The Beneficial Impact of Zinc Supplementation on the Vascular Tissue of the Abdominal Aorta under Repeated Intoxication with Cadmium: A Study in an In Vivo Experimental Model.

In an in vivo rat model of human exposure to cadmium (Cd; 5 and 50 mg/L, 6 months), whether the supplementation with zinc (Zn; 30 and 60 mg/L, increasing its daily intake by 79% and 151%, respectively) protects against the unfavourable impact of this xenobiotic on the vascular tissue of the abdominal aorta was investigated. The treatment with Cd led to oxidative stress and increased the concentrations of pro-inflammatory interleukin 1ß (IL-1ß), total cholesterol (TC), triglycerides (TG), and endothelial nitric oxide synthase (eNOS) and decreased the concentration of anti-inflammatory interleukin 10 (IL-10) in the vascular tissue. Cd decreased the expression of intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), and L-selectin on the endothelial cells. The administration of Zn prevented most of the Cd-induced alterations or at least weakened them (except for the expression of adhesive molecules). In conclusion, Zn supplementation may protect from the toxic impact of Cd on the blood vessels and thus exert a beneficial influence on the cardiovascular system. The increase in the intake of Zn by 79% may be sufficient to provide this protection and the effect is related to the antioxidative, anti-inflammatory, and antiatherogenic properties of this essential element.

Baicalin attenuates angiotensin II-induced blood pressure elevation and modulates MLCK/p-MLC signaling pathway.

Scutellaria baicalensis Georgi is an extensively used medicinal herb for the treatment of hypertension in traditional Chinese medicine. Baicalin, is an important flavonoid in Scutellaria baicalensis Georgi extracts, which exhibits therapeutic effects on anti-hypertension, but its underlying mechanisms remain to be further explored. Therefore, we investigated the effects and molecular mechanisms of Baicalin on anti-hypertension. In vivo studies revealed that Baicalin treatment significantly attenuated the elevation in blood pressure, the pulse propagation and thickening of the abdominal aortic wall in C57BL/6 mice infused with Angiotensin II (Ang II). Moreover, RNA-sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified 537 differentially expressed transcripts and multiple enriched signaling pathways (including vascular smooth muscle contraction and calcium signaling pathway). Consistently, we found that Baicalin pretreatment significantly alleviated the Ang II induced constriction of abdominal aortic ring, while promoted NE pre-contracted vasodilation of abdominal aortic ring at least partly dependent on L-type calcium channel. In addition, Ang II stimulation significantly increased cell viability and PCNA expression, while were attenuated after Baicalin treatment. Moreover, Baicalin pretreatment attenuated Ang II-induced intracellular Ca2+ release, Angiotensin II type 1 receptor (AT1R) expression and activation of MLCK/p-MLC pathway in vascular smooth muscle cells (VSMCs). The present work further addressed the pharmacological and mechanistic insights on anti-hypertension of Baicalin, which may help better understand the therapeutic effect of Scutellaria baicalensis Georgi on anti-hypertension.

Factor Xa inhibitor rivaroxaban suppresses experimental abdominal aortic aneurysm progression via attenuating aortic inflammation.

OBJECTIVE: Rivaroxaban is a specific factor Xa (FXa) inhibitor for venous thromboembolism treatment. Recently, increasing evidence have reported the beneficial effects of rivaroxaban on treating cardiovascular disorders such as coronary and peripheral artery disease. However, its potential influence on abdominal aortic aneurysm (AAA) remains unclear. This study aims to investigate whether rivaroxaban treatment could attenuate experimental AAA progression and its related mechanisms. APPROACHES AND RESULTS: In human aneurysmal aorta, FXa protein expression was significantly upregulated. Further investigations identified a positive correlation among plasma FXa level, AAA severity (the maximal aortic diameter), and intra-aneurysmal thrombus percentage. In Ang II (angiotensin II)-infused ApoE-/- mice, the administration of high dose rivaroxaban (15 mg/kg/d) for 14 days significantly reduced the maximal aortic diameter, while low dose rivaroxaban (5 mg/kg/d) did not display such a protective role. Although rivaroxaban treatments reduced the incidence of AAA and thrombus formation, these differences did not reach statistical significance. Immunohistochemistry revealed a pronounced aortic remodeling including increased collagen content and enhanced elastin degradation in Ang II-induced AAAs, which was inhibited by high dose rivaroxaban treatment. Further analysis demonstrated that rivaroxaban exerted its protective effects by decreasing leukocyte infiltration, inflammatory cytokines expression, and matrix metalloproteinases (MMPs) expression in the aortic wall. The inhibitory effect of rivaroxaban on aneurysm development was also observed in calcium chloride-induced AAA model. Mechanistically, in human aortic endothelial cells, FXa stimulation increased the expression of inflammatory cytokines (interleukin (IL)-1ß, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesive molecules, which were all reversed by the cotreatment of rivaroxaban. Subsequent monocyte-endothelial cell interaction was enhanced after FXa stimulation and was alleviated by rivaroxaban cotreatment. In addition, FXa induced a significantly heightened expression of MMP2 in human aortic endothelial cells, which was ameliorated by rivaroxaban coadministration. CONCLUSIONS: Rivaroxaban attenuated both angiotensin II- and calcium chloride-induced abdominal aortic aneurysm (AAA) progressions, through inhibiting aortic remodeling and inflammation. Rivaroxaban could be a promising therapeutic agent in attenuating AAA development by counteracting FXa-induced aortic wall inflammation.

