Unstable Atherosclerotic Plaques Research Articles

Altered mitochondrial quality control in Atg7-deficient VSMCs promotes enhanced apoptosis and is linked to unstable atherosclerotic plaque phenotype

Vascular smooth muscle cells (VSMCs) are one of the main cellular determinants in arterial pathology. A large body of evidence indicates that death of VSMCs is associated with features of high-risk/vulnerable atherosclerotic plaques. Mitochondrial turnover is an essential aspect of the mitochondrial quality control in which dysfunctional mitochondria are selectively eliminated through autophagy and replaced through expansion of preexisting mitochondria. Even though successful autophagy promotes VSMC survival, it is unclear whether reduced autophagic flux affects mitochondrial quality control of VSMCs in atherosclerotic plaques. By using apolipoprotein E-deficient (ApoE−/−) mice carrying a VSMC-specific deletion of the essential autophagy gene Atg7, we show in the present study that impaired VSMC autophagy promotes an unstable plaque phenotype, as well as the accumulation of fragmented mitochondria with reduced bioenergetic efficiency and more oxidative stress. Furthermore, we demonstrate that disrupted autophagic flux is linked to defective mitophagy and biogenesis of mitochondria, which exacerbate VSMC apoptosis and in turn plaque vulnerability. Overall, our data indicate that mitochondrial quality control is a promising therapeutic target to stabilize atherosclerotic plaques.

The Role of Smooth Myocytes and Macrophages in Development of Complicated Forms of Arterial Atherosclerosis

to conduct morphohistochemical and immunohistochemical study of arterial unstable atherosclerotic plaques for assessment of the state of smooth muscle cells (SMC) and macrophages. The surgical material of the peripheral arteries (femoral, popliteal, external carotid) was obtained from 50 patients aged over 60 years, followed by morphohistochemical, immunohistochemical studies. Hyperplasia of secretory smooth muscle cells (SMC), and new formation of thin-walled capillary vessels was noted in unstable atherosclerotic plaques. Macrophagic infiltration was detected in the intima of arteries, in places of accumulation of foam cells. Unstable atherosclerotic plaque is a cellular-intercellular process with the participation of lipids, macrophages, and with predominance of SMC and newly formed vessels.

Immunohistochemical Features of Different Types of Unstable Atherosclerotic Plaques of Coronary Arteries.

We performed a complex morphological study of samples of different types of unstable atherosclerotic plaques obtained from 33 men with occlusive coronary atherosclerosis, who underwent coronary artery endarterectomy during coronary artery bypass surgery. In the samples, expression of MMP-2 and MMP-9, collagen IV, CD31, CD34, factor VIII, and actin of smooth muscle cells was evaluated by morphometric and immunohistochemical methods. The maximum expression of MMP-9 was found in unstable plaques of the lipid type, where it 1.4- and 1.24-fold surpassed the corresponding levels in plaques of the inflammatory-erosive and degenerative-necrotic types. Unstable plaques of the degenerative-necrotic type are characterized by the most intensive expression of collagen IV in comparison with plaques of the inflammatory-erosive and lipid types (by 2.8 and 2.2 times, respectively). The maximum neovascularization was detected in inflammatory-erosive plaques, which was confirmed by enhanced expression of CD31 and CD34 markers in comparison with plaques of the lipid (by 7.6 and 18.95 times, respectively) and degenerative-necrotic (by 31.1 and 39.8 times) types.

PO555 Theoretical and Practical Training of Teenagers From Public High School to Care For Cardiac Arrest: A Prospective Study In a Developing Country

