Anti-atherosclerotic Therapy Research Articles

A green and highly efficient method to deliver hydrophilic polyphenols of Salvia miltiorrhiza and Carthamus tinctorius for enhanced anti-atherosclerotic effect via metal-phenolic network

Salvia miltiorrhiza and Carthamus tinctorius are traditional Chinese medicines that have been widely used for the treatment of cardiovascular disease. Salvianic acid A (SAA), salvianic acid B (SAB), protocatechuic aldehyde (PCA) and hydroxysafflor yellow A (HSYA) are the major hydrophilic polyphenols of Salvia miltiorrhiza and Carthamus tinctorius, all of which have been documented as active compounds for the prevention and treatment of atherosclerosis (AS). However, high aqueous solubility, low permeability and poor stability properties of the four hydrophilic polyphenols might influence their bioavailability and thus hinder their clinical potential. In this work, we introduced a green and highly efficient method for the efficient delivery of the four hydrophilic components via metal-phenolic network. The four coordination polymers of SAA, SAB, PCA and HSYA were successfully fabricated, and confirmed by UV–vis, FTIR, XPS, ICP-MS and dynamic light scattering analysis. We found all of them displayed potent antioxidant activity, good biocompatibility and stability. Impressively, the four coordination polymers showed remarkably enhanced anti-atherosclerotic effect compared with free drugs. Collectively, metal-phenolic network-based coordination polymer might show great potential for safe and efficient delivery of the hydrophilic polyphenols of Salvia miltiorrhiza and Carthamus tinctorius for anti-atherosclerotic therapy.

Irisin Suppresses Nicotine-Mediated Atherosclerosis by Attenuating Endothelial Cell Migration, Proliferation, Cell Cycle Arrest, and Cell Senescence.

Atherosclerotic disease has become the major cause of death worldwide. Smoking, as a widespread independent risk factor, further strengthens the health burden of atherosclerosis. Irisin is a cytokine that increases after physical activity and shows an atheroprotective effect, while its specific mechanism in the process of atherosclerosis is little known. The reversal effect of irisin on intimal thickening induced by smoking-mediated atherosclerosis was identified in Apoe–/– mice through the integrin αVβ5 receptor. Endothelial cells treated with nicotine and irisin were further subjected to RNA-seq for further illustrating the potential mechanism of irisin in atherosclerosis, as well as the wound healing assays, CCK-8 assays, β-gal staining and cell cycle determination to confirm phenotypic alterations. Endothelial differential expressed gene enrichment showed focal adhesion for migration and proliferation, as well as the P53 signaling pathway for cell senescence and cell cycle control. Irisin exerts antagonistic effects on nicotine-mediated migration and proliferation via the integrin αVβ5/PI3K pathway. In addition, irisin inhibits nicotine-mediated endothelial senescence and cell cycle arrest in G0/G1 phase via P53/P21 pathway. This study further illustrates the molecular mechanism of irisin in atherosclerosis and stresses its potential as an anti-atherosclerotic therapy.

Acid Sphingomyelinase Decreases Atherosclerotic Plaque Stability Monitored with Molecular Imaging

