Treatment Of Atherosclerotic Disease Research Articles

Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study

Animal studies implicate the AP-1 (activator protein-1) pro-inflammatory pathway as a promising target in the treatment of atherosclerotic disease. It is, however, unclear whether these observations apply to human atherosclerosis. Therefore we evaluated the profile of AP-1 activation through histological analysis and tested the potential benefit of AP-1 inhibition in a clinical trial. AP-1 activation was quantified by phospho-c-Jun nuclear translocation (immunohistochemistry) on a biobank of aortic wall samples from organ donors. The effect of AP-1 inhibition on vascular parameters was tested through a double blind placebo-controlled cross-over study of 28 days doxycycline or placebo in patients with symptomatic peripheral artery disease. Vascular function was assessed by brachial dilation as well as by plasma samples analysed for hs-CRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6), IL-8, ICAM-1 (intercellular adhesion molecule-1), vWF (von Willebrand factor), MCP-1 (monocyte chemoattractant protein-1), PAI-1 (plasminogen activator inhibitor-1) and fibrinogen. Histological evaluation of human atherosclerosis showed minimal AP-1 activation in non-diseased arterial wall (i.e. vessel wall without any signs of atherosclerotic disease). A gradual increase of AP-1 activation was found in non-progressive and progressive phases of atherosclerosis respectively (P<0.044). No significant difference was found between progressive and vulnerable lesions. The expression of phospho-c-Jun diminished as the lesion stabilized (P<0.016) and does not significantly differ from the normal aortic wall (P<0.33). Evaluation of the doxycycline intervention only revealed a borderline-significant reduction of circulating hs-CRP levels (−0.51 μg/ml, P=0.05) and did not affect any of the other markers of systemic inflammation and vascular function. Our studies do not characterize AP-1 as a therapeutic target for progressive human atherosclerotic disease.

Effect of Cardiovascular Drugs on the Plasma Levels of Lipoprotein- Associated Phospholipase A2 (Lp-PLA2)~!2009-10-29~!2009-12-28~!2010-04-08~!

Several lines of evidence suggest that the lipoprotein-associated phospholipase A2 (Lp-PLA2) plays an impor- tant role in the pathogenesis of atherosclerotic disease. From a pathophysiological point of view the enzyme bound to apolipoprotein-B-containing lipoproteins (which corresponds to more than 90% of plasma enzymatic activity) may play a proatherogenic role since it generates lysophosphatidylcholine and oxidized fatty acids, molecules that have been shown to promote atherogenesis. On the other hand, the enzyme associated with high-density lipoprotein (HDL) may play an antiatherogenic role since it protects low-density lipoprotein (LDL) from oxidation and diminishes the biological func- tions of oxidized LDL. Several large-scale, prospective studies have shown that both plasma Lp-PLA2 mass and activity represent important predictors of future cardiovascular risk in primary and secondary prevention populations. In this re- view, we summarize the current knowledge on the effect of drugs used in the treatment of cardiovascular disease on the plasma levels of Lp-PLA2. This information may help clinicians to design safe and effective therapeutic strategies for the prevention and treatment of atherosclerotic disease. Keyword: Lipoprotein-associated phospholipase A2, cardiovascular drugs, statins, fibrates.

The prevention and regression of atherosclerotic plaques: emerging treatments

Occlusive vascular diseases, such as sudden coronary syndromes, stroke, and peripheral arterial disease, are a huge burden on the health care systems of developed and developing countries. Tremendous advances have been made over the last few decades in the diagnosis and treatment of atherosclerotic diseases. Intravascular ultrasound has been able to provide detailed information of plaque anatomy and has been used in several studies to assess outcomes. The presence of atherosclerosis disrupts the normal protective mechanism provided by the endothelium and this mechanism has been implicated in the pathophysiology of coronary artery disease and stroke. Efforts are being put into the prevention of atherosclerosis, which has been shown to begin in childhood. This paper reviews the pathophysiology of atherosclerosis and discusses the current options available for the prevention and reversal of plaque formation.

Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats

Statins reduce cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase and have a major place in the treatment of atherosclerotic disease. Recent studies have shown anti-inflammatory properties of statins. The purpose of this study was to evaluate the anti-inflammatory effect of simvastatin on bleomycin (BLM)-induced pulmonary fibrosis in rats. A total of 31 female Sprague-Dawley rats were divided into four groups: (1) intratracheal (IT) phosphate-buffered saline (PBS) + intraperitoneal (IP) PBS (n=7); (2) IT BLM + IP PBS (n=8); (3) IT BLM + low dose (LD) simvastatin (1 mg/kg daily, n=8); (4) IT BLM + high dose (HD) simvastatin (5 mg/kg daily, n=8). Simvastatin was administered IP for 15 days, beginning 1 day prior to IT BLM. The effect of simvastatin on pulmonary fibrosis was studied by measurements of IL-13, PDGF, IFN-γ, TGF-p1 levels in bronchoalveolar lavage (BAL) fluid and lung tissue hydroxyproline (HPL) content and by histopathological examination (Ashcroft score). BLM caused significant change in BAL fluid cytokine levels and increased both HPL content and histopathological score (p<0.001 for all). While LD simvastatin had no effect on cytokine levels, HD significantly reduced IL-13 (15.12 ±7.08 pg/ml vs. 4.43±2.34 pg/mL; p<0.05) and TGF-β1 levels (269.25 ±65.42 pg/mL vs. 131.75±32.65 pg/mL; p<0.05). Neither HD nor LD simvastatin attenuated HPL content or Ashcroft score. In conclusion, this study showed that LD simvastatin had no effect on a BLM-induced pulmonary fibrosis model, while the high dose caused partial improvement in profibrotic cytokine levels.

Antioxidative succinobucol–sterol conjugates: Crystal structures and pseudosymmetry in the crystals

Abstract An extensive study to attach succinobucol to sterols has provided conjugates which comprise two pharmaceutically important compounds into one entity where the components are expected to have a synergistic effect. The motivation to design these novel conjugates was the need to broaden the armamentarium of current agents used in the treatment of atherosclerotic diseases and type 2 diabetes. In desire for detailed information of these compounds in solid state, which also have an influence to their physiological activity, systematic crystallization experiments were performed and as a result, X-ray quality single crystals were obtained from four succinobucol–sterol conjugates. All of these compounds crystallized in space group P1 with two or four molecules in an asymmetric unit and the crystallographically independent molecules were found to be related by pseudosymmetry (i.e. by pseudoinversion in 1–3 and by pseudoinversion plus pseudotranslation in 4).

Early experience with excimer laser angioplasty above and below the knee

Although considerable progress has been made in angioplasty of lower leg arteries, percutaneous treatment of atherosclerotic disease in crural vessels is not considered a routine procedure. When the disease is located only in a short crural segment, percutaneous transluminal angioplasty (PTA) may be successful, but longer segments with crural disease respond less well to PTA. The authors investigated the possibilities of using a 2.2 mm excimer laser catheter, operating at a wavelength of 308 nm, as a stand-alone technique, for angioplasty. Their aim was to establish whether by vaporizing plaque material the excimer laser could be used to create an adequate lumen diameter. They treated 10 patients, 5 for pathology above the knee and 5 below the knee. In this latter group 11 vascular segments underwent laser angioplasty.

Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice

The ability to selectively deliver compounds into atherosclerotic plaques would greatly benefit the detection and treatment of atherosclerotic disease. We describe such a delivery system based on a 9-amino acid cyclic peptide, LyP-1. LyP-1 was originally identified as a tumor-homing peptide that specifically recognizes tumor cells, tumor lymphatics, and tumor-associated macrophages. As the receptor for LyP-1, p32, is expressed in atherosclerotic plaques, we tested the ability of LyP-1 to home to plaques. Fluorescein-labeled LyP-1 was intravenously injected into apolipoprotein E (ApoE)-null mice that had been maintained on a high-fat diet to induce atherosclerosis. LyP-1 accumulated in the plaque interior, predominantly in macrophages. More than 60% of cells released from plaques were positive for LyP-1 fluorescence. Another plaque-homing peptide, CREKA, which binds to fibrin-fibronectin clots and accumulates at the surface of plaques, yielded fewer positive cells. Tissues that did not contain plaque yielded only traces of LyP-1(+) cells. LyP-1 was capable of delivering intravenously injected nanoparticles to plaques; we observed abundant accumulation of LyP-1-coated superparamagnetic iron oxide nanoparticles in the plaque interior, whereas CREKA-nanoworms remained at the surface of the plaques. Intravenous injection of 4-[(18)F]fluorobenzoic acid ([(18)F]FBA)-conjugated LyP-1 showed a four- to sixfold increase in peak PET activity in aortas containing plaques (0.31% ID/g) compared with aortas from normal mice injected with [(18)F]FBA-LyP-1(0.08% ID/g, P < 0.01) or aortas from atherosclerotic ApoE mice injected with [(18)F]FBA-labeled control peptide (0.05% ID/g, P < 0.001). These results indicate that LyP-1 is a promising agent for the targeting of atherosclerotic lesions.

Atherosclerosis regression and high-density lipoproteins

Atherosclerosis regression has been demonstrated clearly in animal experimental models and, to a lesser extent, in human clinical studies. Imaging techniques for study of the arterial wall are playing a key role in promoting our appreciation of regression. LDL lowering remains the mainstay of current lipid treatment, but given the multiple antiatherosclerotic functions of HDL, including reverse cholesterol transport, agents that target HDL may represent the next generation of treatment for atherosclerotic disease. Currently available agents, including nicotinic acid, have documented antiatherosclerotic effects and trials examining clinical outcomes in the context of contemporary LDL treatment are now underway. Future approaches to HDL treatment may include cholesteryl ester transfer protein inhibitors and apolipoprotein A-I mimetics.

Pharmacomodulation of High-Density Lipoprotein Metabolism as a Therapeutic Intervention for Atherosclerotic Disease

The high-density lipoproteins (HDLs) are produced by the liver and small intestine as well as on the surface of lipid-enriched macrophages in the subendothelial space of arterial walls. Unlike the apo B100-containing lipoproteins, the HDLs are uniquely antiatherogenic. Based on prospective observational studies performed throughout the world, there is a consistent inverse relationship between serum levels of HDLs and risk for cardiovascular events: low levels of high-density lipoprotein-cholesterol (HDL-C) are associated with increased risk, whereas high levels are usually associated with reduced risk for myocardial infarction, ischemic stroke, and cardiovascular mortality. Post hoc analyses of a number of studies using statins and fibrates have shown that raising serum HDL-C correlates with a reduction in risk for cardiovascular morbidity and mortality. Given these observations, enormous resources are being committed to the development of novel means by which to pharmacologically increase rates of HDL biosynthesis, modulate the functionality of HDL, and to promote reverse cholesterol transport with intravenous infusions of HDL particles.

Microparticles – messengers of biological information

Endothelial cell apoptosis is a pivotal step in the development of atherosclerotic disease. Regeneration of the damaged endothelium is an attractive therapy option in the prevention and treatment of atherosclerotic disease. Apoptosis is associated with the release of microparticles (MP). Besides their role as marker of cell damage, recent reports have underlined their role as signalling elements in cell–cell communication. In this review, we focus on the emerging role of circulating MP as transmitters of biological information in cardiovascular disease.

