased the content of smooth muscle cells in atherosclerotic lesions. Statin treatment markedly reduced Lp-PLA2 in both plasma and atherosclerotic plaques with attenuation of the local inflammatory response and improved plaque stability due to reduced inflammation and decreased apoptosis of macrophages. Darapladib, an inhibitor of Lp-PLA2 when added to lipid-lowering therapy such as statins, offers great benefit in the reduction of plaque formation. This article explores the atherosclerotic process at molecular level, role of Lp-PLA2 in atherosclerosis, the effect of lipid-lowering drugs on Lp-PLA2, effect of direct Lp-PLA2 inhibitor darapladib in the atherosclerosis process, the therapeutic implications of Lp-PLA2 as risk marker, and finally the net effect on plaque stabilization.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Atherosclerosis; Benzaldehydes; Biomarkers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Inflammation; Lipoproteins, LDL; Oximes; Plaque, Atherosclerotic

Certain members of the phospholipase A(2) superfamily of enzymes have established causal involvement in atherosclerosis, thus at least two groups of this family of enzymes have been considered potential candidates for the prevention of cardiovascular events. Recently completed experimental animal studies, human biomarker data, vascular imaging studies, and genome-wide atherosclerosis studies provide the rationale for proceeding with clinical outcome trials directed at inhibition of secretory phospholipase A(2) and lipoprotein-associated phospholipase A(2). A clinical trial with the sPLA(2) inhibitor varespladib methyl was recently terminated, while clinical trials with the Lp-PLA(2) inhibitor darapladib are being conducted in coronary heart disease patients. This article reviews the available experimental animal and human trial evidence that serve as the basis for the development of these two classes of phospholipase A(2) inhibitors.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Animals; Atherosclerosis; Benzaldehydes; Biomarkers; Cardiovascular Diseases; Clinical Trials as Topic; Enzyme Inhibitors; Guinea Pigs; Humans; Indoles; Keto Acids; Mice; Mutation, Missense; Myocardial Ischemia; Myocytes, Cardiac; Oximes; Phospholipases A2, Secretory; Polymorphism, Genetic; Risk Factors

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is an enzyme that generates inflammatory mediators within atherosclerotic plaques. In epidemiologic studies there is an association between higher plasma Lp-PLA₂ activity and myocardial infarction, stroke and cardiovascular mortality. In animal models, darapladib, a specific inhibitor of Lp-PLA₂, decreases the size of the atheroma necrotic core and plaques with thin fibrous caps. Early clinical trials suggest darapladib effectively and safely inhibits Lp-PLA₂ activity both in plasma and in carotid atheroma. Two large phase III clinical trials that are currently in progress will determine whether darapladib will reduce the risk of myocardial infarction, stroke, and cardiovascular death by stabilizing atherosclerotic plaques.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Atherosclerosis; Benzaldehydes; Biomarkers; Clinical Trials, Phase III as Topic; Disease Models, Animal; Drug Delivery Systems; Female; Humans; Male; Oximes; Plaque, Atherosclerotic; Prognosis; Risk Assessment; Survival Analysis; Treatment Outcome

How to manage residual atherosclerosis risk after the statin therapy is a major concern in cardiovascular medicine. In addition to life-style modifications, new drugs against atherosclerotic and inflammatory vascular diseases are expected. In current clinical trials, phospholipase A2 inhibitors(darapladib, varespladib), RVX-208, D-4F, CETP inhibitors (anacetrapib, dalcetrapib), succinobucol are investigated. Some has been failed, but others are still promising. On molecular target basis of PAF-AH, CETP, PON, ABC transporters of A1 and G1, SR-BI, HO-1, potential benefits and side effects are discussed.

