Target For Atherosclerosis Research Articles

Circulating PCSK9 and cardiovascular events in FH patients with standard lipid-lowering therapy

BackgroundProprotein convertase subtilisin/kexin 9 (PCSK9) has been proposed as a novel target for coronary artery disease (CAD). Familial hypercholesterolemia (FH) is characterized by high prevalence of CAD and major cardiovascular events (MACEs). However, no data is available on the association between PCSK9 levels and MACEs in FH patients with standard lipid lowering therapy.MethodsA total of 338 consecutive heterozygous FH (Dutch Lipid Clinic Network score ≥ 6) was enrolled and followed up for the occurrence of MACEs. Multidetector CT and coronary angiography were performed to determine coronary artery calcification score (CACS) and Gensini score (GS). Multivariable Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Plasma PCSK9 concentrations were determined by enzyme immunoassay.ResultsPCSK9 was independently and positively associated CACS and GS at baseline. During a mean follow-up of 3 years, 33 (9.8%) events occurred. Patients with MACEs had higher median PCSK9 compared with those without (332.47 vs. 311.89 ng/mL, p = 0.038). Kaplan–Meier analysis revealed that patients with higher PCSK9 presented lower event-free survival (p = 0.0017). PCSK9 was statistically correlated with MACEs after adjusting for confounding factors, with the HR per SD being 1.86 (1.31–2.65) and 3.70 (1.16–11.82) for the highest tertile compared with the lowest tertile. Adding PCSK9 to Cox prediction model led to a statistical improvement in net reclassification and integrated discrimination.ConclusionElevated levels of PCSK9 were positively associated with the development of CAD and future cardiovascular events, suggesting that measurement of PCSK9 concentration might be useful for cardiovascular risk stratification. Further studies are needed to confirm our results.

P6168Low PCSK9 plasma level is an independent predictor of coronary atherosclerotic burden in patients with stable coronary artery disease

Abstract Background Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of LDL cholesterol levels and has emerged as a new therapeutic target in coronary artery disease (CAD). Plasma PCSK9 levels have also been related to other components of the lipid profile associated with atherosclerotic risk. Purpose Aim of the present study was to evaluate the relationship of plasma PCSK9 levels with lipid profile and measures of coronary atherosclerotic burden and risk in patients with stable CAD enrolled in the European EValuation of INtegrated Cardiac Imaging (EVINCI) study. Methods PCSK9 was measured in 412 patients (60.3±8.6 years, 256 males) with symptoms of stable CAD fully characterized by clinical risk factors, bio-humoral profiles, and treatment. All patients underwent coronary computed tomography (CT) angiography to assess the presence and characteristics of coronary atherosclerosis. We calculated an individual CT risk score, expressing the coronary atherosclerotic burden, combining extent, severity, composition, and location of plaques. Results Patients were divided in groups according to PCSK9 quartiles: I (<136 ng/mL), II-III (136–266 ng/mL), and IV quartile (>266 ng/mL). LDL and HDL-cholesterol levels were significantly lower while total/HDL-cholesterol ratio was significantly higher in patients in the quartile I than in those in quartile IV (Figure A). CT angiography documented normal vessels in 30 and obstructive CAD in 35% of cases. Compared with patients with the highest levels (quartile IV), patients with the lowest PCSK9 levels (quartile I) had a higher CT risk score, a higher number of mixed plaque and higher hs-cTnI plasma levels (Figure B). PCSK9 itself was not associated with obstructive CAD. At multivariable analysis including clinical variables, medications and lipid variables PCSK9 was an independent predictor of the CT risk score (Coefficient - 0.129 (SE 0.03), p<0.0001), together with age, male gender and statin treatment. Figure 1 Conclusion PCSK9 levels are independently and inversely associated with the coronary atherosclerotic burden in patients with stable CAD. Acknowledgement/Funding AMGEN grant, EU FP7-CP-FP506 2007 project (grant agreement no. 222915)

The Landscape of Proteomic Characteristics of Human Coronary Artery Atherosclerosis