Outcomes of Covered Kissing Stent Placement Compared with Bare Metal Stent Placement in the Treatment of Atherosclerotic Occlusive Disease at the Aortic Bifurcation

To review the outcomes with the use of balloon-expandable covered iliac kissing stents as compared with bare metal stents in the treatment of atherosclerotic disease at the aortic bifurcation. A review of consecutive patients from a single institution with atherosclerotic occlusive disease at the aortic bifurcation treated with balloon-expandable kissing stents was performed between January 1, 2002, and September 1, 2007. Fifty-four patients were identified and divided into two groups: those with bare metal stents and those with covered stents. Technical and clinical success (Fontaine classification), complications, and patency at follow-up were documented. Twenty-six patients (17 men, nine women; mean age, 61 years; age range, 39-79 years) received covered stents and 28 patients (15 men, 13 women; mean age, 61 years; age range, 38-82 years) received bare metal stents. Technical success was achieved in 100% of patients in both groups. Major complications occurred in three of the 26 (11%) with covered stents (P = .66) and two of the 28 patients (7%) with bare metal stents. The median follow-up was 21 months (20 months for covered stents vs 25 months for bare metal stents; range, 1-62 months). Twenty-two of the 26 patients (85%) with covered stents had sustained improvement in clinical symptoms during the follow-up period compared with 15 of the 28 patients (54%) with bare metal stents (P = .02). Primary patency rates at 1 and 2 years were 92% and 92%, respectively, for covered stents and 78% and 62% for bare metal stents (P = .023). The use of covered balloon-expandable kissing stents for atherosclerotic aortic bifurcation occlusive disease provides superior patency at 2 years as compared with bare metal balloon-expandable stents.

Possibility of the regression of atherosclerosis through the prevention of endothelial senescence by the regulation of nitric oxide and free radical scavengers

In the elderly, atherosclerotic diseases such as stroke and myocardial infarction occupy a major part of their causes of death and care. The elderly always have atherosclerosis in their aorta and other arteries and are exposed to risk of attacks. It is the elderly who should receive its safe, harmless and advanced treatment. Advanced stage of atherosclerosis in the elderly is progressed by complicated risk factors such as dyslipidemia and diabetes mellitus and specific risk factors for the elderly, aging (and menopause). Treatment of atherosclerotic disease may need special ones targeted for the elderly. Recent studies reported that frequencies of dyslipidemia were not decreased in the older oldest. In the elderly, impaired glucose tolerance occurs and it progresses atherosclerosis. Endothelial dysfunction like impairment of nitric oxide (NO) bioavailability also progresses atherosclerosis. Although we tried to regress the high cholesterol diet-induced atherosclerosis in rabbit aorta with a normal diet with or without statin, regression could not be achieved. NO targeting gene therapy (adenovirus endothelial nitric oxide synthase [eNOS] gene vector) regressed 20% of atherosclerotic lesions through reduction of lipid contents, however, a more integrated strategy is important for complete regression. We paid attention to NO bioavailability and developed two ways of increasing it in atherosclerosis: citrulline therapy and arginase II inhibition by estrogen. Further, we found a close relation between atherosclerosis and endothelial senescence and that NO can prevent it, especially in a diabetic model. Taken together, regression of atherosclerosis can be achieved by not only regulation of various risk factors but regulation of the cross-talk of NO and free radicals.

Inhibitors of 5-lipoxygenase activating protein: WO 2008/030369

Background: 5-Lipoxygenase activating protein (FLAP) has been implicated in a number of different pathophysiological conditions owing to its involvement in leukotriene synthesis. Development of FLAP inhibitors has attracted considerable attention in recent years owing to genetic data supporting their potential as a valid pharmacological approach in prevention or treatment of atherosclerotic disease. Objective/method: Since 2005, among other companies, Merck applied for several FLAP inhibitor patents. Patent WO 2008/030369 is the most recent and discloses novel molecules that act as potent inhibitors of FLAP. These compounds are claimed to be useful in the treatment of atherosclerosis, asthma, symptoms of allergic rhinitis and chronic obstructive pulmonary disease either in monotherapy or in combination with established treatments for the above-mentioned disorders. Although data for the potency of representative molecules from the current patent are reported, it is difficult to compare these compounds with previously described compounds. Conclusion: Two FLAP inhibitors are already in clinical development for the treatment of respiratory and atherosclerotic disease by other pharmaceutical companies. Based on the in vitro activities of representative tested compounds from this patent, it is probable that these agents could be of therapeutic value but further preclinical studies are needed to evaluate their therapeutic potential and safety before clinical development.