Contrast-enhanced ultrasound (CEUS) of the carotid artery is a potential technique for imaging plaque neovascularization, a feature of unstable atherosclerotic plaques. This study examined whether assessment of intra-plaque neovascularization of the carotid artery using CEUS provides prognostic information in patients with coronary artery disease (CAD).A total of 206 patients with stable CAD underwent a CEUS examination of the carotid artery and were followed up prospectively for < 38 months or until a cardiac event (cardiac death, non-fatal myocardial infarction (MI), unstable angina pectoris (uAP) requiring unplanned coronary revascularization, or heart failure requiring hospitalization). The degree of contrast signals measured within the carotid plaque was quantified by calculating the mean gray scale level within the region of interest of the carotid plaque, expressed as plaque enhanced intensity.During the follow-up period, 31 events occurred (2 cardiac deaths, 7 non-fatal MIs, 16 uAP, and 6 heart failure). Multivariate Cox proportional hazard analysis showed that plaque enhanced intensity was a significant predictor of cardiac events independent of traditional risk factors (HR, 1.13; 95% CI, 1.05–1.21; p < 0.001). The addition of the plaque enhanced intensity to traditional risk factors resulted in net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.62, p = 0.001; and IDI 0.106, p = 0.002).The assessment of carotid plaque neovascularization using quantitative analysis of CEUS may be useful for risk stratification in patients with CAD.

Molecular imaging of MMP activity discriminates unstable from stable plaque phenotypes in shear-stress induced murine atherosclerosis.

PurposeAs atherosclerotic plaque ruptures are the primary cause of ischaemic events, their preventive identification by imaging remains a clinical challenge. Matrix metalloproteinases (MMP) are involved in plaque progression and destabilisation and are therefore promising targets to characterize rupture-prone unstable plaques. This study aims at evaluating MMP imaging to discriminate unstable from stable plaque phenotypes.MethodsApoE deficient mice (ApoE-/-) on a high cholesterol diet underwent implantation of a tapered cuff around the right common carotid artery (CCA) inducing a highly inflamed atherosclerotic plaque upstream (US) and a more stable plaque phenotype downstream (DS) of the cuff. 8 weeks after surgery, the MMP inhibitor-based photoprobe Cy5.5-AF443 was administered i.v. 3h prior to in situ and ex vivo fluorescence reflectance imaging of the CCAs. Thereafter, CCAs were analysed regarding plaque size, presence of macrophages, and MMP-2 and MMP-9 concentrations by immunohistochemistry and ELISA.ResultsWe found a significantly higher uptake of Cy5.5-AF443 in US as compared to DS plaques in situ (1.29 vs. 1.06 plaque-to-background ratio; p<0.001), which was confirmed by ex vivo measurements. Immunohistochemistry revealed a higher presence of macrophages, MMP-2 and MMP-9 in US compared to DS plaques. Accordingly, MMP-2 concentrations were significantly higher in US plaques (47.2±7.6 vs. 29.6±4.6 ng/mg; p<0.05).ConclusionsIn the ApoE-/- cuff model MMP-2 and MMP-9 activities are significantly higher in upstream low shear stress-induced unstable atherosclerotic plaques as compared to downstream more stable plaque phenotypes. MMP inhibitor-based fluorescence molecular imaging allows visualization of these differences in shear stress-induced atherosclerosis.

Immunohistochemical Phenotypes of Stable and Unstable Occlusive Atherosclerotic Plaques in Coronary Arteries.

We performed a complex morphological analysis of atherosclerotic plaques obtained from 68 men with coronary atherosclerosis during coronary bypass surgery with endarterectomy. The expression of MMP-2 and MMP-9, collagen IV, CD31, CD34, factor VIII, and of smooth muscle cell actin was measured in the samples by morphometric and immunohistochemical methods. The expression of MMP-2 and MMP-9 as well as the intensity of neoangiogenesis estimated by the expression of CD31, CD34, and factor VIII in unstable plaques was significantly higher than in stable ones. Immunohistochemical analysis showed more intensive collagen IV expression in stable plaques. The observed differences in immunohistochemical phenotypes of stable and unstable atherosclerotic plaques reflect peculiarities of morphogenesis of atherosclerotic foci in the coronary arteries determining their further development.