Background: To explore the new biomarkers for coronary artery disease detection and improved therapeutic targets, the comprehensive understanding of protein networks and protein expression abundance in coronary artery samples were established by means of LC-MS/MS analysis. Methods: 20 human coronary artery specimens from 2 autopsied adults were employed in the study. The natural history and histological classification of atherosclerotic lesions of the coronary artery samples were analyzed by Haematoxylin and Eosin (H&E) staining, and the human coronary arterial proteome and proteomic features was characterized by mass spectrometry analysis. Findings: In the present study, we identified 2135 proteins in the 20 coronary artery segments samples from 2 cases. Combination with the results of Haematoxylin and Eosin (H&E) staining of coronary artery samples, a total of 174 proteins, including 4 upregulated proteins and 164 downregulated proteins were obtained which associated with coronary artery disease. And, GO and KEGG enrichment of the differentially expressed proteins shown that the mitochondrial energy metabolism maybe underlying in the occurrence and development of coronary artery atherosclerosis. Interpretation: The human coronary arterial proteome can be considered as a complex network whose architectural characteristics vary considerably as a function of the presence or absence, and histological classification of coronary artery atherosclerosis. The data suggest that the prevention of mitochondrial dysfunction via retrieve the mitochondrial associated proteins expression may be a promising target in coronary artery disease. Funding Statement: This study received support from the National Natural Science Foundations of China (grants 81170180, 30400173, 30971257 and 81970302) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. Dr. Enzhi Jia is an Assistant Fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine. Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: Informed consent from the bereaved family was obtained for the research use only of samples and the autopsy was conducted according to the guideline of the university. The methods were performed in accordance with the approved guidelines, and all experimental protocols were approved by the ethics committee of the Nanjing Medical University and the First Affiliated Hospital of Nanjing Medical University.

Capitalizing on Insights from Human Genetics to Identify Novel Therapeutic Targets for Coronary Artery Disease.

Coronary artery disease (CAD) is a major cause of morbidity and mortality. Unfortunately, despite decades of research focused on disease pathogenesis, we still lack a sufficient pharmacopeia for preventing CAD. The failure of many novel cardiovascular drugs to improve clinical outcomes reflects the major substantial challenge of drug development: identifying causal mechanisms that can be therapeutically manipulated to lower disease risk. Identifying genetic variants that are associated with risk of CAD has emerged as a clear path toward improving our understanding of the underlying mechanisms that lead to disease and to the development of new therapies. Here, we review the potential utility and limitations of using human genetics to guide the identification of therapeutic targets for CAD.

Mining the potential therapeutic targets for coronary artery disease by bioinformatics analysis.

The present study aimed to mine therapeutic molecular targets that play an important part in the progression of coronary artery disease (CAD). The gene expression profile GSE28829 dataset and the microRNA (miRNA) expression profile GSE59421 dataset were downloaded from the Gene Expression Omnibus (GEO) database. The GEO2R online analytical tool was used to identify differentially expressed genes (DEGs) and miRNAs (DEMs). The target genes of DEMs were identified using the miRWalk2.0 web-based tool and 2 miRNA-gene regulatory networks were constructed using Cytoscape software. Subsequently, enriched Gene Ontology (GO) terms of miRNA-target DEGs were obtained using the Database for Visualization, Annotation and Integrated Analysis, and locations of these genes in the chromosomes were determined by Map Viewer. In the present study, 350 DEGs and 66 DEMs were screened. A total of 3,588 target genes were identified from the DEMs, and 57 of these target genes and established DEGs were identified to overlap. GO terms associated with 5 processes, and 4 types of composition were identified to be enriched in the miRNA-target DEGs. Furthermore, 26 miRNA-gene regulatory pairs were obtained between the 57 target genes and DEMs. The 26 miRNA-target DEGs were unevenly distributed, and no genes were located on the sex chromosomes. As a result of the present study, potential therapeutic targets for CAD were identified through bioinformatics analysis.

