darapladib and Inflammation

The regulation of the catalytic activity of the various phospholipase A

Topics: Acetates; Animals; Benzaldehydes; Biomarkers; Cardiovascular Diseases; Drug Design; Humans; Indoles; Inflammation; Keto Acids; Oximes; Patents as Topic; Phospholipase A2 Inhibitors

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

Inflammation plays an important role in origin and progression of atheromatous plaque. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered a biomarker of inflammation and a predictor of vascular events. Lp-PLA2 is an enzyme secreted by leukocytes and associated with circulating lipoproteins and macrophages in atherosclerotic plaques. Lp-PLA2 hydrolizes phospholipids of oxidized low density lipoproteins and generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a major role in the development of atherosclerotic lesions, myocardial infarction and ischemic stroke. Recently the first publications appeared about selective inhibitor of phospholipase A2 - darapladib as a novel therapeutic approach for the treatment of patients with coronary artery disease. However, first results need to be confirmed by ongoing large long-term randomized clinical trials.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Benzaldehydes; Biomarkers; Fatty Acids, Nonesterified; Humans; Inflammation; Leukocytes; Lipoproteins; Lysophosphatidylcholines; Myocardial Infarction; Oximes; Plaque, Atherosclerotic; Stroke; Therapies, Investigational

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

Lipoprotein-associated phospholipase A2 (Lp PLA2) is postulated to occupy a key position in the pathogenic sequence leading to formation of complex atherosclerotic lesions. This study reviews evidence supporting its role as a biomarker of vascular disease and as a possible therapeutic target.. Evidence continues to build supporting the usefulness of Lp PLA2 as a predictor of coronary events in the general population and in those with established coronary heart disease. Elevated Lp PLA2 is also associated with stroke and heart failure. The crystal structure of Lp PLA2 is now available and offers insight into the links between structure, function and atherogenic properties. Recently completed studies on the efficacy of darapladib, a specific Lp PLA2 inhibitor, show beneficial changes in plaque morphology in animal models and in humans.. Lp PLA2 is gaining acceptance as a useful biomarker of chronic inflammation and as a predictor of vascular disease. Early results with darapladib offer promise, but not definitive proof, of a potential role for Lp PLA2 inhibition in coronary heart disease prevention.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Anti-Inflammatory Agents; Benzaldehydes; Biomarkers; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Humans; Inflammation; Oximes; Prognosis; Risk Factors; Stroke; United States

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

This study examined the effects of darapladib, a selective lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inhibitor, on biomarkers of cardiovascular (CV) risk.. Elevated Lp-PLA(2) levels are associated with an increased risk of CV events.. Coronary heart disease (CHD) and CHD-risk equivalent patients (n = 959) receiving atorvastatin (20 or 80 mg) were randomized to oral darapladib 40 mg, 80 mg, 160 mg, or placebo once daily for 12 weeks. Blood samples were analyzed for Lp-PLA(2) activity and other biomarkers.. Baseline low-density lipoprotein cholesterol (LDL-C) was 67 +/- 22 mg/dl. Plasma Lp-PLA(2) was higher in older patients (>or=75 years), in men, in those taking atorvastatin 20 mg, at LDL-C >or=70 mg/dl or high-density lipoprotein cholesterol (HDL-C) <40 mg/dl, or in those with documented vascular disease (multivariate regression; p < 0.01). Darapladib 40, 80, and 160 mg inhibited Lp-PLA(2) activity by approximately 43%, 55%, and 66% compared with placebo (p < 0.001 weeks 4 and 12). Sustained dose-dependent inhibition was noted overall in both atorvastatin groups and at different baseline LDL-C (>or=70 vs. <70 mg/dl) and HDL-C (<40 vs. >or=40 mg/dl). At 12 weeks, darapladib 160 mg decreased interleukin (IL)-6 by 12.3% (95% confidence interval [CI] -22% to -1%; p = 0.028) and high-sensitivity C-reactive protein (hs-CRP) by 13.0% (95% CI -28% to +5%; p = 0.15) compared with placebo. The Lp-PLA(2) inhibition produced no detrimental effects on platelet biomarkers (P-selectin, CD40 ligand, urinary 11-dehydrothromboxane B(2)). No major safety concerns were noted.. Darapladib produced sustained inhibition of plasma Lp-PLA(2) activity in patients receiving intensive atorvastatin therapy. Changes in IL-6 and hs-CRP after 12 weeks of darapladib 160 mg suggest a possible reduction in inflammatory burden. Further studies will determine whether Lp-PLA(2) inhibition is associated with favorable effects on CV events.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Anti-Inflammatory Agents; Anticholesteremic Agents; Atorvastatin; Benzaldehydes; Biomarkers; Coronary Artery Disease; Double-Blind Method; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interleukins; Male; Middle Aged; Oximes; Prognosis; Pyrroles; Recurrence; Risk Factors