Роль цитокинов в диагностике нестабильности атеросклеротической бляшки

Роль цитокинов в диагностике нестабильности атеросклеротической бляшки

ASSOCIATION OF COAGULATION FACTORS WITH THE PRESENCE OF UNSTABLE ATHEROSCLEROTIC PLAQUES IN THE CORONARY ARTERIES

Objective. This study was devoted to examinationof some factors of blood coagulation (factor II, factor VII, factor XII, antithrombin III) in order to find their associations with biomarkers of endothelial dysfunction (endothelin 1, monocyticchemoattractant protein type 1, MCP-1, lipoprotein (a), LP (a), adhesive molecules sVCAM-1, asymmetric dimethylarginin, ADMA, homocysteine), inflammation (interleukins, IL-6, IL - 8, C-reactive protein, CRP) and with unstable atherosclerotic plaques in the coronary arteries in men with coronary atherosclerosis.Material and methods. In 93 men with coronary atherosclerosis without acute coronary syndrome, blood coagulation factors concentrations (factor II, factor VII, factor XII, antithrombin III) were studied in the blood with goal to find their associations with biomarkers of endothelial dysfunction (endothelin 1, MCP-1, LP(a), adhesion molecules sVCAM-1, ADMA, homocysteine), of inflammation (IL-6, IL-8, CRP) and with the presence of unstable plaques in the coronary arteries.Results. In men with unstable atherosclerotic plaques in the coronary arteries, the blood levels of factor VII and factor XII were 1.3 and 1.3 times higher, respectively, compared to men who had stable plaques in the coronary arteries. Correlation links between the blood levels of factor II and factor XII and the presence of unstable atherosclerotic plaques in the coronary arteries (r=0.239 and r=0.250, p &lt;0.05, respectively) have been revealed, as well as between coagulation factors and blood levels of LP(a), sVCAM-1, IL-6 and CRP. Results of logistic regression analysis showed that the relative risk of present of unstable atherosclerotic plaques in the coronary arteries is associated with an elevated blood level of factor XII (OR=1.008, 95 % CI 1.000-1.017, p=0.048).Conclusion. Our results indicate that elevated blood levels of the Hageman factor may be a new biomarker of probability of unstable atherosclerotic plaques presence in the coronary arteries.

Transient Ischaemic Attack Rarely Precedes Stroke in a Cohort with Low Proportions of Large Artery Atherosclerosis: A Population-Based Study

Background: Ischaemic stroke is reportedly preceded by transient ischaemic attack (TIA) in 15–30% of all cases. The risk of stroke following TIA is highest in the presence of unstable atherosclerotic plaques in large arteries. The recent population-based Adelaide Stroke Incidence Study describes a population with a low proportion (16%) of stroke attributable to large artery atherosclerosis (LAA). We hypothesized that this population-based ischaemic stroke cohort would have a lower rate of preceding TIA than previously reported. Methods: This paper is a prospective ascertainment of all suspected TIAs and strokes in a 12-month period from 2009 to 2010. Ischaemic stroke pathogenesis was classified by the TOAST criteria. Details of preceding TIA events were scrutinised. Results: In this 12-month period, 318 stroke events in 301 individuals were recorded. Of the total 258 ischaemic strokes, 16% (95% confidence interval [CI] 12–22) were from LAA. Of 258 ischaemic stroke patients, only 11 (4%; 95% CI 2–7) reported symptoms in the preceding 90 days consistent with TIA. Nine (82%) sought medical attention. The median ABCD² score in this group was 4.5 (IQR: 3–7), and the median time of event prior to stroke was 20 days (IQR: 4–32). Conclusion: In our population-based cohort, rates of TIA preceding ischaemic stroke were much lower than previously reported, probably reflective of effective secondary prevention (active TIA clinics) and primary prevention (limiting LAA prevalence). In our population, further enhancements in TIA care will be of limited yield.

Research Progress on the Relationship between Atherosclerosis and Inflammation.

Atherosclerosis is a chronic inflammatory disease; unstable atherosclerotic plaque rupture, vascular stenosis, or occlusion caused by platelet aggregation and thrombosis lead to acute cardiovascular disease. Atherosclerosis-related inflammation is mediated by proinflammatory cytokines, inflammatory signaling pathways, bioactive lipids, and adhesion molecules. This review discusses the effects of inflammation and the systemic inflammatory signaling pathway on atherosclerosis, the role of related signaling pathways in inflammation, the formation of atherosclerosis plaques, and the prospects of treating atherosclerosis by inhibiting inflammation.

