Search
Showing 1041–1060 of 2058 publications.
-
Puri, Rishi; Libby, Peter A.; Nissen, Steven E.; Wolski, Kathy E.; Ballantyne, Christie Mitchell; Barter, Philip J.; Chapman, Martin John; ERBEL, RAIMUND; Raichlen, Joel S.; Uno, Kiyoko; Kataoka, Yu; Tuzcu, Murat Murat; Nicholls, Stephen J.AimsTo evaluate the effect of long-term maximally intensive statin therapy on indices of coronary atheroma composition in a randomized trial, and how these changes relate to modifications of serum lipoproteins and systemic inflammation.Methods and resultsThe Study of coronary Atheroma by inTravascular Ultrasound: the effect of Rosuvastatin vs. atorvastatiN (SATURN) employed serial intravascular ultrasound (IVUS) measures of coronary atheroma in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg daily for 24 months. Seventy-one patients underwent serial assessment of indices of plaque composition by spectral analysis of the radiofrequency IVUS signal. Changes in low-density lipoprotein cholesterol [LDL-C; -52 (-72, -33) mg/dL, P < 0.001], C-reactive protein [CRP -0.2 (-1, 0.1) mg/L, P = 0.01], and high-density lipoprotein cholesterol [HDL-C; +2.8 (-0.3, 7.8) mg/dL, P < 0.001] were associated with regression of percent atheroma volume (PAV: -1.6 3.6%, P < 0.001). A reduction in estimated fibro-fatty tissue volume accompanied atheroma regression (P < 0.001), while dense calcium tissue volume increased (P = 0.002). There were no changes in fibrous or necrotic core tissue volumes. Volumetric changes in necrotic core tissue correlated with on-treatment HDL-C (r = -0.27, P = 0.03) and CRP (r = 0.25, P = 0.03) levels. A per-lesion analysis showed a reduction in the number of pathological intimal thickening lesions (defined by ?3 consecutive IVUS frames containing PAV of ?40%, predominantly fibro-fatty plaque, with <10% confluent necrotic core and <10% confluent dense calcium) at follow-up (67 vs. 38, P = 0.001). Fibroatheromas and fibrotic lesions remained static in number.ConclusionsChanges in indices of atheroma composition accompany regression of coronary atheroma with maximally intensive statin therapy, and associate with anti-inflammatory effects of statins. The Author 2014.
-
Kajer, Tracey B.; Fairfull-Smith, Kathryn E.; Yamasaki, Toshihide; Yamada, Kenichi Iichi; Fu, Shanlin; Bottle, Steven E.; Hawkins, Clare L.; Davies, Michael J.The powerful oxidant HOCl (hypochlorous acid and its corresponding anion, -OCl) generated by the myeloperoxidase (MPO)-H<inf>2</inf>O <inf>2</inf>-Cl- system of activated leukocytes is strongly associated with multiple human inflammatory diseases; consequently there is considerable interest in inhibition of this enzyme. Nitroxides are established antioxidants of low toxicity that can attenuate oxidation in animal models, with this ascribed to superoxide dismutase or radical-scavenging activities. We have shown (M.D. Rees et al., Biochem. J. 421, 79-86, 2009) that nitroxides, including 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-yloxyl radical), are potent inhibitors of HOCl formation by isolated MPO and activated neutrophils, with IC<inf>50</inf> values of ~1 and ~6 ?M respectively. The utility of tetramethyl-substituted nitroxides is, however, limited by their rapid reduction by biological reductants. The corresponding tetraethyl- substituted nitroxides have, however, been reported to be less susceptible to reduction. In this study we show that the tetraethyl species were reduced less rapidly than the tetramethyl species by both human plasma (89-99% decreased rate of reduction) and activated human neutrophils (62-75% decreased rate). The tetraethyl-substituted nitroxides retained their ability to inhibit HOCl production by MPO and activated neutrophils with IC<inf>50</inf> values in the low-micromolar range; in some cases inhibition was enhanced compared to tetramethyl substitution. Nitroxides with rigid structures (fused oxaspiro rings) were, however, inactive. Overall, these data indicate that tetraethyl-substituted nitroxides are potent inhibitors of oxidant formation by MPO, with longer plasma and cellular half-lives compared to the tetramethyl species, potentially allowing lower doses to be employed. 2014 Elsevier Inc. All rights reserved.
