Why are brown bears protected against atherosclerosis even though their plasma cholesterol levels are twice that of humans?

Plasma cholesterol and triglyceride levels are twice as high in hibernating brown bears (Ursus arctos) than in healthy humans. Yet, bears display no sign of atherosclerosis development. To explore this apparent paradox, we analyzed lipoproteins from same ten individual bears plasma collected during winter (hibernation; February) and summer (active; June) in the same year.

Therapeutic potential of the Proprotein Convertase Subtilisin/Kexin family in vascular disease.

Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-7, MBTPS1, and PCSK9. Apart from PCSK9, little is known about PCSKs in cardiovascular disease. Here, we aimed to investigate the expression landscape and druggability potential of the entire PCSK family for CVD.

Chronic Oral Administration of Mineral Oil Compared With Corn Oil: Effects on Gut Permeability and Plasma Inflammatory and Lipid Biomarkers.

We investigated the effects of chronic oral administration of mineral oil, versus corn oil as control, on intestinal permeability, inflammatory markers, and plasma lipids in APOE*3-Leiden.CETP mice. Mice received mineral oil or corn oil 15 or 30 μL/mouse/day for 16 weeks (15 mice/group).

Vasculoprotective properties of plasma lipoproteins from brown bears (Ursus arctos).

Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early stage atherosclerosis development when adult. To explore this apparent paradox, we analyzed plasma lipoproteins from the same 10 bears in winter (hibernation) and summer using size exclusion chromatography, ultracentrifugation, and electrophoresis.

Effects of mineral oil administration on the pharmacokinetics, metabolism and pharmacodynamics of atorvastatin and pravastatin in mice and dogs.

We investigated the effects of mineral oil on statin pharmacokinetics and inflammatory markers in animal models. A new synthesis strategy produced regioisomers that facilitated the characterization of the main metabolite (M1) of atorvastatin, a lipophilic statin, in C57BL/6NCrl mice. The chemical structure of M1 in mice was confirmed as ortho-hydroxy β-oxidized atorvastatin.

3-Hydroxyanthralinic acid metabolism controls the hepatic SREBP/lipoprotein axis, inhibits inflammasome activation in macrophages, and decreases atherosclerosis in Ldlr-/- mice.

Aims: Atherosclerosis is a chronic inflammatory disease involving immunological and metabolic processes. Metabolism of tryptophan (Trp) via the kynurenine pathway has shown immunomodulatory properties and the ability to modulate atherosclerosis. We identified 3-hydroxyanthranilic acid (3-HAA) as a key metabolite of Trp modulating vascular inflammation and lipid metabolism.

Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia.

Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDL-C), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs).

Group IIA Secretory Phospholipase A, Vascular Inflammation, and Incident Cardiovascular Disease.

Objective- Inflammation is a causal risk factor for cardiovascular disease (CVD). sPLA-IIA (group IIA secretory phospholipase A) plays an integral role in regulating vascular inflammation. Although studies investigated sPLA-IIA in secondary prevention, we prospectively evaluated sPLA-IIA mass and genetic variants with CVD events in a primary prevention population with chronic inflammation.

Design of Selective sPLA-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1-indol-1-yl]pyridine-2-yl}propanoic Acid.

A lead generation campaign identified indole-based sPLA-X inhibitors with a promising selectivity profile against other sPLA isoforms. Further optimization of sPLA selectivity and metabolic stability resulted in the design of (-)-, a novel, potent, and selective sPLA-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)- was tested in an ApoE murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA-X inhibition on atherosclerosis development.

Discovery of a Series of Indole-2 Carboxamides as Selective Secreted Phospholipase A Type X (sPLA-X) Inhibitors.

In order to assess the potential of sPLA-X as a therapeutic target for atherosclerosis, novel sPLA inhibitors with improved type X selectivity are required. To achieve the objective of identifying such compounds, we embarked on a lead generation effort that resulted in the identification of a novel series of indole-2-carboxamides as selective sPLA2-X inhibitors with excellent potential for further optimization.

Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis.

Variants in the gene encoding for lipid phosphate phosphohydrolase 3 have been associated with susceptibility to atherosclerosis independently of classical risk factors. PLPP3 inactivates lysophosphatidic acid (LPA), a pro-inflammatory, pro-thrombotic product of phospholipase activity. Here we performed the first exploratory analysis of PLPP3, LPA, and LPA receptors (LPARs 1-6) in human atherosclerosis.

ApoB-100 Lipoprotein Complex Formation with Intima Proteoglycans as a Cause of Atherosclerosis and Its Possible Ex Vivo Evaluation as a Disease Biomarker.