Oxidized lipids in atherosclerotic plaque instability

A large body of evidence suggests a mechanistic link between oxidized lipids and atherosclerosis. Oxysterols and 4-hydroxynonenal (HNE), the major products deriving from LDL oxidation, are consistently present in inflamed and atherosclerotic arteries and they play a key role in the development of atherosclerosis (1,2). Due to the fact that atherosclerosis is a leading cause of mortality in Western countries, it is of increasing importance to understand the various molecular mechanisms induced by oxysterols and HNE, as well as to identify new markers to distinguish between stable and unstable atherosclerotic plaques. Since chronic inflammation and matrix degradation might play a key role in plaque instability, we investigated the effect of oxysterols and HNE on various inflammatory molecules and MMP-9 expression in promonocytic U937 cells. In U937 cells, both oxysterols and HNE induced the expression of several cytokines and MMP-9 through TLR4 activation. These oxidized lipids also sustained inflammation by upregulating COX-2 and mPGES-1 levels, enzymes that cooperate to catalyze the conversion of arachidonic acid to PGE2. Inhibition of inflammatory molecule formation decrease MMP-9 release by macrophages, underlying the crucial role of inflammatory response in MMP-9 overexpression, a major marker of atherosclerotic plaque instability. Recently, it has been reported that proprotein convertase PCSK6, a new marker of plaque instability, is overexpressed in symptomatic carotid plaques. In connection with this, we are now investigating whether an oxysterol mixture and HNE can modulate the expression of PCSK6. Preliminary results indicate that both oxysterols and HNE upregulate PCSK6 in U937 cells. The downregulation of PCSK6 by siRNA significantly reduced MMP-9 activity induced by oxidized lipids, underlying a possible link between PCSK6 activity and MMP activation. Our results suggest that oxysterols and HNE contribute to atherosclerotic plaque instability by enhancing the inflammatory response and favouring matrix degradation through MMP-9 upregulation. Moreover, preliminary results indicate that PCSK6, upregulated by oxysterols or HNE, might play a key role in plaque instability by increasing MMP activity. These results might provide strong incentive for the development of new therapeutic strategies to counteract the risk of atherosclerotic plaque rupture and thrombosis, which cause acute coronary syndromes.

Change of inflammatory, destructive, oxidative, endothelial dysfunction biomolecules contents during of unstable atherosclerotic plaque formation

Aim: Atherogenic inflammatory, destructive, oxidative and endothelial dysfunction factors during of consecutive stages of atherosclerotic plaque formation and in 3 types of plaques instability were studied.

Surface enhanced Raman spectroscopy-detection of the uptake of mannose-modified nanoparticles by macrophages in vitro: A model for detection of vulnerable atherosclerotic plaques.

Atherosclerosis is a process of thickening and stiffening of the arterial walls through the accumulation of lipids and fibrotic material, as a consequence of aging and unhealthy life style. However, not all arterial plaques lead to complications, which can lead to life-threatening events such as stroke and myocardial infarction. Diagnosis of the disease in early stages and identification of unstable atherosclerotic plaques are still challenging. It has been shown that the development of atherosclerotic plaques is an inflammatory process, where the accumulation of macrophages in the arterial walls is immanent in the early as well as late stages of the disease. We present a novel surface enhanced Raman spectroscopy (SERS)-based strategy for the detection of early stage atherosclerosis, based on the uptake of tagged gold nanoparticles by macrophages and subsequent detection by means of SERS. The results presented here provide a basis for future in vivo studies in animal models.The workflow of tracing the SERS-active nanoparticle uptake by macrophages employing confocal Raman imaging.