Optimisation of a high-resolution whole-body MR angiography protocol with parallel imaging and biphasic administration of a single bolus of Gd-BOPTA: preliminary experience in the systemic evaluation of atherosclerotic burden in patients referred for endovascular procedures

This study was performed to validate a high-resolution whole-body magnetic resonance angiography (MRA) protocol with parallel imaging and biphasic administration of a single bolus of contrast agent in the preliminary assessment of systemic atherosclerotic burden in patients referred for endovascular procedures. Forty patients referred for endovascular treatment of atherosclerotic disease of the carotid arteries (n=23), peripheral vessels (n=14) or aorta (n=3) on the basis of previous clinical and diagnostic examinations underwent high-resolution whole-body MRA at 1.5 T with 3D spoiled gradient recalled echo (GRE) sequences, featuring parallel imaging acquisition technique with x2 acceleration factor. Sixty-eight surface coil elements and a four-station imaging protocol were employed. Biphasic intravenous administration of a paramagnetic contrast agent [gadolinium benzyloxyproprionic-tetraacetic acid (Gd-BOPTA)] was performed with the following protocol: 10 ml at a speed of 1 ml/s followed by further 10 ml at a speed of 0.5 ml/s. For image analysis, the arterial system was divided into 42 segments for evaluation. The presence or absence of atherosclerotic lesions was evaluated by two observers in consensus; segments were classified as having clinically significant disease (>or=50% stenosis or an aneurysmal dilatation) or no significant disease (<50% stenosis). The presence of stenoocclusive disease, determined at all segments, was compared with findings on digital subtraction angiography (DSA), which were interpreted by a third independent reader. Sensitivity, specificity and concordance of whole-body MRA findings with DSA were calculated, and receiver operating characteristic (ROC) analysis was performed for all vascular territories. A total of 1,680 arterial segments was evaluated; 138 (8.3%) were affected by atherosclerotic alterations. Carotid lesions were confirmed in 23 patients (34 segments), involvement of peripheral vessels in 14 (57 segments) and abdominal aneurysms in three. Sensitivity and specificity of whole-body MRA were, respectively, 95%-97% for head and neck vessels, 100%-100% for thoracoabdominal vessels, 98%-97% for thigh vessels and 84%-88% for calf vessels; concordance with the DSA findings was significant (p<0.05). Subclinical atherosclerotic lesions were evidenced in 25 patients, involving carotid arteries (12 segments), peripheral vessels (21 segments) and abdominal aorta (one segment). All these lesions were confirmed by a second modality, and ten of these patients required further care. High-resolution whole-body MRA with Gd-BOPTA may be considered a reliable modality for imaging systemic atherosclerosis in candidates for endovascular procedures. The subclinical detection of the total atherosclerotic burden has potential implications for secondary care in this population.

Succinobucol: review of the metabolic, antiplatelet and cardiovascular effects

Background: Succinobucol (AGI-1067) was developed as a probucol derivative with anti-inflammatory and antioxidant properties. It has undergone Phase III clinical trials to determine its place in the treatment of atherosclerotic disease. Objective: This paper reviews the available history, pharmacology and preclinical and clinical trial data of succinobucol. Methods: Data were compiled following review of publications indexed in Medline and International Pharmaceutical s, industry media releases and relevant bibliographies. Results/conclusion: In preclinical studies, succinobucol exhibited antioxidant, anti-inflammatory, antihyperglycemic and antiplatelet properties; however, these effects have not resulted in a reduction in cardiovascular clinical end points in clinical trials. Although proposed antihyperglycemic effects are being investigated, safety concerns and lack of clear cardiovascular benefit may limit its clinical use as an antihyperglycemic agent.