Identification of biomarkers and intervention targets for coronary artery disease based on results of genome-wide association scans

Identification of biomarkers and intervention targets for coronary artery disease based on results of genome-wide association scans

Systematic RNA-interference in primary human monocyte-derived macrophages: A high-throughput platform to study foam cell formation

Macrophage-derived foam cells are key regulators of atherogenesis. They accumulate in atherosclerotic plaques and support inflammatory processes by producing cytokines and chemokines. Identifying factors that regulate macrophage lipid uptake may reveal therapeutic targets for coronary artery disease (CAD). Here, we establish a high-throughput screening workflow to systematically identify genes that impact the uptake of DiI-labeled low-density lipoprotein (LDL) into monocyte-derived primary human macrophages. For this, monocytes isolated from peripheral blood were seeded onto 384-well plates, solid-phase transfected with siRNAs, differentiated in vitro into macrophages, and LDL-uptake per cell was measured by automated microscopy and quantitative image analysis. We applied this workflow to study how silencing of 89 genes impacts LDL-uptake into cells from 16 patients with CAD and 16 age-matched controls. Silencing of four novel genes (APOC1, CMTM6, FABP4, WBP5) reduced macrophage LDL-uptake. Additionally, knockdown of the chemokine receptor CXCR4 reduced LDL-uptake, most likely through a G-protein coupled mechanism that involves the CXCR4 ligand macrophage-induced factor (MIF), but is independent of CXCL12. We introduce a high-throughput strategy to systematically study gene function directly in primary CAD-patient cells. Our results propose a function for the MIF/CXCR4 signaling pathway, as well as several novel candidate genes impacting lipid uptake into human macrophages.

Sphingosine-1-phosphate promotes the proliferation and attenuates apoptosis of Endothelial progenitor cells via S1PR1/S1PR3/PI3K/Akt pathway.

Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that involves in numerous pathophysiological processes. Endothelial progenitor cells (EPCs) play a crucial role in endothelial repair and tumor angiogenesis. The aim of study was to determine the effects of S1P on proliferation and anti-apoptosis of EPCs and their signaling pathways. In this study, we showed that S1P, SEW2871 (a selective S1P receptor 1 (S1PR1) agonist), or CYM5541 (a selective S1P receptor 3 (S1PR3) allosteric agonist promotes the proliferation and attenuates apoptosis of bone marrow (BM)-derived EPCs. Futhermore, it was showed that S1P could promote EPCs proliferation, which could be significantly inhibited by pretreatment with CAY10444 (an S1PR3 antagonist), VPC23019 (a selective S1PR(1)/S1PR(3) antagonist), or LY294002 (a PI3K inhibitor). Moveover, we discovered that S1P could significantly attenuate H2 O2 -induced apoptosis and activation of caspase-3 in vitro, while W146 (an S1PR1 antagonist), VPC23019, or LY294002 could significantly increase the activation of caspase-3 and subsequent augmented apoptosis. Our results indicated that the protective effect of S1P is mediated by activating the PI3K/Akt pathway. In addition, S1P promotion of EPCs proliferation was observed to be mainly mediated through S1PR3 and attenuation of EPCs apoptosis induced by H2 O2 was mainly mediated through S1PR1; both of these effects are mediated by activating the PI3K/Akt pathway, which provides potentially useful therapeutic targets for coronary artery disease, diabetes mellitus, and cancer treatment.

Translating GWAS Findings to Novel Therapeutic Targets for Coronary Artery Disease.

The success of genome-wide association studies (GWAS) has significantly advanced our understanding of the etiology of coronary artery disease (CAD) and opens new opportunities to reinvigorate the stalling CAD drug development. However, there exists remarkable disconnection between the CAD GWAS findings and commercialized drugs. While this could implicate major untapped translational and therapeutic potentials in CAD GWAS, it also brings forward extensive technical challenges. In this review we summarize the motivation to leverage GWAS for drug discovery, outline the critical bottlenecks in the field, and highlight several promising strategies such as functional genomics and network-based approaches to enhance the translational value of CAD GWAS findings in driving novel therapeutics