Topics: Acetates; Amides; Apolipoprotein A-I; Atherosclerosis; Benzaldehydes; Blood Proteins; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Drug Design; Esters; Humans; Indoles; Keto Acids; Molecular Targeted Therapy; Oxazolidinones; Oximes; Probucol; Quinazolines; Quinazolinones; Sulfhydryl Compounds

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a calcium-independent phospholipase A2 that circulates in plasma in association with lipoprotein particles, whereas in atherosclerotic plaques it is co-localized with macrophages. Lp-PLA2 generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. Epidemiologic studies demonstrate that increased circulating levels of Lp-PLA2 predict an increased risk of myocardial infarction, stroke and cardiovascular mortality. Furthermore, histologic examination of diseased human coronary arteries reveals intense presence of the enzyme in atherosclerotic plaques that are prone to rupture. These considerations suggest Lp-PLA2 as a promising therapeutic target in cardiovascular disease. Plasma levels of Lp-PLA2 are increased in various types of hyperlipidemias, while hypolipidemic drugs reduce plasma Lp-PLA2 activity and mass along with the improvement of plasma lipid profile. A selective inhibitor of Lp-PLA2 activity, darapladib, has been developed and studies in animal models and humans have shown that it effectively and safely reduces Lp-PLA2 activity in plasma and in atherosclerotic plaques. Furthermore, in animal models darapladib decreases plaque area and necrotic core area whereas in humans it prevents the expansion of necrotic core volume. Whether the results obtained from the use of darapladib in studies in vitro, as well as in preclinical and clinical studies would translate into benefits on cardiovascular event outcomes, awaits to be proved in 2 ongoing phase 3 trials.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Atherosclerosis; Benzaldehydes; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Oximes; Risk

Atherosclerosis is an inflammatory-immune mediated disease process. Plaque rupture is responsible for the clinical events of ischemic death, myocardial infarction, acute coronary syndromes and ischemic strokes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) seems to play a major role in the development of such high-risk lesions, in both the coronary and carotid arteries. Darapladib is a selective inhibitor of Lp-PLA(2).. An overview of darapladib by reviewing the studies (1990 - 2009) that have provided the rationale for the development of darapladib; and a discussion of its potential merit as a new therapeutic drug to target high-risk atherosclerosis.. The reader should gain an understanding of the importance of inflammation during atherogenesis as well as of the biology of Lp-PLA(2) and its proatherogenic role. Additional insights will be gained into the role of selective inhibitors of Lp-PLA(2) as new therapeutic agents.. Darapladib is a selective inhibitor of Lp-PLA(2) and represents a new class of therapeutic agents that target inflammation to treat high-risk atherosclerosis.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Benzaldehydes; Clinical Trials as Topic; Drug Discovery; Humans; Molecular Structure; Oximes

The potential for phospholipases as targets for treating atherogenesis has become more prominent over the past year with the publication of the results of Phase 2 clinical trials of two inhibitors of forms of phospholipase A2: darapladib (GSK) which inhibits lipoprotein-associated phospholipase A2 and varespladib (Anthera) an inhibitor of several secreted phospholipase A2s. Although some aspects of their biology overlap, these are distinct targets with different potential for influencing atherogenesis. The background science to these two targets is discussed in this review, noting the balance of data, from human, preclinical species and in vitro that support further development of the inhibitors into Phase 3. Note is taken of another phospholipase A2 (cytosolic) which has been less fully described but for which there has been some interest.

Topics: Acetates; Animals; Atherosclerosis; Benzaldehydes; Biomarkers; Cytosol; Drug Design; Enzyme Inhibitors; Humans; Indoles; Keto Acids; Lipoproteins; Mice; Oximes; Phospholipase A2 Inhibitors; Phospholipases A2

Despite a reduction in cardiovascular risk conferred by therapies that modify circulating lipids, a need remains for novel treatments to further decrease the occurrence of complications of atherosclerotic cardiovascular diseases. Lipoprotein-associated phospholipase-A(2) is an important regulator of lipid metabolism and inflammation that circulates with lipoprotein particles and is carried into the arterial wall with low-density lipoprotein particles during the progression of atherosclerosis. Within the vessel wall, lipoprotein-associated phospholipase-A(2) releases small molecules that stimulate macrophage recruitment and evolution to foam cells, leading to plaque vulnerability. Epidemiologic studies demonstrate that elevated circulating levels of lipoprotein-associated phospholipase-A(2) predict an increased risk of myocardial infarction and stroke, whereas histologic examination of diseased human coronary arteries reveals intense presence of the enzyme in atherosclerotic plaques that are prone to rupture. These considerations suggest lipoprotein-associated phospholipase-A(2) as a promising therapeutic target, and a specific inhibitor, darapladib, has been under development for this application. This review summarizes the completed preclinical and early phase clinical studies that underlie two recently commenced phase III clinical trials that will investigate the efficacy and safety of darapladib in nearly 13,000 individuals with coronary heart disease. When completed, these trials should provide important insights into the utility of darapladib to reduce myocardial infarction, stroke and cardiovascular death.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Atherosclerosis; Benzaldehydes; Cardiovascular Diseases; Enzyme Inhibitors; Evidence-Based Medicine; Humans; Hypolipidemic Agents; Lipids; Oximes; Treatment Outcome