Background: Acid sphingomyelinase (ASM) promotes atherogenesis and acute cardiovascular events. We previously demonstrated ASM inhibitor desipramine attenuated oxidized-LDL induced macrophage apoptosis in vitro. Here, we aim to determine whether ASM mediated apoptosis in plaque and improve stability in vivo. Methods: In this study, rabbits with abdominal aorta balloon injury and 12-week high-cholesterol diet (HCD) were used to simulate atherosclerotic plaque model. Atherosclerotic rabbits received oral administration of saline (Control group), atorvastatin (Ator group), or desipramine (DES group). ASM activity and ceramide level were measured by ultra-performance liquid chromatography (UPLC). Plaque morphology was assessed by histochemistry and immunohistochemistry. Apoptosis was evaluated by SPECT/CT imaging of 99mTc-duramycin uptake and TUNEL Results: We found that increasing ASM activity and ceramide level in atherosclerotic rabbits was abated by additional atorvastatin and desipramine treatment. Meanwhile, the DES and Ator groups were similar with regard to plaque stability, with smaller plaque size, areas of macrophages, higher smooth muscle cell content, and decreased apoptosis and matrix metalloproteinase (MMP) activities relative to the Control group. 99mTc-duramycin uptake of rabbit aorta was significantly higher in Control than in Normal group, while it was reduced by desipramine and atorvastatin administration. Moreover, uptake of 99mTc-duramycin positively correlated with apoptotic cell number, macrophage infiltration and plaque instability. Conclusion: The present study demonstrated that desipramine exerted plaque-stabilizing effects partially by suppressing apoptosis and MMP activity in rabbit model. And 99mTc-duramycin SPECT/CT imaging allowed noninvasively monitoring atherosclerotic disease and evaluating anti-atherosclerotic therapy. Funding Information: This work was supported by grants from the National Natural Science Foundation of China (No. 81901784 to ZM, No. 81170261 to ZGG). Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics Approval Statement: All animal protocols were approved by the Committee of Animal Care and Use at Xiangya Hospital, Central South University, China. All procedures were conducted to minimize the number of animals used and their suffering.

Inhibition of Rac1 GTPase Decreases Vascular Oxidative Stress, Improves Endothelial Function, and Attenuates Atherosclerosis Development in Mice.

Aims: Oxidative stress and inflammation contribute to atherogenesis. Rac1 GTPase regulates pro-oxidant NADPH oxidase activity, reactive oxygen species (ROS) formation, actin cytoskeleton organization and monocyte adhesion. We investigated the vascular effects of pharmacological inhibition of Rac1 GTPase in mice.Methods and Results: We treated wild-type and apolipoprotein E-deficient (ApoE−/−) mice with Clostridium sordellii lethal toxin (LT), a Rac1 inhibitor, and assessed vascular oxidative stress, expression and activity of involved proteins, endothelial function, macrophage infiltration, and atherosclerosis development. LT-treated wild-type mice displayed decreased vascular NADPH oxidase activity and ROS production. Therapeutic LT doses had no impact on behavior, food intake, body weight, heart rate, blood pressure, vascular and myocardial function, differential blood count, and vascular permeability. ApoE−/− mice were fed a cholesterol-rich diet and were treated with LT or vehicle. LT treatment led to decreased aortic Rac1 GTPase activity, NADPH oxidase activity and ROS production, but had no impact on expression and membrane translocation of NADPH oxidase subunits and RhoA GTPase activity. LT-treated mice showed improved aortic endothelium-dependent vasodilation, attenuated atherosclerotic lesion formation and reduced macrophage infiltration of atherosclerotic plaques. Concomitant treatment of cholesterol-fed ApoE−/− mice with LT, the specific synthetic Rac1 inhibitor NSC 23766 or simvastatin comparably reduced aortic Rac1 activity, NADPH oxidase activity, oxidative stress, endothelial dysfunction, atherosclerosis development, and macrophage infiltration.Conclusions: These findings identify an important role of the small GTPase Rac1 in atherogenesis and provide a potential target for anti-atherosclerotic therapy.

Platelet-derived extracellular vesicles to target plaque inflammation for effective anti-atherosclerotic therapy

Atherosclerosis is a kind of chronic inflammatory diseases characterized by dysfunction of local immune responses. Here we engineer platelet-derived extracellular vesicles (PEVs) to load MCC950, an NLRP3-inflammasome inhibitor, for atherosclerosis-targeted therapy. PEVs which are readily collected from the activated platelets selectively bind multiple cell types associated with the formation of atherosclerotic plaque in vivo. Intravenous administration of MCC950-PEVs could significantly reduce the formation of atherosclerotic plaques, lower the local inflammation and inhibit proliferation of macrophages and T cells at the plaque site compared with free drug administration in ApoE-KO mice. Our strategy suggests the promise of PEVs for targeted drug delivery for treatment of atherosclerosis.