Atheroprotective Effects of Tumor Necrosis Factor–Stimulated Gene-6

Tumor necrosis factor-stimulated gene-6 (TSG-6), an anti-inflammatory protein, was shown to be localized in the neointima of injury-induced rat arteries. However, the modulatory effect of TSG-6 on atherogenesis has not yet been reported. We aimed to evaluate the atheroprotective effects of TSG-6 on human endothelial cells (HECs), human monocyte-derived macrophages (HMDMs), human aortic smooth muscle cells (HASMCs) invitro, and aortic lesions in apolipoprotein E-deficient mice, along with expression levels of TSG-6 in coronary lesions and plasma from patients with coronary artery disease (CAD). TSG-6 was abundantly expressed in HECs, HMDMs, and HASMCs invitro. TSG-6 significantly suppressed cell proliferation and lipopolysaccharide-induced up-regulation of monocyte chemotactic protein-1, intercellular adhesion molecule-1, and vascular adhesion molecule-1 in HECs. TSG-6 significantly suppressed inflammatory M1 phenotype and suppressed oxidized low-density lipoprotein-induced foam cell formation associated with down-regulation of CD36 and acyl-CoA:cholesterol acyltransferase-1 in HMDMs. In HASMCs, TSG-6 significantly suppressed migration and proliferation, but increased collagen-1 and -3 expressions. Four-week infusion of TSG-6 intoapolipoprotein E-deficient mice significantly retarded the development of aortic atherosclerotic lesions with decreased vascular inflammation, monocyte/macrophage, and SMC contents and increased collagen fibers. In addition, it decreased peritoneal M1 macrophages with down-regulation of inflammatory molecules and lowered plasma totalcholesterol levels. In patients with CAD, plasma TSG-6 levels were significantly increased, and TSG-6 was highlyexpressed in the fibrous cap within coronary atherosclerotic plaques. These results suggest that TSG-6 contributes to the prevention and stability of atherosclerotic plaques. Thus, TSG-6 may serve as a novel therapeutic targetfor CAD.

Classification of ADAMTS binding sites: The first step toward selective ADAMTS7 inhibitors

Genome-wide association studies identified ADAMTS7 as a risk locus for coronary artery disease. In carotid arteries of rats, neointima formation after balloon-mediated injury goes along with enhanced Adamts7 expression. Vice versa, Adamts7-deficient mice display reduced neointima formation following vascular injury. Although a causal link between ADAMTS7 and coronary artery disease remains to be proven, inhibition of ADAMTS7 represents a potential new target for intervention in this disease.ADAMTS7, a member of the ‘a disintegrin and metalloproteinase with thrombospondin motifs’ (ADAMTS) family of proteins, contains a catalytic zinc ion in the binding site of its metalloproteinase domain. The structure of ADAMTS7 and its inhibitors are unknown. In this study, we used in silico methods, including homology modeling and pharmacophore modeling, to analyze the ADAMTS7 metalloproteinase domain, particularly its binding site. The results revealed structural and sequence differences relative to the binding sites of the other ADAMTS proteins; these non-conserved regions represent potential binding regions for selective ADAMTS7 inhibitors. The main contribution of this study is the proposal of a pharmacophore for ADAMTS7. The characterization of the ADAMTS7 binding site and definition of a pharmacophore are the first step toward developing a new therapeutic target for coronary artery disease.

Identifying new Risk Markers and Potential Targets for Coronary Artery Disease: The Value of the Lipidome and Metabolome.

This systematic review was performed to summarize published data on lipidomic and metabolomic risk markers of coronary artery disease. Studies were identified from a literature search of PubMed. Published data shows that analysis of metabolites and lipids offers an opportunity to increase our knowledge of the biological processes related to development and progression of atherosclerotic coronary disease. It is evident that advanced analytical technologies are able to detect and identify a large number of molecules that may have important structural and functional roles over and above currently used biomarkers in the cardiovascular field. It is suggested in a number of reports that the novel biomarkers can be used to improve risk stratification and patient selection for different treatments. Also, monitoring treatment efficacy and safety as well as lifestyle changes should be facilitated by such novel markers. Until now a plethora of biomarker candidates associated with cardiovascular event risk have been identified, but very few have passed through clinical and analytical validation and found their way into clinical use. Consequently, the appetite of physicians to use these novel tests in daily clinical routine has not yet been truly tested.