Selective inhibitors of secretory phospholipase A2 and lipoprotein-associated phospholipase A2 are potential candidates for reducing recurrent cardiovascular events in patients with established coronary heart disease (CHD). With the active enrollment of CHD patients into phase III clinical trials with both classes of inhibitors, this article reviews the available experimental animal and human trial evidence that provides the rationale for the development of the phospholipase A2 inhibitors varespladib methyl and darapladib as preventive therapy.. Recently completed experimental animal studies, human biomarker data, and vascular imaging studies provide support for proceeding with clinical outcome trials secretory phospholipase A2 and lipoprotein-associated phospholipase A2 inhibition.. Both secretory phospholipase A2 and lipoprotein-associated phospholipase A2 inhibitors hold promise for the reduction of recurrent cardiovascular events in patients treated with current standards of care. The completion of the ongoing clinical event trials has the potential to provide a new dimension to secondary preventive therapy.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Animals; Atherosclerosis; Benzaldehydes; Biomarkers; Controlled Clinical Trials as Topic; Disease Models, Animal; Dosage Forms; Humans; Indoles; Keto Acids; Mice; Mice, Transgenic; Molecular Targeted Therapy; Oximes; Phospholipases A2, Secretory; Risk Factors

As the role of lipids and inflammation in the genesis and progression of the atherosclerosis disease is unquestionable, novel treatment modalities that target both aspects are currently under investigation.. For a long time atherosclerosis was regarded as a lipid-driven disease, but now it is evident that it also involves the simultaneous and combined effect of inflammation and immunological pathways. The secreted PLA2s and the lipoprotein-associated phospholipase A2 (Lp-PLA2) have been associated with atherogenesis and its complications. These two enzymes produce biologically active metabolites that are involved in several phases of the atherosclerosis process.. In animal, pathological and epidemiological studies, the increased levels of these two phospholipases (i.e. PLA2s and Lp-PLA2) have been related with an increase in complex coronary lesions and increase in major cardiovascular clinical events, respectively. Therefore, inhibition of these enzymes has become the focus of research in this last decennium. Novel pharmacological inhibitors of those enzymes such as darapladib and varespladib emerge as promising therapeutical options for treating patients with coronary artery disease. Ongoing mechanistic and clinical outcome trials will further elucidate their role in this context.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Animals; Atherosclerosis; Benzaldehydes; Blood Proteins; Humans; Indoles; Inflammation; Keto Acids; Oximes

There is great interest in developing a reliable measure of atherosclerotic disease activity that can serve as an index of response to antiatherosclerotic therapies. The epidemiologic relationship between lipid measures, most notably low-density lipoprotein cholesterol (LDL-C), and binary cardiovascular events has been confirmed in treatment trials reliably demonstrating a reduction in LDL-C translating into improved cardiovascular outcomes. Lipoprotein-associated phospholipase A2 (LpPLA2) is part of a family of lipases involved in the modification of lipids within the atheroma and may be a complimentary therapeutic target to the reduction of LDL-C in patients with advanced atherosclerosis. Darapladib is an orally available, specific inhibitor of LpPLA2 activity and has been shown to reduce lysophosphatidylcholine content and expression of multiple genes associated with macrophage and T-lymphocyte functioning, with considerable decrease in plaque and necrotic core area. Thus, this agent holds the hope of being a bona fide antiatherosclerotic therapy that can be gauged through blood measurement of LpPLA2 activity.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Atherosclerosis; Benzaldehydes; Humans; Oximes; Treatment Outcome