Subcellular anti-atherosclerotic therapy: 5-aminolevulinic acid as a potential drug affecting dysfunctional mitochondria

Background and Aims: Earlier we found mithochondrial mutations associated with atherosclerosis. It is our assumption that elimination of mitochondria burdened with such mutations may be a novel approach to anti-atherosclerotic therapy. As a promising agent, we consider 5-aminolevulinic acid (5-ALA). Exogenous 5-ALA causes excessive accumulation of protoporfyrine IX (PpIX). PpIX is produced in mitochondria from 5-aminolevulinic acid (5-ALA) in course of heme synthesis cascade. In this work we studied 5-ALA-induced PpIX accumulation on mutation-bearing cybrid cell lines.

Twenty-year survival of patients with atherosclerotic non-obstructive coronary plaques

Abstract Background Atherosclerotic non-obstructive coronary artery disease (NObCAD) is frequently observed in patients referred for coronary angiography. No available data exist for the long-term prognosis of NObCAD patients beyond 10 years. Purpose We sought to compare the 15- and 20-year survival among patients presenting with chronic stable angina who had smooth coronary vessels, NobCAD, and obstructive (ObCAD), on invasive coronary angiography. Methods Coronary angiography of 671 consecutive patients presented with suspected CAD were retrospectively evaluated from single center registry between January and December 1998 and linked to administrative databases for outcomes evaluation. No CAD, NobCAD, and ObCAD were defined as 0%, 1% to 49%, and ≥50% luminal narrowing in epicardial coronary artery, respectively. The 15- and the 20-year survival rates were compared by Kaplan-Meier curve and multivariate Cox proportional hazards regression was used to identify significant independent predictors of mortality. Results Of 613 individuals (78.7% men with median age of 55.6 (51.0–65.2) years), 74 (12.1%) had normal coronary arteries, 42 (6.9%) had NobCAD, and 497 (81%) had ObCAD. The 15- and the 20-year survival rates were 89%, 66.7%, 62.4% and 79.7%, 54.7%, 42,5% in patients with normal, NobCAD, and ObCAD, respectively, (P=0.050 for no versus NobCAD; P=0.001 for no versus ObCAD at 20-year), These angiographic severity categories showed a strong gradient (P<0.001) (Figure 1). At 15-year follow-up, both ObCAD (adjusted HR=2.42, 95% CI (1.21–4.85), p=0.013) and NobCAD patients (HR=2.65, 95% CI (1.15–6.11), p=0.023) showed higher mortality compared to no CAD group. Independent predictors of mortality were, obstructive CAD (HR=2.34, 95% CI (1.407–3.916), P=0.001 for no versus NobCAD; HR=1.93, 95% CI (1.0–3.72), P=0.050, for no versus obstructive CAD), and age at addmission (HR=1.06, 95% CI (1.04–1.07), P<0.001). Conclusion The result of this analysis highlighted the less benign course of NobCAD that carries a mortality risk similar to patients with ObCAD at 15-and at 20-year follow-up. These findings support the need for aggressive anti-atherosclerotic drug therapy in such individuals and underscore the necessary efforts to improve the risk stratification and management of patients with non-obstructive CAD. Funding Acknowledgement Type of funding source: None

Prospects for the Use of Sialidase Inhibitors in Anti-atherosclerotic Therapy.

The most typical feature of atherogenesis in humans at its early stage is the formation of foam cells in subendothelial arterial intima, which occurs as the consequence of intracellular cholesterol deposition. The main source of lipids accumulating in the arterial wall is circulating low-density lipoprotein (LDL). However, LDL particles should undergo proatherogenic modification to acquire atherogenic properties. One of the known types of atherogenic modification of LDL is enzymatic deglycosilation, namely, desialylation, which is the earliest change in the cascade of following multiple LDL modifications. The accumulating data make sialidases an intriguing and plausible therapeutic target, since pharmacological modulation of activity of these enzymes may have beneficial effects in several pathologies, including atherosclerosis. The hypothesis exists that decreasing LDL enzymatic desialylation may result in the prevention of lipid accumulation in arterial wall, thus breaking down one of the key players in atherogenesis at the cellular level. Several drugs acting as glycomimetics and inhibiting sialidase enzymatic activity already exist, but the concept of sialidase inhibition as an anti-atherosclerosis strategy remains unexplored to date. This review is focused on the potential possibilities of the repurposing of sialidase inhibitors for pathogenetic anti-atherosclerotic therapy.