Serum Heat Shock Protein 27 Levels Represent a Potential Therapeutic Target for Atherosclerosis: Observations From a Human Cohort and Treatment of Female Mice

The aim of this study was to evaluate the potential of serum heat shock protein 27 (HSP27) as a therapeutic target in coronary artery disease. Expression of HSP27 in human coronary arteries diminishes with the progression of atherosclerosis, whereas ubiquitous HSP27 overexpression in apolipoprotein E(-/-) (ApoE(-/-)) mice attenuates atherogenesis. However, it remains unclear whether increasing serum HSP27 levels alone is sufficient for atheroprotection. Low- and intermediate-risk patients undergoing coronary or computed tomography angiography had serum HSP27 levels measured. Elevated serum HSP27 levels in female atheroprone ApoE(-/-) mice were achieved by transplantation with HSP27 overexpressing bone marrow or by administering recombinant HSP27. Patients with >50% stenosis in any major epicardial artery had lower HSP27 levels compared with those free of atherosclerosis (median [interquartile range]: 2,176 pg/ml [551-5,475] vs. 6,200 pg/ml [2,575-9,560]; p < 0.001). After a 5-year period of clinical follow-up, low serum HSP27 levels (<50th percentile) were predictive of subsequent major adverse cardiovascular events (hazard ratio: 2.93, 95% confidence interval: 1.06 to 8.12; p = 0.04). In experimental murine models of atherosclerosis, increasing serum HSP27 levels both reduced de novo atherosclerotic lesion formation and enhanced features of plaque stability. In humans, low serum HSP27 levels are associated with the presence of coronary artery disease and prognostic of future adverse clinical events. In mouse models of atherosclerosis, increasing HSP27 levels reduced lesion progression and promoted features of plaque stability. Serum HSP27 levels may represent a potential therapeutic target for atherosclerosis.

Protease-Activated Receptor (PAR)2, but Not PAR1, Is Involved in Collateral Formation and Anti-Inflammatory Monocyte Polarization in a Mouse Hind Limb Ischemia Model

AimsIn collateral development (i.e. arteriogenesis), mononuclear cells are important and exist as a heterogeneous population consisting of pro-inflammatory and anti-inflammatory/repair-associated cells. Protease-activated receptor (PAR)1 and PAR2 are G-protein-coupled receptors that are both expressed by mononuclear cells and are involved in pro-inflammatory reactions, while PAR2 also plays a role in repair-associated responses. Here, we investigated the physiological role of PAR1 and PAR2 in arteriogenesis in a murine hind limb ischemia model.Methods and ResultsPAR1-deficient (PAR1-/-), PAR2-deficient (PAR2-/-) and wild-type (WT) mice underwent femoral artery ligation. Laser Doppler measurements revealed reduced post-ischemic blood flow recovery in PAR2-/- hind limbs when compared to WT, while PAR1-/- mice were not affected. Upon ischemia, reduced numbers of smooth muscle actin (SMA)-positive collaterals and CD31-positive capillaries were found in PAR2-/- mice when compared to WT mice, whereas these parameters in PAR1-/- mice did not differ from WT mice. The pool of circulating repair-associated (Ly6C-low) monocytes and the number of repair-associated (CD206-positive) macrophages surrounding collaterals in the hind limbs were increased in WT and PAR1-/- mice, but unaffected in PAR2-/- mice. The number of repair-associated macrophages in PAR2-/- hind limbs correlated with CD11b- and CD115-expression on the circulating monocytes in these animals, suggesting that monocyte extravasation and M-CSF-dependent differentiation into repair-associated cells are hampered.ConclusionPAR2, but not PAR1, is involved in arteriogenesis and promotes the repair-associated response in ischemic tissues. Therefore, PAR2 potentially forms a new pro-arteriogenic target in coronary artery disease (CAD) patients.