Darapladib, under development by GlaxoSmithKline plc, is a novel inhibitor of lipoprotein-associated phospholipase A2 (PLA2), an enzyme that may link lipid metabolism with inflammation, leading to the increased stability of atherosclerotic plaques present in the major arteries. Darapladib exhibits favorable pharmacokinetics, minimal predicted drug-drug interactions, sustained blood levels with once-daily oral dosing and limited inhibition of other PLA2 isozymes. Preclinical studies in diabetic-hypercholesterolemic swine (useful for the study of human atherosclerosis mechanisms) demonstrated that darapladib attenuated the progression of arterial plaques to a higher-risk phenotype by reducing the number of inflammatory macrophages within plaques and dampening T-cell responses. Two phase II clinical trials demonstrated sustained lipoprotein-associated PLA2 inhibition with daily oral dosing, and favorable effects on markers of inflammation and plaque stability. Phase III trials are ongoing to assess the safety and efficacy of darapladib in reducing adverse clinical events in patients with atherosclerosis.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Administration, Oral; Animals; Atherosclerosis; Benzaldehydes; Coronary Artery Disease; Enzyme Inhibitors; Humans; Oximes

Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with increased risk of cardiovascular (CV) events. Direct inhibition of this proinflammatory enzyme with darapladib may benefit CV patients when given as an adjunct to standard of care, including lipid-lowering and antiplatelet therapies.. STABILITY is a randomized, placebo-controlled, double-blind, international, multicenter, event-driven trial. The study has randomized 15,828 patients with chronic coronary heart disease (CHD) receiving standard of care to darapladib enteric-coated (EC) tablets, 160 mg or placebo.. The primary end point is the composite of major adverse cardiovascular events (MACE): CV death, nonfatal myocardial infarction, and nonfatal stroke. The key secondary end points will include major coronary events, total coronary events, individual components of MACE, and all-cause mortality. Prespecified substudies include 24-hour ambulatory blood pressure monitoring, albuminuria progression, changes in cognitive function, and pharmacokinetic and biomarker analyses. Health economic outcomes and characterization of baseline lifestyle risk factors also will be assessed. The study will continue until 1,500 primary end points have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be 2.75 years.. STABILITY will assess whether direct inhibition of Lp-PLA(2) with darapladib added to the standard of care confers clinical benefit to patients with CHD.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Administration, Oral; Aged; Atherosclerosis; Benzaldehydes; Biomarkers; Blood Pressure Monitoring, Ambulatory; Coronary Disease; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Oximes; Tablets, Enteric-Coated; Treatment Outcome

Increase in the low-density lipoprotein (LDL) level in diabetes mellitus and atherosclerosis is related to lipoprotein associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is an enzyme that produces lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids (oxNEFA). LysoPC regulates inflammation mediators, including intra-cellular adhesion molecule-1 (ICAM-1). Darapladib is known as a Lp-PLA2 specific inhibitor. The aim of this study was to reveal the effect of darapladib on the foam cell number, inducible nitric oxide synthase (iNOS), and ICAM-1 expression in aorta at early stages of the atherosclerosis in type 2 diabetes mellitus Sprague-Dawley rat model.. Thirty Sprague-Dawley male rats were divided into 3 main groups: control, rats with type 2 diabetes mellitus (T2DM), and T2DM rats treated with darapladib (T2DM-DP). Each group was divided into 2 subgroups according the time of treatment: 8-week and 16-week treatment group. Fasting blood glucose, insulin resistance, and lipid profile were measured and analyzed to ensure T2DM model. The foam cells number were detected using hematoxylin-eosin (HE) staining and the expression of iNOS and ICAM-1 was analyzed using double immunofluorescence staining.. Induction of T2DM in male Sprague-Dawley rats after high fat diet and streptozotocin injection was confirmed by elevated levels of total cholesterol and LDL and increased fasting glucose and insulin levels compared to controls after both times of treatment. Moreover, T2DM in rats induced a significant increase (p<0.05) in the foam cells number and iNOS and ICAM-1 expression in aorta compared to controls after both treatment times. Darapladib treatment significantly reduced (p<0.05) foam cells number as well as iNOS expression in aorta in rats with T2DM after both treatment times. A significant decrease (p<0.05) in ICAM-1 expression in aorta was observed after darapladib treatment in rats with T2DM only after 8 weeks of treatment.. Our data indicate that darapladib can decrease the foam cells number, iNOS, and ICAM-1 expression in aorta at the early stages of atherosclerosis in T2DM rat model.