Experimental and clinical data indicate that the initiation and progress of atherosclerosis and its clinical manifestations are first caused by circulating apoB-100 lipoproteins that enter and are retained in the arterial intima. Extracellular sulfated proteoglycans (PGs) of the intima are the retention agents. The PGs also initiate physical and biochemical lipoprotein degradation with the production of bioactive, lipid products that trigger an inflammatory response that leads to atherosclerosis.

Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review.

Background: Epidemiological and genetic studies suggest that elevated triglyceride (TG)-rich lipoprotein levels in the circulation increase the risk of cardiovascular disease. Prescription formulations of omega-3 fatty acids (OM3FAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce plasma TG levels and are approved for the treatment of patients with severe hypertriglyceridemia. Many preclinical studies have investigated the TG-lowering mechanisms of action of OM3FAs, but less is known from clinical studies.

Does statins promote vascular calcification in chronic kidney disease?

Background: In end-stage renal disease (ESRD), coronary artery calcification (CAC) and inflammation contribute to cardiovascular disease (CVD). Statins do not improve survival in patients with ESRD, and their effect on vascular calcification is unclear. We explored associations between CAC, inflammatory biomarkers, statins and mortality in ESRD.

Discovery of AZD2716: A Novel Secreted Phospholipase A (sPLA) Inhibitor for the Treatment of Coronary Artery Disease.

Expedited structure-based optimization of the initial fragment hit led to the design of ()- (AZD2716) a novel, potent secreted phospholipase A (sPLA) inhibitor with excellent preclinical pharmacokinetic properties across species, clear efficacy, and minimized safety risk. Based on accumulated profiling data, ()- was selected as a clinical candidate for the treatment of coronary artery disease.

Suppression of abdominal aortic aneurysm formation by AR-R17779, an agonist for the α7 nicotinic acetylcholine receptor.

Objective: Activation of vagal nerve suppresses inflammatory responses through activation of α7 nicotinic acetylcholine receptor (nAchR). We sought to determine whether AR-R17779, a selective agonist of α7nAchR, affects the development of abdominal aortic aneurysm (AAA).

Methods And Results: AAA was induced by topical application of calcium chloride (CaCl2) to abdominal aorta (AAA group).

Lipids around the Clock: Focus on Circadian Rhythms and Lipid Metabolism.

Disorders of lipid and lipoprotein metabolism and transport are responsible for the development of a large spectrum of pathologies, ranging from cardiovascular diseases, to metabolic syndrome, even to tumour development. Recently, a deeper knowledge of the molecular mechanisms that control our biological clock and circadian rhythms has been achieved. From these studies it has clearly emerged how the molecular clock tightly regulates every aspect of our lives, including our metabolism.

Stimulation of α7 nicotinic acetylcholine receptor by AR-R17779 suppresses atherosclerosis and aortic aneurysm formation in apolipoprotein E-deficient mice.

Atherosclerosis is a chronic inflammatory disease. It has been appreciated that vagus nerve inhibits macrophage activation via α7 nicotinic acetylcholine receptor (nAChR), termed the cholinergic anti-inflammatory pathway. We explored the effects of AR-R17779, a selective α7nAChR agonist, on atherosclerosis and aneurysm formation in apolipoprotein E (ApoE)-deficient mice.

Expression of type IIA secretory phospholipase A2 inhibits cholesteryl ester transfer protein activity in transgenic mice.

Objective: High circulating levels of group IIA secretory phospholipase A2 (sPLA2-IIA) activity and mass are independent cardiovascular risk factors. Therefore, inhibition of sPLA2-IIA may be a target for the treatment of atherosclerotic cardiovascular disease. The present study evaluated the effects of sPLA2-IIA inhibition with varespladib acid in a novel mouse model, human apolipoprotein B (apoB)/human cholesteryl ester transfer protein (CETP)/human sPLA2-IIA triple transgenic mice (TTT) fed a Western-type diet.

HDL2 interferes with LDL association with arterial proteoglycans: a possible athero-protective effect.

Objectives: High levels of large HDL (HDL2) reduce cardiovascular disease risks apparently because it mediates reverse cholesterol transport, and it has anti-inflammatory properties. Here we explored the mechanism behind an additional athero-protective HDL effect related to its capacity to interfere with formation of insoluble LDL-proteoglycans associations, a key step in LDL entrapment in the intima and in atherogenesis.

Methods And Results: We found that HDL2 levels from type 2 diabetes patients and controls are inversely correlated with complex formation between serum LDL and the arterial proteoglycans versican.

Phospholipase A2 enzymes and the risk of atherosclerosis.

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.