-
Wise, Steven G.; Yeo, Giselle C.; Hiob, Matti A.; Rnjak-Kovacina, Jelena; Kaplan, David L.; Ng, Martin K.C.; Weiss, Anthony StevenElastin provides structural integrity, biological cues and persistent elasticity to a range of important tissues, including the vasculature and lungs. Its critical importance to normal physiology makes it a desirable component of biomaterials that seek to repair or replace these tissues. The recent availability of large quantities of the highly purified elastin monomer, tropoelastin, has allowed for a thorough characterization of the mechanical and biological mechanisms underpinning the benefits of mature elastin. While tropoelastin is a flexible molecule, a combination of optical and structural analyses has defined key regions of the molecule that directly contribute to the elastomeric properties and control the cell interactions of the protein. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated elastin-like biomaterials, evolving from classically manufactured hydrogels and fibers to new forms, stabilized in the absence of incorporated cross-linkers. Tropoelastin is also compatible with synthetic and natural co-polymers, expanding the applications of its potential use beyond traditional elastin-rich tissues and facilitating finer control of biomaterial properties and the design of next-generation tailored bioactive materials. 2013 Acta Materialia Inc.
-
McGrath, Kristine C.Y.; Li, Xiaohong; Whitworth, Phillippa Tess; Kasz, Robert; Tan, Joanne Tsui Ming; McLennan, Susan Virginia; Celermajer, David S.; Barter, Philip J.; Rye, Kerry Anne; Heather, Alison KayObesity-induced liver inflammation can drive insulin resistance. HDL has anti-inflammatory properties, so we hypothesized that low levels of HDL would perpetuate inflammatory responses in the liver and that HDL treatment would suppress liver inflammation and insulin resistance. The aim of this study was to investigate the effects of lipid-free apoAI on hepatic inflammation and insulin resistance in mice. We also investigated apoAI as a component of reconstituted HDLs (rHDLs) in hepatocytes to confirm results we observed in vivo. To test our hypothesis, C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks and administered either saline or lipid-free apoAI. Injections of lipid-free apoAI twice a week for 2 or 4 weeks with lipid-free apoAI resulted in: i) improved insulin sensitivity associated with decreased systemic and hepatic inflammation; ii) suppression of hepatic mRNA expression for key transcriptional regulators of lipogenic gene expression; and iii) suppression of nuclear factor ?B (NF-?B) activation. Human hepatoma HuH-7 cells exposed to rHDLs showed suppressed TNF?-induced NF-?B activation, correlating with decreased NF-?B target gene expression. We conclude that apoAI suppresses liver inflammation in HFD mice and improves insulin resistance via a mechanism that involves a downregulation of NF-?B activation. Copyright 2014 by the American Society for Biochemistry and Molecular Biology, Inc.
-
Tan, Joanne Tsui Ming; Prosser, Hamish C.G.; Vanags, Laura Z.; Monger, Steven A.; Ng, Martin K.C.; Bursill, C. A.Increasing evidence suggests that highdensity lipoproteins (HDLs) promote hypoxia-induced angiogenesis. The hypoxia-inducible factor 1? (HIF- 1?)/vascular endothelial growth factor (VEGF) pathway is important in hypoxia and is modulated posttranslationally by prolyl hydroxylases (PHD1-PHD3) and E3 ubiquitin ligases (Siah1 and Siah2). We aimed to elucidate the mechanisms by which HDLs augment hypoxia-induced angiogenesis. Preincubation (16 h) of human coronary artery endothelial cells with reconstituted high-density lipoprotein (rHDL) containing apolipoprotein A-I (apoA-I) and phosphatidylcholine (20 ?M, final apoA-I concentration), before hypoxia, increased Siah1 (58%) and Siah2 (88%) mRNA levels and suppressed PHD2 (32%) and PHD3 (45%) protein levels compared with hypoxia-induced control levels. After Siah1/2 small interfering RNA knockdown, rHDL was unable to suppress PHD2/3 and failed to induce HIF-1?, VEGF, and tubulogenesis in hypoxia. Inhibition of the upstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway also abrogated the effects of rHDL. Furthermore, knockdown of the scavenger receptor SR-BI attenuated rHDL-induced elevations in Siah1/2 and tubulogenesis in hypoxia, indicating that SR-BI plays a key role. Finally, the importance of VEGF in mediating the ability of rHDL to drive hypoxia-induced angiogenesis was confirmed using a VEGF-neutralizing antibody. In summary, rHDL augments the HIF-1?/VEGF pathway via SR-BI and modulation of the post-translational regulators of HIF-1? (PI3K/Siahs/PHDs). HDL-induced augmentation of angiogenesis in hypoxia may have implications for therapeutic modulation of ischemic injury.