Impact of Mitochondrial DNA Mutations on Carotid Intima-Media Thickness in the Novosibirsk Region.

The search for markers of predisposition to atherosclerosis development is very important for early identification of individuals with a high risk of cardiovascular disease. The aim of the present study was to investigate the association of mitochondrial DNA mutations with carotid intima-media thickness and to determine the impact of mitochondrial heteroplasmy measurements in the prognosis of atherosclerosis development. This cross-sectional, population-based study was conducted in 468 subjects from the Novosibirsk region. It was shown that the mean (carotid intima-media thickness) cIMT correlated with the following mtDNA mutations: m.15059G>A (r = 0.159, p = 0.001), m.12315G>A (r = 0.119; p = 0.011), m.5178C>A (r = 0.114, p = 0.014), and m.3256C>T (r = 0.130, p = 0.011); a negative correlation with mtDNA mutations m.14846G>A (r = −0.111, p = 0.042) and m.13513G>A (r = −0.133, p = 0.004) was observed. In the linear regression analysis, the addition of the set of mtDNA mutations to the conventional cardiovascular risk factors increased the ability to predict the cIMT variability from 17 to 27%. Multi-step linear regression analysis revealed the most important predictors of mean cIMT variability: age, systolic blood pressure, blood levels of total cholesterol, LDL and triglycerides, as well as the mtDNA mutations m.13513G>A, m.15059G>A, m.12315G>A, and m.3256C>T. Thus, a high predictive value of mtDNA mutations for cIMT variability was demonstrated. The association of mutation m.13513G>A and m.14846G>A with a low value of cIMT, demonstrated in several studies, represents a potential for the development of anti-atherosclerotic gene therapy.

Novel Approaches to Anti-atherosclerotic Therapy: Cell-based Models and Herbal Preparations (Review of Our Own Data).

Atherosclerosis is a chronic arterial disease characterized by vascular inflammation, accumulation of lipids in the arterial wall, and formation and growth of atherosclerotic plaques followed by ischemia. In subclinical atherosclerosis, cholesterol retention in subendothelial cells leads to induction of local inflammation, generation of foam cells and lesion formation, followed by a chain of other pathogenic events. Atherosclerotic progression can frequently be fatal, since plaque rupture may lead to thrombosis and acute events, such as myocardial infarction, stroke and sudden death. Traditional anti-atherosclerotic therapy is mainly focused on improving the blood lipid profile and does not target various stages of plaque progression. Obviously, treating the disease at initial stages is better than beginning treatment at advanced stages and, in that regard, current atherosclerosis management can be improved. Cholesterol retention is an important component of atherogenesis that precedes plaque formation. Therapeutic targeting of cholesterol retention may be beneficial for preventing further atherogenic progression. For this purpose, we suggest using herbal preparations due to good tolerability and suitability for long-lasting treatment. We developed test systems based on cultured human intimal aortic cells for rapid screening of potential anti-atherogenic drugs. With the help of these test systems, we selected several natural substances with significant anti-atherogenic activity and further use these compounds to prepare herbal preparations for anti-atherosclerotic therapy. These preparations were clinically tested and showed good safety and a potent anti-atherogenic potential.

Atheroprotective Effects Induced by Glyceraldehyde‐3′‐phosphate Dehydrogenase (GAPDH) in Murine Model of Atherosclerosis