Topics: Animals; Aorta; Atherosclerosis; Benzaldehydes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Oximes; Phospholipase A2 Inhibitors; Rats; Rats, Sprague-Dawley

Atherosclerosis is a chronic inflammatory disease which may lead to major cardiovascular events. The primary cause of atherosclerosis is Dyslipidemia. The increased level of lipid profile triggers endothelial dysfunction. This results in inflammation with the recruitment of monocyte, macrophage, T lymphocyte, and Mast cells secreted by an Lp-PLA2 enzyme which causes binding between macrophage and oxidized LDL. This binding results in the formation of foam cells and also the migration of smooth muscle cells. Following that, an Lp-PLA2 receptor hydrolizes OxPC which results in LysoPC and OxNEFA, bioactive compounds which stimulate the progression of atherosclerosis plaques. This process leads to cell hypoxia, which may result in the increase of HIF-1α and VEGF expressions and induction of vasa vasorum angiogenesis. Employing darapladib as an agent of Lp-PLA2 selective inhibitors, this study aimed to find out the effect of darapladib as an Lp- PLA2 selective inhibitor agent on the formation of vasa vasorum angiogenesis and the decrease of HIF-1α and VEGF expression in aortic tissue of rats with dyslipidemia.. A true laboratory experiment with a randomized post-test control group design used 30 male spraque dowley rats as animal models which were divided into 6 groups: Normal 8 weeks, Normal 16 weeks, Dyslipidemia (DL) 8 weeks, Dyslipidemia (DL) 16 weeks, Dyslipidemia with darapladib treatment (DLDP) 8 weeks and Dyslipidemia with darapladib treatment (DLDP) 16 weeks. The data measured in this study were the lipid profile (total cholesterol, HDL, and LDL). Using EnzyChrom TM kit, hematoxylin eosin, and double-labelling immunofluorescene, the levels of lipid profile, vasa vasorum, HIF-1α and VEGF were measured.. The study results which were analyzed using NOVA test showed that with darapladib administration, there was a significant decrease in vasa vasorum angiogenesis (p=0.000), HIF-1α (p=0.005) and VEGF (p=0.009) expression in each time series. This result proves that Lp-PLA2 inhibitor reduces inflammatory process.. Darapladib injection as an Lp-PLA2 selective inhibitor correlates with the decreasing vasa vasorum angiogenesis through alteration in HIF-1α and VEGF expressions in the aorta of high fat diet rats. We recommend further experiments to determine the effectiveness of darapladib with earlier time series in the atherosclerosis process.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Atherosclerosis; Benzaldehydes; Dyslipidemias; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Neovascularization, Pathologic; Oximes; Rats, Sprague-Dawley; Vasa Vasorum; Vascular Endothelial Growth Factor A

Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and Rho kinase activity may be associated with atherosclerosis. The principal aim of this study was to examine whether darapladib (a selective Lp-PLA2 inhibitor) could reduce the elevated Lp-PLA2 and Rho kinase activity in atherosclerosis.. Studies were performed in male Sprague-Dawley rats. The atherosclerosis rats were prepared by feeding them with a high-cholesterol diet for 10 weeks. Low-dose darapladib (25 mg·kg⁻¹·d⁻¹) and high-dose darapladib (50 mg·kg⁻¹·d⁻¹) interventions were then administered over the course of 2 weeks.. The serum levels of triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hs-CRP), and Lp-PLA2, significantly increased in atherosclerosis model groups, as did Rho kinase activity and cardiomyocyte apoptosis (p<0.05 vs. sham group), whereas nitric oxide (NO) production was reduced. Levels of TC, LDL-C, CRP, Lp-PLA2, and Rho kinase activity were respectively reduced in darapladib groups, whereas NO production was enhanced. When compared to the low-dose darapladib group, the reduction of the levels of TC, LDL-C, CRP, and Lp-PLA2 was more prominent in the high-dose darapladib group (p<0.05), and the increase of NO production was more prominent (p<0.05). Cardiomyocyte apoptosis of the high-dose darapladib group was also significantly reduced compared to the low-dose darapladib group (p<0.05). However, there was no significant difference in Rho kinase activity between the low-dose darapladib group and the high-dose darapladib group (p>0.05).. Darapladib, a Lp-PLA2 inhibitor, leads to cardiovascular protection that might be mediated by its inhibition of both Rho kinase and Lp-PLA2 in atherosclerosis.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Atherosclerosis; Benzaldehydes; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dose-Response Relationship, Drug; Male; Oximes; Phospholipase A2 Inhibitors; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Triglycerides

Despite systemic exposure to risk factors, the circulatory system develops varying patterns of atherosclerosis for unclear reasons. In a porcine model, we investigated the relationship between site-specific lesion development and inflammatory pathways involved in the coronary arteries (CORs) and distal abdominal aortas (AAs).. Diabetes mellitus (DM) and hypercholesterolemia (HC) were induced in 37 pigs with 3 healthy controls. Site-specific plaque development was studied by comparing plaque severity, macrophage infiltration, and inflammatory gene expression between CORs and AAs of 17 DM/HC pigs. To assess the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in plaque development, 20 DM/HC pigs were treated with the Lp-PLA2 inhibitor darapladib and compared with the 17 DM/HC untreated pigs. DM/HC caused site-specific differences in plaque severity. In the AAs, normalized plaque area was 4.4-fold higher (P<0.001) and there were more fibroatheromas (9 of the 17 animals had a fibroatheroma in the AA and not the COR, P=0.004), while normalized macrophage staining area was 1.5-fold higher (P=0.011) compared with CORs. DM/HC caused differential expression of 8 of 87 atherosclerotic genes studied, including 3 important in inflammation with higher expression in the CORs. Darapladib-induced attenuation of normalized plaque area was site-specific, as CORs responded 2.9-fold more than AAs (P=0.045).. While plaque severity was worse in the AAs, inflammatory genes and inflammatory pathways that use Lp-PLA2 were more important in the CORs. Our results suggest fundamental differences in inflammation between vascular sites, an important finding for the development of novel anti-inflammatory therapeutics.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Aorta, Abdominal; Atherosclerosis; Benzaldehydes; Coronary Vessels; Diabetes Mellitus; Disease Models, Animal; Gene Expression; Hypercholesterolemia; Inflammation; Macrophages; Male; Oximes; Phospholipase A2 Inhibitors; Plaque, Atherosclerotic; Swine

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is involved in the pathogenesis of atherosclerosis, especially in advanced plaques. In the present study, the abilities of darapladib, a selective Lp-PLA(2) inhibitor, and lentivirus-mediated Lp-PLA(2) silencing on inflammation and atherosclerosis in apolipoprotein E-deficient mice were compared.. Apolipoprotein E-deficient mice were fed on a high-fat diet and a constrictive collar was placed around the left carotid artery to induce plaque formation. The mice were randomly divided into control, negative control (NC), darapladib and RNA interference (RNAi) groups. Eight weeks after surgery, lentivirus-mediated RNAi construct or darapladib were used to decrease the expression of Lp-PLA(2). Plaques were collected five weeks later for histological analysis. Inflammatory gene expression in the atherosclerotic lesions were then determined at the mRNA and protein level.. The expression of pro-inflammatory cytokines was significantly reduced in the treatment group, compared to nontreatment group, whereas the plasma concentration of anti-inflammatory cytokines increased markedly. Moreover, our results demonstrated a significant reduction in plaque lipid content, as well as a rise in collagen content following Lp-PLA(2) inhibition. Interestingly, when comparing the two methods of Lp-PLA(2) inhibition, animals treated with Lp-PLA(2) RNAi were found to exhibit lower plaque areas and enhanced improvement of plaque stability as compared with animals treated with darapladib. Darapladib had no attenuating effect on atherosclerotic plaque area. These therapeutic effects were independent of plasma lipoprotein levels.. Lp-PLA(2) inhibition by darapladib or lentivirus-mediated RNAi ameliorated inflammation and atherosclerosis in apolipoprotein E-deficient mice. The effect was more prominent in the RNAi group.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Apolipoproteins E; Atherosclerosis; Benzaldehydes; Blotting, Western; Body Weight; Cell Line; Interleukin-6; Male; Matrix Metalloproteinase 8; Mice; Oximes; Real-Time Polymerase Chain Reaction; RNA Interference