-
Nidorf, Stefan Mark; Eikelboom, John W.; Thompson, Peter LindsayPreliminary evidence demonstrating that adding 0.5 mg of colchicine per day to statin and antiplatelet therapy reduced the risk of acute coronary events in patients with stable coronary artery disease has raised the hope that it may prove effective for the long-term secondary prevention of cardiovascular disease. The ability of colchicine to suppress blood levels of inflammatory mediators and prevent cholesterol-crystal-induced neutrophil-mediated inflammation implicated in the progression and instability of atherosclerosis adds plausibility to this clinical observation. Early intestinal intolerance in some patients is well recognized, but clinical experience gained over more than half a century with the continuous use of colchicine for the prevention of neutrophil-mediated inflammation in patients with familial Mediterranean fever and gout indicates that low-dose long-term therapy is safe. Nonetheless, before colchicine can be recommended for the secondary prevention of cardiovascular disease, further studies are required to confirm its safety and efficacy in a broad range of patients with coronary disease, and to determine whether doses of colchicine less than 0.5 mg/day might be effective and even better tolerated. Trials exploring the role of colchicine in the treatment of patients with acute coronary syndromes would also be of special interest but may require the use of doses higher than those used for long-term secondary prevention. Springer Science+Business Media 2014.
-
Prosser, Hamish C.G.; Tan, Joanne Tsui Ming; Dunn, Louise L.; Patel, Sanjay; Vanags, Laura Z.; Bao, Shishan San; Ng, Martin K.C.; Bursill, C. A.AimsHigh-density lipoproteins (HDL) exert striking anti-inflammatory effects and emerging evidence suggests that they may augment ischaemia-mediated neovascularization. We sought to determine whether HDL conditionally regulates angiogenesis, depending on the pathophysiological context by (i) inhibiting inflammation-induced angiogenesis, but also; (ii) enhancing ischaemia-mediated angiogenesis.Methods and resultsIntravenously delivered apolipoprotein (apo) A-I attenuated neovascularization in the murine femoral collar model of inflammation-induced angiogenesis, compared with phosphate-buffered saline infused C57BL6/J mice (58%), P < 0.05. Conversely, apoA-I delivery augmented neovessel formation (75%) and enhanced blood perfusion (45%) in the murine hindlimb ischaemia model, P < 0.05. Reconstituted HDL (rHDL) was tested on key angiogenic cell functions in vitro. rHDL inhibited human coronary artery endothelial cell migration (37.9 and 76.9%), proliferation (15.7 and 40.4%), and tubulogenesis on matrigel (52 and 98.7%) when exposed to two inflammatory stimuli: tumour necrosis factor- (TNF-) and macrophage-conditioned media (MCM). In contrast, rHDL significantly augmented hypoxia-stimulated migration (36.9%), proliferation (135%), and tubulogenesis (22.9%), P < 0.05. Western blot and RT-PCR analyses revealed that these divergent actions of rHDL were associated with conditional regulation of hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF) and VEGF receptor 2, which were attenuated in response to TNF- (40.4, 41.0, and 33.2%) and MCM (72.5, 30.7, and 69.5%), but augmented by rHDL in hypoxia (39.8, 152.6, and 15.7%%), all P < 0.05.ConclusionHDL differentially regulates angiogenesis dependent upon the pathophysiological setting, characterized by suppression of inflammation- associated angiogenesis, and conversely, by the enhancement of hypoxia-mediated angiogenesis. This has significant implications for therapeutic modulation of neovascularization. 2013 The Author.
-
Nidorf, Stefan Mark; Eikelboom, John W.; Thompson, Peter LindsayCholesterol crystals are present in nascent and advanced atherosclerotic plaque. Under some conditions, they may enlarge and cause direct plaque trauma or trigger an inflammatory cascade that promotes the growth and instability of atherosclerotic plaque. Therapies that reduce the risk of cholesterol crystal formation or prevent the associated inflammatory response have the potential to improve the clinical outcome of patients with cardiovascular disease. Statins have pleiotropic effects that can reduce the size of the free cholesterol pool contained within atherosclerotic plaques and prevent the formation of cholesterol crystals. Colchicine prevents crystal-induced inflammation by virtue of its ability to inhibit macrophage and neutrophil function. Both statins and colchicine have been demonstrated to reduce the risk of cardiovascular events in patients with stable coronary disease. The efficacy of statins and colchicine for cardiovascular prevention supports the hypothesis that crystal-induced inflammation plays an integral role in the progression and instability of coronary disease. Inhibition of cholesterol crystal-induced inflammation offers a promising new target for the secondary prevention of cardiovascular disease.