GAPDH was shown to protect smooth muscle cells (SMC) against oxidant‐induced apoptosis via stimulation of DNA repair. GAPDH levels were reduced in atherosclerotic plaque SMC and therefore we hypothesized that SMC‐specific GAPDH overexpression will reduce atherosclerosis. GAPDH protein levels were increased >2‐fold (P<0.05) in aortas isolated from Apoe‐null mice with SM22α promoter‐driven GAPDH overexpression (SM‐GAPDH mice) compared to Apoe‐null controls. SM‐GAPDH mice have BW and BP similar to control. Aortic circumference, lumen area and media area were not changed by GAPDH overexpression. SMC GAPDH did not change pulse wave velocity (SM‐GAPDH, 1.1±0.1 m/s, control, 1.2±0.3 m/s) (ultrasound imaging) as well as endothelium‐dependent and ‐independent vascular responses to PE, Ach or SNP (organ chamber assay with thoracic aortic rings). High‐cholesterol fed SM‐GAPDH had reduced atherosclerotic burden (H&E‐stained aortic valve cross‐sections: 28±3% decrease, P<0.05), elevated plaque SMC levels (IHC for a‐SM actin, 3.1‐fold increase, P<0.01; IHC for calponin, 3.8‐fold increase, P<0.05), increased plaque collagen (Trichrome, 2.1‐fold increase, P<0.05), reduced plaque SMC apoptosis (TUNEL assay with IHC for calponin, 3.2‐fold decrease, IHC for cleaved caspase‐3, 2.6‐fold decrease both are P<0.05) without changes in macrophages (IHC with Mac3, P=NS). Aortas isolated from SM‐GAPDH have increased expression of Ape1 endonuclease (major DNA repair enzyme, 31±5% increase, P<0.05), reduced cleaved PARP (apoptotic marker, 74±12% decrease, P<0.001) and decreased oxidative DNA damage (AP sites assay, 2.5‐fold decrease, P<0.05; pSer139 histone H2AX, 33±3% decrease, P<0.05) compared to controls. Plaques in SM‐GAPDH mice had thicker SMC‐rich fibrous plaque cap (3.5‐fold increase, P<0.05) and decreased area of necrotic core (1.8‐fold reduction, P<0.05) suggesting enhanced plaque stability. These data taken together with our in vitro findings indicate that Ape1 upregulation mediates GAPDH effect on DNA and apoptosis. Our results suggest that stimulation of GAPDH/Ape1 axis is a novel potential anti‐atherosclerotic therapy.Support or Funding InformationStudy was supported by NIH/NHLBI 1R01HL142796‐01A1 (SS), AHA Grant‐in‐aid (SS) and NIH/NHLBI 7R01HL070241 (PD).

P4498Subcellular anti-atherosclerotic therapy: an approach to elimination of dysfunctional mithohondria by photodynamic therapy

Abstract Photo-theranostics is a therapeutic and diagnostic approach that uses photosensibilization. This approach makes part of the medicine of the future – subcellular therapy. Photo-theranostics targets cells and tissues that are affected by pathological changes inducing apoptotic cell death. However, the approach allows targeting cellular organelles, if the photo-sensitizing agent is accumulated selectively. Such selectivity can result from the organelle's functional state, as in the case of mitochondria affected by mitochondrial genome abnormalities. For instance, some pro-atherogenic mitochondrial DNA (mtDNA) mutations can lead to mitochondrial dysfunction Some photo-sensitizing agents accumulate selectively in mitochondria making the photodynamic targeting efficient enough. For instance, protoporfyrine IX (PpIX), which is widely used in clinical practice, is produced from a prodrug 5-aminolevulinic acid (5-ALC) in course of heme synthesis cascade in the mitochondria. Exogenous 5-ALC causes excessive formation of PpIX, which cannot be efficiently processed by ferrochelatase and accumulates in the cells. PpIX accumulation directly depends on the cell's metabolic activity. We studied 5-ALC-induced PpIX accumulation on cybrid lines derived from thrombocytes with mutation-bearing mitochondria and THP-1 monocytes devoid of mitochondria. We used 3 cybrid lines and 2 THP-1 monocyte cultures cultured independently by different research groups. The mitochondrial functional state was assessed by fluorescence intensity of mitochondrial dye MitoTracker™ Orange CMTMRos (Thermo Fisher Scientific). Measurement of fluorescence was performed by laser scanning microscopy with spectral unmixing. MitoTracker and PpIX dyes were excited with a 561 nm laser, and fluorescence was measured at 570–750 nm wavelength. The signal was spectrally unmixed to obtain separate MitoTracker and PpIX signals. Individual cells areas were traced on microscopic images taken under identical conditions, and mean values of PpIX and MitoTracker fluorescence intensity were obtained for each cell. We found that PpIX accumulation varied significantly from cell to cell within cell populations. Cybrid lines had increased PpIX accumulation in comparison with original THP-1 monocyte lines. A positive correlation between PpIX amount and mitochondrial membrane potential was observed (Figure 1). Therefore, selective elimination of dysfunctional (mutated) mitochondria can be achieved by adjusting laser intensity sufficient to induce photodynamic destruction of the organelles, while normal mitochondria and the cells as a whole should be preserved at the used light intensities. This work was supported by the Russian Science Foundation (Grant #19-15-00010). Acknowledgement/Funding Russian Science Foundation (Grant # 19-15-00010)