Fasting serum concentration of apolipoprotein B48 represents residual risks in patients with new-onset and chronic coronary artery disease

BackgroundTo identify new therapeutic targets for coronary artery disease (CAD), we investigated whether fasting serum concentration of apolipoprotein (apo) B48 could be a marker for CAD. MethodsPatients with CAD were divided into those with new-onset CAD [i.e., those receiving percutaneous coronary intervention (PCI) for the first time] and those with chronic CAD (i.e., those receiving follow-up coronary angiography). Fasting serum biochemical analyses were performed on admission and 6months after the PCI. ResultsOn admission, serum LDL-C concentrations in patients with chronic CAD (n=138), presumably receiving statin treatment, were lower than in patients with new-onset CAD (n=50, p<0.02) or without CAD (n=71, p<0.001). Nevertheless, apoB48 was higher in CAD patients than in those without CAD (p<0.001). After adjusting for classic cardiovascular risk factors, multivariate logistic regression analyses showed apoB48 to be an independent predictor of coronary risk in new-onset or chronic CAD, irrespective of the LDL-C levels. Moreover, apoB48 was markedly increased during the follow-up period in CAD patients having new lesion progression after the prior PCI. ConclusionFasting serum apoB48 concentration could be a marker of new onset as well as chronic CAD, and predict new lesion progression in secondary prevention.

Chemerin: A potential target in Coronary Artery Disease – A Review

Currently, Coronary Artery Disease (CAD) is considered as a major ailment in humans with widespread prevalence. CAD also accounts for high mortality rates around the world that involves several known risk factors. Recently, it was discovered that epicardial adipose tissue (EAT) and its secretory adipokines play an imperative role in the development of CAD. Among the secretory adipokines, chemerin , a serpentine chemotactic agonist has been identified as one of the factor which contributes for the progression of CAD. Since serum chemerin levels are elevated during CAD condition, it is being considered to be a valiant marker but then the chimeric property of chemerin is yet to be explored. Though chemerin has been identified as one of the factors responsible for the development of CAD, it is still being studied at the marker level. This review aims to study whether chemerin can only be used as a marker or can it also be used as a novel target for treating or suppressing or delaying the progression of coronary artery disease.

Pharmacological profile of phosphatidylinositol 3-kinases and related phosphatidylinositols mediating endothelin(A) receptor-operated native TRPC channels in rabbit coronary artery myocytes.

Endothelin(A) (ET(A) ) receptor-operated canonical transient receptor potential (TRPC) channels mediate Ca²⁺ influx pathways, which are important in coronary artery function. Biochemical pathways linking ET(A) receptor stimulation to TRPC channel opening are unknown. We investigated the involvement of phosphatidylinositol 3-kinases (PI3K) in ET(A) receptor activation of native heteromeric TRPC1/C5/C6 and TRPC3/C7 channels in rabbit coronary artery vascular smooth muscle cells (VSMCs). A pharmacological profile of PI3K was created by studying the effect of pan-PI3K, pan-Class I PI3K and Class I PI3K isoform-selective inhibitors on ET(A) receptor-evoked single TRPC1/C5/C6 and TRPC3/C7 channel activities in cell-attached patches from rabbit freshly isolated coronary artery VSMCs. The action of phosphatidylinositol 3-phosphate- [PI(3)P], 4-phosphate- [PI(4)P] and 5-phosphate- [PI(5)P] containing molecules involved in PI3K-mediated reactions were studied in inside-out patches. Expression of PI3K family members in coronary artery tissue lysates were analysed using quantitative PCR. ET(A) receptor-operated TRPC1/C5/C6 and TRPC3/C7 channel activities were inhibited by wortmannin. However, ZSTK474 and AS252424 reduced ET(A) receptor-evoked TRPC1/C5/C6 channel activity but potentiated TRPC3/C7 channel activity. All the PI(3)P-, PI(4)P- and PI(5)P-containing molecules tested induced TRPC1/C5/C6 channel activation, whereas only PI(3)P stimulated TRPC3/C7 channels. ET(A) receptor-operated native TRPC1/C5/C6 and TRPC3/C7 channel activities are likely to be mediated by Class I PI3Kγ and Class II/III PI3K isoforms, respectively. ET(A) receptor-evoked and constitutively active PI3Kγ-mediated pathways inhibit TRPC3/C7 channel activation. PI3K-mediated pathways are novel regulators of native TRPC channels in VSMCs, and these signalling cascades are potential pharmacological targets for coronary artery disease.