-
Talib, Jihan; Kwan, Jair; Suryo Rahmanto, Aldwin; Davies, Michael J.; Witting, Paul KennethSmokers have an elevated risk of cardiovascular disease but the origin(s) of this increased risk are incompletely defined. Considerable evidence supports an accumulation of the oxidantgenerating enzyme MPO (myeloperoxidase) in the inflamed artery wall, and smokers have high levels of SCN- , a preferred MPO substrate, with this resulting in HOSCN (hypothiocyanous acid) formation. We hypothesized that this thiol-specific oxidant may target the Zn2+ -thiol cluster of eNOS (endothelial nitric oxide synthase), resulting in enzyme dysfunction and reduced formation of the critical signallingmolecule NO.Decreased NO bioavailability is an early and critical event in atherogenesis, and HOSCN-mediated damage to eNOS may contribute to smokingassociated disease. In the present study it is shown that exposure of isolated eNOS to HOSCN or MPO/H<inf>2</inf>O<inf>2</inf>/SCN- decreased active dimeric eNOS levels, and increased inactive monomer and Zn2+ release, compared with controls, HOCl (hypochlorous acid)- or MPO/H<inf>2</inf>O <inf>2</inf>/Cl- -treated samples. eNOS activity was increasingly compromised byMPO/H<inf>2</inf>O<inf>2</inf>/Cl- with increasing SCN- concentrations. Exposure ofHCAEC (human coronary artery endothelial cell) lysates to pre-formed HOSCN, or MPO/H<inf>2</inf>O<inf>2</inf>/Cl- with increasing SCN- , increased eNOS monomerization and Zn2+ release, and decreased activity. Intact HCAECs exposed to HOCl and HOSCN had decreased eNOS activity and NO<inf>2</inf> - /NO<inf>3</inf> - formation (products of NO decomposition), and increased free Zn2+ . Exposure of isolated rat aortic rings to HOSCN resulted in thiol loss, and decreased eNOS activity and cGMP levels. Overall these data indicate that high SCN- levels, as seen in smokers, can increase HOSCN formation and enhance eNOS dysfunction in human endothelial cells, with this potentially contributing to increased atherogenesis in smokers. 2014 Biochemical Society.
-
Xu, Bei; Charlton, Francesca; Makris, Angela; Hennessy, AnnemarieOBJECTIVES: The interaction between trophoblasts and maternal endothelium is important for placental vascular modeling. Failure of uterine spiral artery transformation is linked to the etiopathology of preeclampsia. Antihypertensive medications used to control hypertension in early pregnancy can alter placental and circulating cytokines. This study investigated whether selected antihypertensive drugs can modulate the interaction between trophoblast and endothelial cells. METHODS: Human uterine myometrial microvascular endothelial cells were preincubated with (or without) low-dose tumor necrosis factor-? (TNF-?; 0.5ng/ml) or TNF-? and soluble fms-like tyrosine kinase 1 (sFlt-1; 100ng/ml). Red fluorescent-labeled endothelial cells were then cultured on Matrigel. After appearance of endothelial cellular networks, green fluorescent-labeled HTR-8/SVneo trophoblast cells were cocultured in the presence of pharmacological doses of methyldopa, labetalol, hydralazine, and clonidine. Images were captured after 24h and drug effects on HTR-8/SVneo cell integration were quantified by Image Analysis software. The conditioned medium was collected to measure sFlt-1, vascular endothelial growth factor (VEGF), placental growth factor, interleukin-10, and interleukin-6 by ELISA. RESULTS: Methyldopa, labetalol, hydralazine, and clonidine increased trophoblast integration into TNF-?-preincubated endothelial cellular networks. In conditioned medium, sFlt-1 was reduced by methyldopa, hydralazine, and clonidine alone. VEGF was increased by methyldopa. A decrease in placental growth factor was seen by methyldopa and also in nontreated endothelial cell coculture of the other three drugs. CONCLUSION: Some antihypertensive drugs used in pregnancy may improve the cellular interaction between trophoblast and endothelial cells exposed to TNF-?. Methyldopa, hydralazine, and clonidine reduced sFlt-1 concentration in culture medium, whereas labetalol increased trophoblast integration independently of sFlt-1. Methyldopa increased VEGF concentration. Some pregnancy-related antihypertensives may affect placental vascularization. 2014 Wolters Kluwer Health / Lippincott Williams & Wilkins.