Risk-adjusted 30-day outcomes of carotid stenting and endarterectomy: Results from the SVS Vascular Registry

As the first operational societal registry of carotid procedures, the Outcomes Committee of the Society for Vascular Surgery (SVS) developed the Vascular Registry (VR) in response to the Centers for Medicare and Medicaid Services' (CMS) National Coverage Decision on carotid artery stenting (CAS). Although CMS requires data submission only on CAS, the VR collects similar data on carotid endarterectomy (CEA) to allow comparison of outcomes, as well as potential for expansion to other procedures. SVS-VR on-line provider-reported data include baseline through follow-up visits to better understand long-term risks and benefits associated with CAS and CEA. The primary outcomes are combined death, stroke, and myocardial infarction (MI). An independent data coordinating center maintains the database, which is Health Insurance Portability and Accountability Act (HIPAA)-compliant and auditable. As of December 26, 2007, 6403 procedures with discharge data were entered by 287 providers at 56 centers on 2763 CAS patients (1450 with 30-day outcomes, 52.5%) and 3259 CEA patients (1368 with 30-day outcomes, 42%). Of the total cohort, 98% of CEA and 70.7% of CAS (P < .001) were performed for atherosclerotic disease. Restenosis accounted for 22.3% and post-radiation induced stenosis in 4.5% of CAS patients. Preprocedure lateralizing neurologic symptoms were present in a greater proportion of CAS patients (49.2%) than CEA patients (42.4%, P < .001). CAS patients also had higher preprocedure prevalence of coronary artery disease (CAD), MI, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and cardiac arrhythmia. For CAS, death/stroke/MI at 30 days was 7.13% for symptomatic patients and 4.60% for asymptomatic patients (P = .04). For CEA, death/stroke/MI at 30 days was 3.75% in symptomatic patients and 1.97% in asymptomatic patients (P = .05). After risk-adjustment for age, history of stroke, diabetes, and American Society of Anesthesiologists (ASA) grade (ie, factors found to be significant confounders in outcomes using backwards elimination), logistic regression analysis suggested better outcomes following CEA. There were no statistically significant differences when examining CAS outcomes based on center volume. CAS in atherosclerotic disease had significantly worse outcomes than in nonatherosclerotic stenosis. When CAS and CEA were compared in the treatment of atherosclerotic disease only, the difference in outcomes between the two procedures was more pronounced, with death/stroke/MI 6.42% after CAS vs 2.62% following CEA, P < .0001. Following best possible risk adjustment of these unmatched groups, symptomatic and asymptomatic CAS patients had significantly higher 30-day postprocedure incidence of death/stroke/MI when compared with CEA patients. The initial 1.5 years of data collection provide proof of concept that a specialty society based VR can succeed in meeting regulatory and scientific goals. With continued enrollment and follow-up, analysis of SVS-VR will supplement randomized trials by providing real-world comparisons of CAS and CEA with sufficient numbers to serve as an outcome assessment tool of important patient subsets and across the spectrum of peripheral vascular procedures.

Statins as emerging treatments for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) represent increasingly common respiratory conditions with a clear unmet need for more effective and safer therapy. Airway inflammation is key to both asthma pathogenesis and exacerbation of symptoms in COPD. Several lines of evidence are now emerging, demonstrasting that, in addition to their established effectiveness in the treatment of atherosclerotic disease, statins also exhibit anti-inflammatory properties, which may be of relevance for the treatment of chronic lung disease, including asthma and COPD. This review will examine the diverse in vitro and in vivo anti-inflammatory properties of statins and consider the available evidence that statins represent novel therapeutic interventions for asthma and COPD.