Loss of Insulin Actions on Arterial Smooth Muscle Cells May Enhance Unstable Atherosclerotic Plaque Formation

Formation of unstable atherosclerotic plaque, a major cause of cardiovascular mortality, is accelerated in insulin resistance and diabetes. Previous studies have suggested that endothelial dysfunction and systemic hyperlipidemia due to loss of insulin actions can accelerated its formation. However, the mechanism for insulin resistance to accelerate the various pathologies of unstable plaque, such as decreases in VSMC and extra cellular matrix (ECM) and increased inflammatory cells, have not been defined. Since insulin actions on the vascular wall are diminished in insulin resistant states, we assessed the loss of insulin action in VSMC and its effect on the formation of atherosclerotic plaque. Insulin receptor (IR) was specifically deleted from VSMC by breeding SM22 a promoter Cre and IR Flox mice to produce SMIRKO mice which were mated with ApoE-/- mice to generate SMIRKO/ ApoE-/- mice. Cultured VSMC from SMIRKO/ApoE-/- mice showed decreased insulin signaling and stimulated proliferation by &amp;gt;50%, but not to PDGF. Weight, blood pressure, glucose, and systemic insulin tolerance were comparable between ApoE-/- and SMIRKO/ApoE-/- mice; which were fed with normal chow to mimic pathophysiological hyperlipidemia encountered clinically. Surprisingly, SMIRKO/ ApoE-/- mice developed significantly more atherosclerotic aortic plaques (Sudan IV staining for lipid content) compared to ApoE-/- mice with parallel increases of macrophage content and inflammatory cytokines such as IL18 and ICAM1. In contrast, SMC as measured by SM22α staining was decreased with elevation of necrotic plaques (p&amp;lt;0.05). Further, proliferative index of VSMC as measured by Ki67 staining and expression of hyaluronan synthase-2 were decreased. Thus, surprisingly, the loss of insulin’s specific actions on VSMC to increase proliferation increased inflammatory cell influx as observed in insulin resistance, may accelerated formation of unstable plaques in diabetes. Disclosure Q. Li: None. J. Fu: None. K. Park: None. C. Rask-Madsen: Research Support; Self; Novo Nordisk A/S. G.L. King: Research Support; Self; Sanofi-Aventis.

Activatable fluorescence imaging of macrophages in atherosclerotic plaques using iron oxide nanoparticles conjugated with indocyanine green

Background and aimsMacrophages are key factors in the formation of unstable atherosclerotic plaques, which may be identified through macrophage imaging. We tested whether activatable fluorescence probes of iron oxide nanoparticles (IONPs) conjugated with indocyanine green (ICG) (IONP-ICG), consisting of biocompatible reagents, can visualize macrophages present in atherosclerotic plaques. MethodsIONP-based probes conjugated with different numbers of ICG molecules were synthesized. Six-week-old spontaneously hyperlipidemic (SHL) mice were fed either a Western or normal diet for 14 weeks, and were intravenously injected with IONP-ICG (55.8 mg Fe/kg). Aortas were harvested 48 h later, and aortas containing atherosclerotic plaques were imaged. ResultsPhantom imaging studies using IONP-ICG solution demonstrated that the addition of surfactants to IONP-ICG solutions yielded fluorescence activation. Incubation of macrophages with IONP-ICG led to internalization of IONP-ICG and near infrared fluorescence (NIRF) activation. In NIRF imaging studies, intense fluorescence signals were clearly visible primarily at the margins of atherosclerotic plaques, and relatively weak signals were evident inside the plaques, demonstrating the feasibility of detection of NIRF signals at atherosclerotic plaques. In the quantitative evaluation of NIRF, administration of a probe conjugated with more ICG molecules led to a significant increase in the NIRF signal, indicating that probes with greater numbers of ICG molecules are effective for sensitive NIRF detection. SHL mice given a low-cholesterol normal diet showed a significantly lower NIRF signal compared with mice given the Western diet. Histologically, NIRF signals in atherosclerotic plaques strongly correlated with the location of macrophages, suggesting the possibility of NIRF macrophage imaging using IONP-ICG. ConclusionsLocalization of macrophages in atherosclerotic plaques may be achieved using the activatable NIRF probe, IONP-ICG.