P4144Pericyte-specific deletion of ninjurin1 induces abnormal vasa vasorum formation and persistent inflammation and enhances intimal hyperplasia of injured vasculature

Abstract Introduction Atherosclerosis is fundamental pathological condition inducing severe ischemic diseases such as ischemic heart disease and stroke. New concept has been proposed that adventitial abnormalities including enhanced malformation of adventitial microvessel, vasa vasorum are associated with development and vulnerability of atherosclerotic plaque. However, the role of vasa vasorum malformation in vascular remodelling has not been fully clarified. We recently reported that Ninjurin1 (Ninj1) is critical adhesion molecule to associate pericytes (PCs) with endothelial (EC) tubes to form stabilized mature neovessels. The purpose of this study is to examine if formation of adventitial microvessels affects the vascular remodelling of injured vessels using PCs-specific Ninj1 deletion mouse model. Methods and results Deletion of Ninj1 gene in NG2-positive PCs was induced by tamoxifen (Tam)-treated NG2-CreER/Ninj1loxp mice (Ninj1KO, n=9). Tam-treated-NG2-CreER (n=4) or Tam-nontreated NG2-CreER/Ninj1loxp (n=5) mice were used as Control (Ct1 and Ct2 respectively). Femoral arteries were injured by insertion of coiled wire. After 4 weeks of surgery, blood vessels were stained by venous injection of FITC-lectin. Isolated femoral arteries were fixed with paraformaldehyde and decolorized with CUBIC reagent. Wire-mediated vessel injury induced intimal hyperplasia, as assessed by intima/media (I/M) ratio and accordingly grew microvessels in adventitia. Intimal hyperplasia in Ninj1KO were significantly enhanced compared to Controls. Although there was no significant difference in total length of adventitial microvessels among three groups, extravasation of FITC-lectin from adventitial microvessels were significantly enhanced in Ninj1KO. The number of infiltrated macrophages in adventitia were increased in Ninj1KO. Conclusion Deletion of Ninj1 in PCs contributes to formation of immature microvessels in adventitia of injured vasculature and to adventitial microbleeding, and subsequently enhances intimal hyperplasia. Ninj1 is an attractive target to normalize microvessels for anti-atherosclerotic therapy.

Rational Design of Lovastatin-Loaded Spherical Reconstituted High Density Lipoprotein for Efficient and Safe Anti-Atherosclerotic Therapy.

Reconstituted high density lipoprotein (rHDL) is a biomimetic nanoparticle with plaque targeting and anti-atherosclerotic efficacy. In this work, we report on a strategy to rational design of lovastatin (LOV)-loaded spherical rHDL (LOV-s-rHDL) for efficient and safe anti-atherosclerotic therapy. Briefly, three LOV-s-rHDLs were formulated with LOV/s-rHDL at ratios of 8:1, 10:1, and 15:1 upon their respective median-effect values ( Dm). The combined inhibitory effect between LOV and s-rHDL of different LOV-s-rHDL formulations on DiI-labeled oxLDL internalization was systemically investigated in RAW 264.7 cells based on the median-effect principle. Median-effect analysis demonstrated that the optimized LOV-s-rHDL was formulated with a ratio of 10:1 ( DmLOV: Dms-rHDL), in which LOV and s-rHDL carrier showed the best synergistic effect, presumably ascribed to their inhibitory effect on CD36 and SR-A expression according to the Western blot analysis. In vivo pharmacodynamics studies showed that the optimized LOV-s-rHDL displayed the most pronounced anti-atherosclerotic effect on decreasing plaque area and reducing the MMP level following an 8-week dosing regimen. In vivo atherosclerotic plaque targeting analysis revealed that s-rHDL had potent plaque targeting efficacy, probably owing to the interaction between apoA-I and scavenger receptor B-I. Furthermore, we observed that the optimized LOV-s-rHDL exhibited a favorable safety profile as evidenced by the results of a hemolysis assay, cell cytotoxicity study, and in vivo safety test. Collectively, the rational design of the biomimetic LOV-s-rHDL based on the median-effect analysis provides an efficient strategy to achieve a synergistic and safe anti-atherosclerotic therapy.