“Pro-resolution” and anti-inflammation, a role of RvE1 in anti-atherosclerosis and plaque stabilization

Inflammation governs atherosclerosis and is firmly regulated. Endogenous mechanisms to keep inflammation self-limiting are unclear. In the present article, we propose that RvE1 (resolution E1), an endogenous lipid mediator, inhibits inflammation through "pro-resolution" and counter-modulating immunity in atherosclerosis. The background comes from studies on the potent programming of resolution and immuno-inflammation of RvE1 and its precursor, eicosapentaenoic acid, in treating chronic inflammatory disease with unknown mechanisms. In light of the interaction between RvE1 and leukotrieneB4 (LTB4) and their potential impaired immunity regulation hematostasis, we hypothesize that RvE1 play an anti-atherosclerosis and plaque stabilization role through "pro-resolution" and anti-inflammation which may be realized by blocking LTB4/BLT1 (receptor of LTB4) pathway. Our hypothesis generates potentially clinical viewpoint to systematically look for pro- and anti-inflammation and "pro-resolution" process in atherosclerosis. Furthermore, we suggest that RvE1 might be particularly indicated for the treatment of atherosclerotic diseases and plaque stabilization which might ensure an effective management for patients with coronary artery disease.

Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI

Treatment of atherosclerotic disease often focuses on reducing plasma LDL-cholesterol or increasing plasma HDL-cholesterol. We examined in vitro the effects on HDL receptor [scavenger receptor class B type I (SR-BI)] activity of three classes of clinical and experimental plasma HDL-cholesterol-elevating compounds: niacin, fibrates, and HDL376. Fenofibrate (FF) and HDL376 were potent (IC(50) approximately 1 microM), direct inhibitors of SR-BI-mediated lipid transport in cells and in liposomes reconstituted with purified SR-BI. FF, a prodrug, was a more potent inhibitor of SR-BI than an activator of peroxisome proliferator-activated receptor alpha, a target of its active fenofibric acid (FFA) derivative. Nevertheless, FFA, four other fibrates (clofibrate, gemfibrozil, ciprofibrate, and bezafibrate), and niacin had little, if any, effect on SR-BI, suggesting that they do not directly target SR-BI in vivo. However, similarities of HDL376 treatment and SR-BI gene knockout on HDL metabolism in vivo (increased HDL-cholesterol and HDL particle sizes) and structure-activity relationship analysis suggest that SR-BI may be a target of HDL376 in vivo. HDL376 and other inhibitors may help elucidate SR-BI function in diverse mammalian models and determine the therapeutic potential of SR-BI-directed pharmaceuticals.

Connexins: New genes in atherosclerosis

Atherosclerosis, the main cause of death and disability in adult populations of industrialized societies, is a multifactorial progressive process involving a variety of pathogenic mechanisms. Our current view on the pathogenesis of the disease implies complex patterns of interactions between a dysfunctional endothelium, leukocytes, and activated smooth muscle cells in which cytokines and growth factors are known to play a crucial role. Apart from paracrine cell‐to‐cell signalling, a role for gap junction‐mediated intercellular communication in the development of the disease has been recently suggested. Gap junction channels result from the docking of two hemichannels or connexons, formed by the hexameric assembly of connexins, and directly connect the cytoplasm of adjacent cells. In this review, we summarize existing evidence implicating connexins in atherosclerosis. Indeed, the expression pattern of vascular connexins is altered during atherosclerotic plaque formation. In addition, changes in connexin expression or gap junctional communication have been observed in vascular cells in vitro by disturbances in blood flow, cholesterol, inflammatory cytokines, and growth factors. Furthermore, genetically modifying connexin expression affects the course of the atherosclerotic process in mouse models of the disease. Finally, the involvement of connexins in treatment of atherosclerotic disease will be discussed.