SINGLE AND MULTIPLE ISCHEMIC BRAIN MICROLESIONS AFTER CAROTID ARTERY STENTING

Aim. To identify most probable cardiovascular predictors of periprocedural ischemic brain microlesions after carotid artery stenting (CAS) accounting its presumable pathogenesis. Material and methods. 84 patients with carotid artery stenosis undergoing CAS in a specialized medical center were examined. Diffusion-weighted imaging (DWI) magnetic resonance imaging was performed in all patients before and after intervention. Results. Among selected patients aged 40 to 83 years (mean age of 60.6Ѓ}3.9 years, male 80.95%) 39 (46.4%) patients had new ischemic brain microlesions after CAS, differently located. Among all patients (n=84) microlesion count correlated with age (γ=0.243; p<0.01), preprocedural hemoglobin level (γ=-0.278; p<0.01), systolic blood pressure (SBP) level before CAS (γ=0.190; p<0.05) and diastolic blood pressure (DBP) level 1 hour after CAS (γ=-0.201; p<0.05). In patients with microlesions their count (n=39) correlated with SBP and DBP levels 15 min after CAS (γ=-0.370; p<0.01 and γ=-0.369; p<0.01, respectively), percentage of SBP and DBP levels decrease during CAS (γ=0.404; p<0.01 and γ=0.458; p<0.001, respectively), SBP level 24 h after CAS (γ=-0.272; p<0.05) and body mass index (γ=-0.260; p<0.05). Patients with multiple microlesions (n=25) differed from patients without lesions (n=45) older age (67.0 [64.0; 77.0] vs 64.0 [60.0; 70.0], p<0.05), lower preprocedural hemoglobin level (130.9Ѓ}14.5 vs 139.5Ѓ}13.6, p<0.01), lower percentage of smokers (32.0% vs 57.8%, p<0.05), previous ipsilateral stroke (36.0% vs 13.3%, p<0.05) and persistent periprocedural arterial hypotension (12.0% vs 2.2%, p<0.05). These patients with multiple microlesions had more significant DBP level decrease (17.0 [10.0; 25.0] vs 6.5 [1.3; 11.8], p<0.05) compared with patients with single lesions (n=14). In the group of patients with single brain microlesion, unstable (71.4% vs 40.0%, p<0.05) and calcified (64.3% vs 28.0%, p<0.05) atherosclerotic plaques were seen more often compared with patients with multiple lesions. Patients with single brain microlesion differed from patients without lesions greater frequency of calcified atherosclerotic plaques (64.3% vs 31.1%, p<0.05), usage of proximal embolic protection devices (21.4% vs 0.0% p<0.01) and predilatation (35.7% vs 13.3%, p<0.05), perioperative neurological symptoms (21.4% vs 4.4%, p<0.05, and higher SBP levels during 24 h after CAS (mean values 137-122 mm Hg vs 120-112 mm Hg, p<0.05). Conclusion. Single microlesion is associated with unstable or calcified plaques and CAS technical complexities. Multiple microlesions may be associated with periprocedural hemodynamic instability and cerebral hypoperfusion risk factors.

Abstract 661: Regulation of CCL2 Expression in Vascular Endothelial Cells by a Long Noncoding RNA

Vascular inflammation is a critical driver of chronic diseases such as atherosclerosis. A network of NF-κB-dependent leukocyte adhesion molecules and chemokines are induced in endothelial cells (ECs) in response to inflammatory mediators. This includes chemokine (C-C motif) ligand 2 ( CCL2 ), which contributes to atherosclerosis by recruiting monocytes to the endothelium. Recently, long noncoding RNAs (lncRNAs) have been implicated in regulating gene expression through epigenetic mechanisms, but lncRNAs remain poorly studied in the context of vascular inflammation and NF-kB pathway regulation. LncRNAs are frequently retained in the nucleus where they interact with chromatin remodelling complexes to modulate the expression of neighboring protein-coding genes. Hence, identifying NF-kB-regulated neighboring mRNA-lncRNA pairs in vascular endothelial cells may uncover functional lncRNAs that play a role in fine-tuning the expression of their neighboring inflammatory genes. The Arraystar human lncRNA microarray V3 was employed to identify differentially expressed lncRNAs and mRNAs in ECs stimulated with the pro-inflammatory cytokine, IL-1β. Neighboring IL-1β-regulated mRNA-lncRNA pairs demonstrated a larger magnitude of mRNA induction than mRNAs lacking a neighboring lncRNA. This phenomenon was associated with shared regulatory elements and localization within the same topologically associated domain. Follow-up analysis was performed on the nuclear-enriched, lncRNA-CCL2 , which is transcribed through a super-enhancer near CCL2 . Both lncRNA-CCL2 and CCL2 responded to the same inflammatory stimuli. Similar to CCL2 , lncRNA-CCL2 transcript was elevated in unstable human atherosclerotic plaques. Knockdown of lncRNA-CCL2 decreased CCL2 mRNA levels in multiple EC cell lines, but had no effect on other inflammatory genes or distal CCL genes. Hence, our approach has uncovered neighboring IL-1β-regulated mRNA-lncRNA pairs and identified a novel functional lncRNA, lncRNA-CCL2 .