EXPANDING OUR KNOWLEDGE: Natural lipocyclocarbamate natural products have provided the inspiration for the first-in-class synthetic phospholipase inhibitor darapladib, currently in phase III clinical trials for the treatment of atherosclerosis. Here, we discuss their biosynthesis by a nonribosomal peptide synthetase.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Atherosclerosis; Benzaldehydes; Biological Products; Carbamates; Enzyme Inhibitors; Models, Molecular; Oximes; Peptide Synthases; Pseudomonas fluorescens

To investigate the effects of darapladib, a specific inhibitor of lipoprotein-associated phospholipase A2 (lp-PLA2), on inflammation and atherosclerotic formation in the low density lipoprotein receptor (LDLR)-deficient mice.. Six-week-old LDLR-deficient mice were fed an atherogenic high-fat diet for 17 weeks and then randomly divided into two groups. One group was administered darapladib (50 mg·kg(-1)·d(-1); po) for 6 weeks. The other group was administered saline as a control. Serum lipid levels were measured using the corresponding kits, and three inflammatory markers--interleukin-6 (IL-6), C reactive protein (hs-CRP), and platelet activating factor (PAF)--were determined using ELISA. Atherosclerotic plaque areas were stained with Sudan IV, and inflammatory gene expression at the lesions was evaluated using quantitative real-time PCR.. The body weight and serum lipid level between the two groups were similar at the end of the dietary period. The serum lp-PLA2 activity, hs-CRP and IL-6 levels, however, were significantly reduced in the darpladib group. The inhibition of lp-PLA2 did not alter the serum PAF level. Furthermore, the plaque area, from the aortic arch to the abdominal aorta, was significantly reduced in the darpladib group. Additionally, the expression of inflammatory genes monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) was significantly reduced at the lesions in the darapladib group.. Inhibition of lp-PLA2 by darapladib decreases the inflammatory burden and atherosclerotic plaque formation in LDLR-deficient mice, which may be a new strategy for the treatment of atherosclerosis.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Atherosclerosis; Benzaldehydes; C-Reactive Protein; Chemokine CCL2; Enzyme Inhibitors; Gene Deletion; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Oximes; Plaque, Atherosclerotic; Receptors, LDL; Vascular Cell Adhesion Molecule-1

Topics: Atherosclerosis; Benzaldehydes; Cardiovascular Diseases; Clinical Trials as Topic; Coronary Disease; Humans; Meta-Analysis as Topic; Oximes; Phospholipase A2 Inhibitors

Phase II results of the trials of two phospholipase A2 inhibitors which may be of value in the treatment of atherosclerosis and cardiovascular disease have been reported in the past year. Darapladib (GlaxoSmithKline) is an inhibitor of lipoprotein-associated phospholipase A2 and varespladib (Anthera) inhibits several forms of the secreted phospholipase A2s. Despite the apparent similarity of mechanism, which is also built into the compounds' names, the role of the two types of phospholipase in atherogenesis is very different. Evidence for this comes from a range of preclinical studies and from epidemiological data which are summarised here. These data provide a basis for the Phase II studies and support decisions to move into Phase III, a decision which in the case of darapladib has been made and studies commenced (STABILITY trial). For varespladib the FRANCIS-ACS trial in acute coronary syndrome patients is in progress.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Animals; Atherosclerosis; Benzaldehydes; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Indoles; Keto Acids; Oximes; Phospholipase A2 Inhibitors