-
Thompson, Peter Lindsay; Nidorf, Stefan Mark; Eikelboom, John W.Background: Rupture or erosion of an unstable atherosclerotic plaque is the typical pathology and usual cause of acute coronary syndromes. Despite detailed understanding of the processes of lipid accumulation, thinning of the fibrous cap, and inflammation leading to plaque instability, there are no strategies in clinical use that uniquely target the unstable plaque. Objective: A critical review of recent publications on potential therapies that could be used to stabilize unstable plaque. Methods: We searched PubMed, other literature databases, drug development sites, and clinical trial registries to retrieve clinical studies on anti-inflammatory and lipid-modulating therapies that could be used to stabilize unstable atherosclerotic plaque. Results: Multiple experimental targets involving lipid and inflammatory pathways have the potential to stabilize the plaque and expand the armamentarium against coronary artery disease. Randomized clinical trials of darapladib, methotrexate, canakinumab, and colchicine are well advanced to establish if plaque stabilization is feasible and effective in patients with acute coronary syndromes. Conclusions: Although there are still no agents in clinical use for plaque stabilization, there are important advances in understanding plaque instability and several encouraging approaches are being evaluated in Phase III clinical trials. 2013 Elsevier HS Journals, Inc.
-
Li, Xiaohong; McGrath, Kristine C.Y.; Tran, Van Hoan; Li, Yiming; Mandadi, Sravan; Duke, Colin Charles; Heather, Alison Kay; Roufogalis, Basil D.Calcium signals in hepatocytes control cell growth, proliferation, and death. Members of the transient receptor potential (TRP) cation channel superfamily are candidate calcium influx channels. NFB activation strictly depends on calcium influx and often induces antiapoptotic genes favouring cell survival. Previously, we reported that S-[6]-gingerol is an efficacious agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in neurones. In this study, we tested the effect of S-[6]-gingerol on HuH-7 cells using the Fluo-4 calcium assay, RT-qPCR, transient cell transfection, and luciferase measurements. We found that S-[6]-gingerol induced a transient rise in [ Ca2+ ] i in HuH-7 cells. The increase in [ Ca2+ ] i induced by S-[6]-gingerol was abolished by preincubation with EGTA and was also inhibited by the TRPV1 channel antagonist capsazepine. Expression of TRPV1 in HuH-7 cells was confirmed by mRNA analysis as well as a test for increase of [ Ca2+ ] i by TRPV1 agonist capsaicin and its inhibition by capsazepine. We found that S-[6]-gingerol induced rapid NFB activation through TRPV1 in HuH-7 cells. Furthermore, S-[6]-gingerol-induced NFB activation was dependent on the calcium gradient and TRPV1. The rapid NFB activation by S-[6]-gingerol was associated with an increase in mRNA levels of NFB-target genes: cIAP-2, XIAP, and Bcl-2 that encode antiapoptotic proteins. 2013 Xiao-Hong Li et al.