AMPKα inactivation destabilizes atherosclerotic plaque in streptozotocin-induced diabetic mice through AP-2α/miRNA-124 axis.

Hyperglycemia reduced collagen synthesis, leading to the formation of unstable atherosclerotic plaque induced by collar placement around carotid in apolipoprotein E knockout mice. Hyperglycemia destabilizes atherosclerotic plaque in vivo through an AMPKα/AP-2α/miRNA-124/P4Hα1-dependent collagen synthesis. Metformin functions as a stabilizer of atherosclerotic plaque to reduce acute coronary accent.

Ultra-rapid progression of coronary artery disease or undiagnosed unstable plaque? A brief review from a case report

Coronary artery disease rarely manifests itself in the first decades of life, which explains why this population is underrepresented in clinical studies. The mechanisms and natural history of the disease seem to differ between this population and older patients. Recent studies suggest a more rapid disease progression in youth, presenting more unstable atherosclerotic plaques, although this correlation has yet to be proven. In this paper, we present the case of a 41-year-old man who presented with a non-ST elevation myocardial infarction, with percutaneous coronary intervention of the culprit lesion (70-90% lesion at bifurcation of the circumflex artery with the first marginal obtuse artery and a sub-occlusive lesion of the ramus intermedius). There was also a non-significant lesion (estimated at 30%) located in the left anterior descending coronary artery. Ten days after discharge, the patient suffered another non-ST elevation myocardial infarction. The coronary angiography revealed a surprising sub-occlusive lesion of the left anterior descending coronary artery. Regarding this case, the authors reviewed the literature on the pathophysiology of rapidly progressive coronary artery disease and the approach for non-significant lesions in patients with acute coronary syndrome, especially in the younger population.

Palmitate induces glycosylation of cyclooxygenase-2 in primary human vascular smooth muscle cells.

Vascular basal cyclooxygenase-2 (COX-2) expression and activity can be induced by endotoxin, hypoxia, or ischemia. During vascular pathologies such as atherosclerosis, increases in COX-2 activity result in prostanoid production, a contributor to the development and progression of vascular inflammation leading to unstable atherosclerotic plaques and increased risk for thrombotic events. Recent studies demonstrate that select free fatty acids, such as palmitate, can act as proinflammatory mediators. However, the effect of palmitate on COX-2 expression and activity, and its impact on the development and progression of vascular inflammation, are not well elucidated. We investigated the effect of palmitate on COX-2 expression and function in human vascular smooth muscle cells. Cells were treated with palmitate, COX-2 protein levels were assessed using Western analysis, and activity was assessed via ELISA. We observed that palmitate dose-dependently increased COX-2 levels and specifically enhanced band intensity of the COX-2 74 kDa band (slowest migrating band). This response was attenuated by N-linked glycosylation inhibition, suggesting that palmitate impacts expression of the fully activated glycoform of COX-2. Palmitate-induced increases in COX-2 levels correlated with an increase in prostaglandin E2 production that was also attenuated by a glycosylation inhibitor. Additionally, palmitate altered cell morphology and increased cell density which were reversed by selective COX-2 inhibition. Thus, we conclude that palmitate acts on COX-2 by two separate mechanisms of action in human vascular smooth muscle. It elicits dose-dependent increases in COX-2 protein expression and modulates regulation of COX-2 activity via modification of posttranslational glycosylation.