060 Plasma aldosterone levels predict long-term clinical outcome after percutaneous coronary revascularization

The renin-angiotensin-aldosterone system is a major therapeutic target in coronary artery disease (CAD). Recent data suggest that plasma aldosterone has a high prognostic value in acute coronary syndrome (ACS). We tested whether plasma aldosterone could predict clinical outcome in patients undergoing scheduled percutaneous coronary revascularization (PCR). Methods From June 2001 to September 2002, we included all consecutive patients referred to Lille's University Hospital for scheduled PCR. Blood samples were taken during the PCR. The primary endpoint was cardiac death throughout at least 12 months of follow-up. Results 807 patients were included, with a mean age of 61 years. Most were men (78%), smokers (71%). 32% were diabetics, mean LVEF was 58±15% and 93% received stents. 50% had stable angina. The mean plasma aldosterone level was 25(13-45)pg/mL. BMI (p=0.003), NYHA class>1 (p=0.0001) and elevated baseline troponine (p=0.01) were associated with increased aldosterone level. Old age (p=0.0001), normal GFR (p=0.01) and betablockers (p=0.01) were associated with decreased aldosterone level. The mean follow-up was 14.9 months and there were 40 cardiac deaths during this period. In multivariate analysis, old age (HR=1.42, p=0.04), low LVEF (HR=1.58, p=0.001), diabetes mellitus (HR=2.2, p=0.04), a recent history of ACS (HR=3.23, p=0.02), high usCRP (HR=2.59, p=0.004) and high plasma aldosterone (HR=3.48, p=0.004) were independent predictors of cardiac mortality. Conclusion Plasma aldosterone level seems to have an independent prognostic value in patients referred for PCR and could be useful in determining the individual cardiovascular risk. Whether this is the result of direct deleterious effects (promotion of endothelial dysfunction, pro-fibrotic, pro-inflammatory and pro-thrombotic effects) or the marker of a global activation of the neuroendocrine system remains to be determined. However plasma aldosterone appears to be an attractive risk marker in CAD. Download : Download full-size image

Estrogen induces endothelial progenitor cells proliferation and migration by estrogen receptors and PI3K-dependent pathways

Estrogen induces endothelial progenitor cells (EPCs) migration and proliferation, which may serve as a potential target for coronary artery disease, but the mechanisms are unclear. We hypothesized that estrogen receptors (ERs) and phosphatidylinositol 3-kinase (PI3K) signaling pathway, which represent particularly important roles of action for estrogen, may contribute to estrogen-induced EPCs migration and proliferation. Bone marrow mononuclear cells (MNCs) were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with growth factors as previously described. A total of 87.32 ± 5.13% of adherent cells showed uptake of acetylated low-density lipoprotein and lectin binding. Immunostaining and fluorescence activated cell sorting confirmed the endothelial progenitor phenotype. RT-PCR, immunocytochemistry staining and Western blot demonstrated expression of ERs. Exposure to 17β-estradiol significantly improved EPCs migration and proliferation. Those effects were blocked by pretreatment with the pharmacological PI3K blockers LY294002 (1 h, 10 umol/L) and ICI-182780 (1 h, 10 umol/L), a specific estrogen receptor antagonist, which show involvement of estrogen receptors and PI3K pathway. These results suggest that estrogen induces EPCs migration and proliferation via ERs and PI3K pathway which provided a novel insight and treatment strategy of vascular biology.

Endothelial function as a therapeutic target in coronary artery disease.

In healthy individuals, endothelial cells regulate a host of functions including vasomotor tone, thrombosis/ fibrinolysis, and cell-cell interactions. The development of endothelial dysfunction may be a common pathway by which cardiovascular risk factors impact plaque formation, growth, and rupture. Many pharmacologic and nonpharmacologic interventions known to decrease cardiovascular risk also improve endothelial function. For these reasons, some have suggested that improvement in endothelial function may be an important therapeutic target in the treatment of coronary artery disease.