-
Almine, Jessica F.; Wise, Steven G.; Hiob, Matti A.; Singh, Neeraj Kumar; Tiwari, Krishna Kumar; Vali, Shireen; Abbasi, Taher; Weiss, Anthony StevenFollowing penetrating injury of the skin, a highly orchestrated and overlapping sequence of events helps to facilitate wound resolution. Inflammation is a hallmark that is initiated early, but the reciprocal relationship between cells and matrix molecules that triggers and maintains inflammation is poorly appreciated. Elastin is enriched in the deep dermis of skin. We propose that deep tissue injury encompasses elastin damage, yielding solubilized elastin that triggers inflammation. As dermal fibroblasts dominate the deep dermis, this means that a direct interaction between elastin sequences and fibroblasts would reveal a proinflammatory signature. Tropoelastin was used as a surrogate for elastin sequences. Tropoelastin triggered fibroblast expression of the metalloelastase MMP-12, which is normally expressed by macrophages. MMP-12 expression increased 1056 286-fold by 6 h and persisted for 24 h. Chemokine expression was more transient, as chemokine C-X-C motif ligand 8 (CXCL8), CXCL1, and CXCL5 transcripts increased 11.8 2.6-, 10.2 0.4-, and 8593 996-fold, respectively, by 6-12 h and then decreased. Through the use of specific inhibitors and protein truncation, we found that transduction of the tropoelastin signal was mediated by the fibroblast elastin binding protein (EBP). In silico modeling using a predictive computational fibroblast model confirmed the up-regulation, and simulations revealed PKA as a key part of the signaling circuit. We tested this prediction with 1 ?M PKA inhibitor H-89 and found that 2 h of exposure correspondingly reduced expression of MMP-12 (63.9 12.3%) and all chemokine markers, consistent with the levels seen with EBP inhibition, and validated PKA as a novel node and druggable target to ameliorate the proinflammatory state. A separate trigger that utilized C-terminal RKRK of tropoelastin reduced marker expression to 65.0-76.5% and suggests the parallel involvement of integrin ?<inf>V</inf>?<inf>3</inf>. We propose that the solubilization of elastin as a result of dermal damage leads to rapid chemokine up-regulation by fibroblasts that is quenched when exposed elastin is removed by MMP-12.-Almine, J. F., Wise, S. G., Hiob, M., Kumar Singh, N. K., Tiwari, K. K., Vali, S., Abbasi, T., and Weiss, A. S. Elastin sequences trigger transient proinflammatory responses by human dermal fibroblasts. FASEB.
-
Th, Peter Paul; Barter, Philip J.; Rosenson, Robert Sidney; Boden, William E.; Chapman, Martin John; Cuchel, Marina A.; DAgostino, Ralph B.; Davidson, Michael H.; Davidson, William Sean; Heinecke, Jay W.; Karas, Richard H.; Kontush, Anatol S.; Krauss, Ronald M.; Miller, Michael G.; Rader, Daniel J.For >4 decades it has been recognized that elevated serum levels of high-density lipoprotein cholesterol (HDL-C) are associated with reduced risk of cardiovascular disease (CVD) and its sequelae. Many prospective observational studies performed around the world have confirmed an inverse relationship between HDL-C and cardiovascular risk in people irrespective of sex, race, or ethnicity. Consequently, it was assumed that, by extension, raising HDL-C through lifestyle modification and pharmacologic intervention would reduce risk of CVD. Animal studies are consistent with this assumption. Lipid treatment guidelines around the world promoted the recognition of HDL-C as a therapeutic target, especially in high-risk patients. Some post hoc analyses from randomized controlled trials also suggest that raising HDL-C beneficially affects the risk of CVD. However, a number of recent randomized studies putatively designed to test the "HDL hypothesis" have failed to show benefit. The results of these trials have caused many clinicians to question whether HDL-C is a legitimate therapeutic target. In response to the many questions and uncertainties raised by the results of these trials, the National Lipid Association convened an expert panel to evaluate the current status of HDL-C as a therapeutic target; to review the current state of knowledge of HDL particle structure, composition, and function; and to identify the salient questions yet to be answered about the role of HDL in either preventing or contributing to atherosclerotic disease. The expert panel's conclusions and clinical recommendations are summarized herein. The panel concludes that, although low HDL-C identifies patients at elevated risk, and much investigation suggests that HDL may play a variety of antiatherogenic roles, HDL-C is not a therapeutic target at the present time. Risk stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non-HDL-C) should remain the primary and secondary targets of therapy in patients at risk, as described by established guidelines. The National Lipid Association emphasizes that rigorous research into the biology and clinical significance of low HDL-C should continue. The development of novel drugs designed to modulate the serum levels and functionality of HDL particles should also continue. On the basis of an enormous amount of basic scientific and clinical investigation, a considerable number of reasons support the need to continue to investigate the therapeutic effect of modulating HDL structure and function. 2013 National Lipid Association. All rights reserved.