Subcellular anti-atherosclerotic therapy

Vessel Plus is an open acccess journal, which publishes articles related to vascular diseases, including acute respiratory distress syndrome, aneurysm, atherosclerosis, hypertension, stroke, peripheral vascular or pulmonary vascular diseases, etc.

Screening of biopolymeric materials for cardiovascular surgery toxicity-Evaluation of their surface relief with assessment of morphological aspects of monocyte/macrophage polarization in atherosclerosis patients.

The morphotypes of human macrophages (MPh) were studied in the culture on nano-structured biopolymer substrates, made from polyhydroxyalcanoates (PHAs) of five various monomer compositions, followed by the solvent evaporation. Its surface relief, which was further in direct contact with human cells in vitro, was analyzed by atomic force microscopy (AFM) and scanning electron microscopy (SEM). It was shown, that the features of the micro/nano relief depend on the monomeric composition of the polymer substrates. Monocytes (MN) of patients with atherosclerosis and cardiac ischemia, undergoing stenting and conventional anti-atherosclerotic therapy, were harvested prior and after stenting. MN were isolated and cultured, with the transformation into MPh in direct contact with biopolymer culture substrates with different monomer composition and nano-reliefs, and transformed into MPh, in comparison with the same process on standard culture plastic. Sub-populations of cells with characteristic morphology in each phenotypic class were described, and their quantitative ratios for each sample of polymers were counted as an intermediate result in the development of "smart" material for cardiovascular devices. The results obtained allow us to assume, that the processes of MPh differentiation and polarization in vitro depend not only on the features of the micro/nano relief of biopolymer substrates, but also on the initial state of MN in vivo and general response of patients.

MULTIVESSEL CORONARY ARTERY ANEURYSMS PRESENTING AS MYOCARDIAL ISCHEMIA

SESSION TITLE: Cardiovascular Disease SESSION TYPE: Med Student/Res Case Report PRESENTED ON: 10/09/2018 07:30 AM - 08:30 AM INTRODUCTION: Aneurysmal disease of the coronary artery tree (CAA) is a rare condition with an incidence of 0.3-4.9% of patients undergoing coronary angiography. The majority of cases occur in the proximal segments of the epicardial arteries and typically involve only one artery [1]. Involvement of three coronary vessels or the left main coronary artery is particularly rare, found in only 3.5% of CAA patients [2]. Multi-vessel CAA can present as an ischemic coronary syndrome, and can be challenging to manage. CASE PRESENTATION: A 48 year old African American non-smoking female with history of Parry Romberg syndrome, hypertension, obesity, and chronic kidney disease presented with progressive, intermittent, non-exertional chest pain. EKG showed voltage criteria for left ventricular hypertrophy (LVH). Bedside echocardiogram showed moderate LVH and akinesis of the basal inferior myocardial segment. Initial troponin I was 0.7ng/mL, and rose to peak of 6.16ng/mL. She was given aspirin, clopidogrel, and intravenous heparin drip. Coronary angiography showed aneurysmal disease of the left main, left anterior descending, left circumflex, and right coronary arteries, without evidence of thrombus angiographically. There were diffuse mild luminal irregularities, and a discrete 90% stenosis of the proximal right posterior descending artery. Percutaneous intervention was not performed. The patient denied history of Kawasaki’s disease. Subsequent vascular evaluation included an MR angiogram of the head, chest, abdomen and pelvis which were negative. Antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibodies were all negative. C-reactive protein and erythrocyte sedimentation rate were mildly elevated (1.01mg/dL and 32mm/Hr respectively). Her lipid profile demonstrated LDL 114mg/dL. She was discharged with dual antiplatelet therapy and high intensity statin. At 3 month follow up, she reported occasional palpitations with no chest pain, and at one year follow up she reported no symptoms. DISCUSSION: CAA is typically atherosclerotic in origin, as in our patient, although other causes exist. Previously it was believed that atherosclerosis caused CAA by increased pressure and shear stress due to luminal narrowing; however, it is now postulated that it may be due to generalized endovascular inflammation [2]. There is no known association between Parry Romberg syndrome and atherosclerosis or CAA. Medical management of CAA is limited to anticoagulant, antiplatelet, and anti-atherosclerotic therapy. Consensus Indications for percutaneous or surgical interventions are limited given the rarity of the disease; however, they are typically reserved for symptomatic flow limiting disease or if there is high risk of rupture. CONCLUSIONS: CAA is a rare condition that may mimic myocardial ischemia on presentation. Treatment options for multi-vessel CAA are limited given the paucity of data on the disease. Reference #1: 1. Abou Sherif, S. et al. “Coronary Artery Aneurysms: A Review of the Epidemiology, Pathophysiology, Diagnosis, and Treatment.” Frontiers in Cardiovascular Medicine 4 (2017): 24. PMC. 17 Feb. 2018. Reference #2: 2. Mata, Karina M. et al. “Coronary Artery Aneurysms: An Update.” Novel Strategies in Ischemic Heart Disease, 2017. Dr.Umashankar Lakshmanadoss (Ed.) DISCLOSURES: No relevant relationships by Michael Berlowitz, source=Web Response No relevant relationships by Andrew Mehlman, source=Web Response