Macrophage polarization is a dynamic and integral process in tissue inflammation and remodeling. In this study, we describe that lipoprotein-associated phospholipase A

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Abietanes; Animals; Antibodies, Neutralizing; Benzaldehydes; Case-Control Studies; Cell Cycle Proteins; Cell Polarity; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Knockout Techniques; Humans; Inflammation; Macrophage Activation; Macrophages; Male; Monocytes; Multiple Sclerosis; Oximes; Phospholipases A2, Secretory; Rats; Rats, Transgenic; Receptors, G-Protein-Coupled; Signal Transduction; Treatment Outcome

Macrophage-mediated inflammation plays an important role in hypertensive cardiac remodeling, whereas effective pharmacological treatments targeting cardiac inflammation remain unclear. Lipoprotein-associated phospholipase A2 (Lp-PLA2) contributes to vascular inflammation-related diseases by mediating macrophage migration and activation. Darapladib, the most advanced Lp-PLA2 inhibitor, has been evaluated in phase III trials in atherosclerosis patients. However, the role of darapladib in inhibiting hypertensive cardiac fibrosis remains unknown. Using a murine angiotensin II (Ang II) infusion-induced hypertension model, we found that Pla2g7 (the gene of Lp-PLA2) was the only upregulated PLA2 gene detected in hypertensive cardiac tissue, and it was primarily localized in heart-infiltrating macrophages. As expected, darapladib significantly prevented Ang II-induced cardiac fibrosis, ventricular hypertrophy, and cardiac dysfunction, with potent abatement of macrophage infiltration and inflammatory response. RNA sequencing revealed that darapladib strongly downregulated the expression of genes and signaling pathways related to inflammation, extracellular matrix, and proliferation. Moreover, darapladib substantially reduced the Ang II infusion-induced expression of nucleotide-binding oligomerization domain-like receptor with pyrin domain 3 (NLRP3) and interleukin (IL)-1β and markedly attenuated caspase-1 activation in cardiac tissues. Furthermore, darapladib ameliorated Ang II-stimulated macrophage migration and IL-1β secretion in macrophages by blocking NLRP3 inflammasome activation. Darapladib also effectively blocked macrophage-mediated transformation of fibroblasts into myofibroblasts by inhibiting the activation of the NLRP3 inflammasome in macrophages. Overall, our study identifies a novel anti-inflammatory and anti-cardiac fibrosis role of darapladib in Lp-PLA2 inhibition, elucidating the protective effects of suppressing NLRP3 inflammasome activation. Lp-PLA2 inhibition by darapladib represents a novel therapeutic strategy for hypertensive cardiac damage treatment.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Angiotensin II; Animals; Anti-Inflammatory Agents; Benzaldehydes; Cardiomegaly; Cardiotonic Agents; Enzyme Inhibitors; Fibrosis; Heart; Inflammasomes; Inflammation; Macrophages; Male; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Oximes

Topics: Benzaldehydes; Biomarkers; C-Reactive Protein; Coronary Disease; Humans; Inflammation; Interleukin-6; Oximes; Plaque, Atherosclerotic

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 A2 (Lp-PLA2) is thought to play modulatory roles in the development of atherosclerosis. Here we evaluated the effects of a specific lp-PLA2 inhibitor on atherosclerosis in ApoE-deficient mice and its associated mechanisms.. ApoE-deficient mice fed an atherogenic high-fat diet for 17 weeks were divided into two groups. One group was administered the specific lp-PLA2 inhibitor, darapladib (50 mg/kg/day; p.o.) daily for 6 weeks, while the control group was administered saline. We observed no differences in body weight and serum lipids levels between the two groups at the end of the dietary period. Notably, serum lp-PLA2 activity as well as hs-CRP (C-reactive protein) and IL-6 (Interleukin-6) levels were significantly reduced in the darapladib group, compared with the vehicle group, while the serum PAF (platelet-activating factor) levels were similar between the two groups. Furthermore, the plaque area through the arch to the abdominal aorta was reduced in the darapladib group. Another finding of interest was that the macrophage content was decreased while collagen content was increased in atherosclerotic lesions at the aortic sinus in the darapladib group, compared with the vehicle group. Finally, quantitative RT-PCR performed to determine the expression patterns of specific inflammatory genes at atherosclerotic aortas revealed lower expression of MCP-1, VCAM-1 and TNF-α in the darapladib group.. Inhibition of lp-PLA2 by darapladib leads to attenuation of in vivo inflammation and decreased plaque formation in ApoE-deficient mice, supporting an anti-atherogenic role during the progression of atherosclerosis.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Apolipoproteins E; Benzaldehydes; Biomarkers; C-Reactive Protein; Gene Expression Regulation; Humans; Inflammation; Inflammation Mediators; Lipids; Mice; Mice, Inbred C57BL; Oximes; Plaque, Atherosclerotic; Sinus of Valsalva