-
Thorpe, Geoffrey W.; Reodica, Mayfebelle; Davies, Michael J.; Heeren, Gino; Jarolim, Stefanie; Pillay, Bethany A.; Breitenbach, Michael; Higgins, Vincent J.; Dawes, Ian W.W.Reactive oxygen species (ROS) consist of potentially toxic, partly reduced oxygen species and free radicals. After H<inf>2</inf>O<inf>2</inf> treatment, yeast cells significantly increase superoxide radical production. Respiratory chain complex III and possibly cytochrome b function are essential for this increase. Disruption of complex III renders cells sensitive to H <inf>2</inf>O<inf>2</inf> but not to the superoxide radical generator menadione. Of interest, the same H<inf>2</inf>O<inf>2</inf>-sensitive mutant strains have the lowest superoxide radical levels, and strains with the highest resistance to H<inf>2</inf>O<inf>2</inf> have the highest levels of superoxide radicals. Consistent with this correlation, overexpression of superoxide dismutase increases sensitivity to H<inf>2</inf>O<inf>2</inf>, and this phenotype is partially rescued by addition of small concentrations of menadione. Small increases in levels of mitochondrially produced superoxide radicals have a protective effect during H<inf>2</inf>O<inf>2</inf>-induced stress, and in response to H<inf>2</inf>O<inf>2</inf>, the wild-type strain increases superoxide radical production to activate this defense mechanism. This provides a direct link between complex III as the main source of ROS and its role in defense against ROS. High levels of the superoxide radical are still toxic. These opposing, concentration-dependent roles of the superoxide radical comprise a form of hormesis and show one ROS having a hormetic effect on the toxicity of another. 2013 Thorpe et al.
-
Hiob, Matti A.; Wise, Steven G.; Kondyurin, Alexey V.; Waterhouse, Anna; Bilek, Marcela M.M.; Ng, Martin K.C.; Weiss, Anthony StevenAll current metallic vascular prostheses, including stents, exhibit suboptimal biocompatibility. Improving the re-endothelialization and reducing the thrombogenicity of these devices would substantially improve their clinical efficacy. Tropoelastin (TE), the soluble precursor of elastin, mediates favorable endothelial cell interactions while having low thrombogenicity. Here we show that constructs of TE corresponding to the first 10 ("N10") and first 18 ("N18") N-terminal domains of the molecule facilitate endothelial cell attachment and proliferation equivalent to the performance of full-length TE. This N-terminal ability contrasts with the known role of the C-terminus of TE in facilitating cell attachment, particularly of fibroblasts. When immobilized on a plasma-activated coating ("PAC"), N10 and N18 retained their bioactivity and endothelial cell interactive properties, demonstrating attachment and proliferation equivalent to full-length TE. In whole blood assays, both N10 and N18 maintained the low thrombogenicity of PAC. Furthermore, these N-terminal constructs displayed far greater resistance to protease degradation by blood serine proteases kallikrein and thrombin than did full-length TE. When immobilized onto a PAC surface, these shorter constructs form a modified metal interface to establish a platform technology for biologically compatible, implantable cardiovascular devices. 2013 Elsevier Ltd.
-
Wong, Hoi Kin; Ong, Kwok Leung; Leung, Raymond Y.H.; Lam, Tai Hing; Neil Thomas, Graham Neil; Lam, Karen Siu Ling; Cheung, Bernard Man YungObjective Elevated plasma adrenomedullin (ADM) levels are associated with cardiovascular diseases. Single nucleotide polymorphisms (SNPs) in the gene encoding ADM (ADM) are associated with plasma ADM levels. The presence of a nuclear factor for interleukin-6 (IL-6) expression binding site in the promoter region of the ADM gene suggests a possible relationship between the expression of the ADM and IL-6. Therefore, we investigated whether plasma ADM levels are related to SNPs in the gene encoding IL-6 (IL6). Methods Plasma ADM levels were measured in 476 subjects in the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS2). The subjects were genotyped for three tagging SNPs in the IL6 gene. Results The minor allele frequencies of the IL6 SNPs rs17147230, rs1800796 and rs2069837 were 418%, 200% and 154%, respectively. The tagging SNP, rs17147230, was associated with plasma ADM levels after adjusting for age and sex (?=-0096, P = 0034). The association was significant in women (?=-0115, P = 0021) but not in men. Among all subjects, plasma ADM levels decreased with an increasing number of minor alleles of rs17147230 in multivariate analysis (P = 0034). Compared to subjects with the AA genotype, subjects with the TT genotype had plasma ADM levels 128% lower (95% CI: 06- 235%, P = 0041). Haplotype analysis demonstrated a significant association of the haplotype ACA with plasma ADM levels in women (P < 005). Conclusion Plasma ADM levels are related to the SNP rs17147230 in IL6 gene. The effect of the polymorphism on inflammation and cardiovascular disease remains to be determined. 2012 John Wiley & Sons Ltd.