RAGE and TLRs as Key Targets for Antiatherosclerotic Therapy.

Receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) are the key factors indicating a danger to the organism. They recognize the microbial origin pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The primary response induced by PAMPs or DAMPs is inflammation. Excessive stimulation of the innate immune system occurs in arterial wall with the participation of effector cells. Persistent adaptive responses can also cause tissue damage and disease. However, inflammation mediated by the molecules innate responses is an important way in which the adaptive immune system protects us from infection. The specific detection of PAMPs and DAMPs by host receptors drives a cascade of signaling that converges at nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) and induces the secretion of proinflammatory cytokines, type I interferon (IFN), and chemokines, which promote direct killing of the pathogen. Therefore, signaling of these receptors' pathways also appear to present new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets for antiatherosclerotic therapy.

Novel LXR agonist inhibit atherosclerosis through cross-regulating cholesterol metabolism and inflammation

Aim: Liver X receptor (LXR) is associated with cholesterol metabolism and anti-inflammatory processes, and activation of LXR makes beneficial to anti-atherosclerotic therapy. However, existing agonists that target LXR are related to unwanted side effects. In our previous study, we identified a novel dual LXRα/ β agonist LA-09, which possessed a distinct predictive binding pattern for the LXR ligand-binding domain compared to TO901317. In this present study, we found LA-09 had anti-atherosclerotic effect through cross-regulating cholesterol metabolism and inflammation.

Correction to Fine Tuning of Core–Shell Structure of Hyaluronic Acid/Cell-Penetrating Peptides/siRNA Nanoparticles for Enhanced Gene Delivery to Macrophages in Antiatherosclerotic Therapy

Hyaluronic-acid (HA)-coated LOX-1-specific siRNA-condensed cell-penetrating peptide (CPP) nanocomplexes (NCs) were developed for targeted gene delivery to macrophages and suppression of lipid accumulation. The HA coating facilitated the accumulation of nanoparticles at leaky endothelium overexpressing CD44 receptors and was further degraded by hyaluronidase (HAase) intraplaques for exposing the naked CPP NCs and achieving the ultimate location into macrophages. The surface coating of HA was verified by the increased particle size, inverted zeta potential, and TEM images. The targeting mechanism was studied on the established injured endothelium–macrophage coculture system, which revealed that modification of higher molecular weight HA and higher HA coating density on NCs, termed as NPs-3, improved the intracellular uptake of nanoparticles by macrophages. Macrophages internalized NCs via caveolae-mediated endocytosis pathway. Moreover, NPs-3 exhibited better cellular drug efficacy in preventing macrophage-...