-
Simpson, Philippa J.L.; Hoyos, Camilla M.; Celermajer, David S.; Liu, Peter Y.; Ng, Martin K.C.Objective Obstructive sleep apnoea (OSA) is characterised by reoccurring apnoeas and hypopneas, causing repetitive hypoxia and reoxygenation, and is associated with endothelial dysfunction and reduced levels of circulating progenitor cells (CPCs). The potential to improve endothelial function and CPC levels in people with OSA by preventing hypoxic episodes with Continuous Positive Airway Pressure (CPAP) was investigated in a sham-controlled CPAP study. Methods Men with moderate-to-severe OSA (mean SD: age = 49 12 y, apnoea hypopnea index (AHI) = 37.6 16.4 events/h, body mass index = 31.5 5.7 kg/m2) who were CPAP nae without diabetes mellitus were randomised in a 12-week double-blind sham-controlled parallel group study to receive either active (n = 25) or sham (n = 21) CPAP. CPCs, isolated from blood, were measured by flow cytometry and by co-staining cultured cells (7 days) with acetylated low-density lipoprotein (acLDL) and lectin. Endothelial function was assessed by peripheral arterial tonometry (PAT). Results Compared to sham, CPAP significantly decreased AHI (mean between-group difference - 36.0 events/h; 95%CI, - 49.7 to - 22.3, p < 0.0001) after 12 weeks. Despite this improvement in AHI, CPAP had no effect on change in CPC levels (including CD34+/KDR+ (565 cells/mL; - 977 to 2106, p = 0.45), CD34+/KDR+/CD45- (37.0 cells/mL; - 17.7 to 85.7, p = 0.13), acLDL+/lectin+ (- 43.1 cells/field, - 247 to 161, p = 0.67)) or change in endothelial function (0.27; - 0.14 to 0.67, p = 0.19) compared to sham therapy. Conclusions Despite the improvement in OSA parameters and ablation of apnoeic events by CPAP, CPC counts and endothelial function in men with moderate-to-severe OSA were not significantly improved after 12 weeks of therapeutic CPAP when compared to sham control. 2013 Elsevier Ireland Ltd. All rights reserved.
-
Palmer, Mike K.; Nicholls, Stephen J.; Lundman, Pia; Barter, Philip J.; Karlson, Bjn WilgotBackground: Reducing low-density lipoprotein cholesterol (LDL-C) levels decreases cardiovascular risk in direct proportion to the decrease in LDL-C. Design: The aim of this study was to assess the importance of baseline LDL-C and choice and dose of statin in achievement of LDL-C goals of 100 and 70 mg/dl, using a novel statistical model. The analysis included 30,102 patient exposures to rosuvastatin 10-40 mg or atorvastatin 10-80 mg from 31 direct comparative trials in the VOYAGER database. Methods: For each statin dose, percentage goal achievement was plotted for 20 equally large subgroups defined by baseline LDL-C. Logistic regression analysis was then performed for each statin dose to estimate the percentage of patients reaching target. Best-fit logistic regression curves were plotted 'pair-wise', comparing each rosuvastatin dose with equal or higher doses of atorvastatin. Results: LDL-C 100 mg/dl was achieved by 53.7-85.5% of patients on rosuvastatin 10-40 mg and 43.3-80.0% of those on atorvastatin 10-80 mg, whereas LDL-C 70 mg/dl was achieved by 4.5-44.0% of rosuvastatin-treated patients and 6.5-41.4% of those on atorvastatin. Similar differences in efficacy favouring rosuvastatin over equal or double doses of atorvastatin were observed across the range of baseline LDL-C levels for both LDL-C goals, being more pronounced at higher baseline values. Conclusions: Baseline LDL-C and choice and dose of statin are important for LDL-C goal achievement. The present analysis may allow prediction of individual patient response to different statins at different doses. 2012 The European Society of Cardiology.
-
Simonneau, Gald; Gatzoulis, Michael Athanasios; Adatia, Ian T.; Celermajer, David S.; Denton, Christopher Paul; Ghofrani, Hossein Ardeschir; Gez-Schez, Miguel gel; Kumar, R. Krishna; Landzberg, Michael Job; Machado, Roberto F.P.; Olschewski, Horst; Robbins, Ivan M.; Souza, Rogerio DeIn 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4. 2013 by the American College of Cardiology Foundation. Published by Elsevier Inc.