Vitamin D deficiency promotes large rupture-prone abdominal aortic aneurysms and cholecalciferol supplementation limits progression of aneurysms in a mouse model.

Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P<0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P<0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit.

BACKGROUND: Previous studies have indicated that the JAK/STAT signaling pathway is involved in modulating arterial adventitia inflammation response. In this study, we designed experiments to further investigate the effect of JAK2/STAT3/SOCS3 signaling in rabbit atherosclerosis process. METHODS: Atherosclerosis was induced in the abdominal arteries of rabbits by balloon injury of the aorta supplemented by the atherogenic diet. Simultaneously, in the process of atherosclerosis, animals underwent either ruxolitinib treatment or not for 12 weeks. At the end of the experimental period, all rabbits were sacrificed. The plaque areas in abdominal artery, the lipid burden of plaque and the calcium burden of plaque were detected by H&E staining, Oil Red O staining and Alizarin Red staining, respectively. In addition, rabbit plasma lipids and inflammatory cytokines were measured by biochemical test kits or ELISA kits. Finally, the expression and phosphorylation levels of JAK2/STAT3/SOCS3 pathway-related proteins were detected by RT-qPCR, western blot and immunohistochemistry assays. RESULTS: H&E staining and CT scan analysis showed that rabbit atherosclerosis model was constructed successfully. Ruxolitinib, an inhibitor of the Janus kinase 2 (JAK2), substantially reduced the area of atherosclerotic plaques in rabbits treated with high fat diet and balloon injury of the aorta. Moreover, ruxolitinib significantly decreased IL-6, IL-1ß, IFN-γ and TNF-α, but increased IL-10 and IL-17 levels in plasma of atherosclerotic rabbits. Additionally, ruxolitinib reduced plasma TC, TG and LDL-C contents and AIP value, while enhanced HDL-C level in atherosclerotic rabbits. Furthermore, we found that JAK2 and STAT3 phosphorylation were up-regulated in rabbits with atherosclerosis when compared with those of the control group, followed by the expression of SOCS3 was also increased due to the activation of JAK2 and STAT3. Interestingly, ruxolitinib could inactivate JAK2 and STAT3 pathway and decrease SOCS3 expression. CONCLUSION: Taken together, the inhibition of JAK2/STAT3/SOCS3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.

Association between dietary zinc intake and abdominal aortic calcification in US adults.

BACKGROUND: In animal studies, zinc supplementation inhibited phosphate-induced arterial calcification. We tested the hypothesis that higher intake of dietary zinc was associated with lower abdominal aortic calcification (AAC) among adults in the USA. We also explored the associations of AAC with supplemental zinc intake, total zinc intake and serum zinc level. METHODS: We performed cross-sectional analyses of 2535 participants from the National Health and Nutrition Examination Survey 2013-14. Dietary and supplemental zinc intakes were obtained from two 24-h dietary recall interviews. Total zinc intake was the sum of dietary and supplemental zinc. AAC was measured using dual-energy X-ray absorptiometry in adults ≥40 years of age and quantified using the Kauppila score system. AAC scores were categorized into three groups: no AAC (AAC = 0, reference group), mild-moderate (AAC >0-≤6) and severe AAC (AAC >6). RESULTS: Dietary zinc intake (mean ± SE) was 10.5 ± 0.1 mg/day; 28% had AAC (20% mild-moderate and 8% severe), 17% had diabetes mellitus and 51% had hypertension. Higher intake of dietary zinc was associated with lower odds of having severe AAC. Per 1 mg/day higher intake of dietary zinc, the odds of having severe AAC were 8% lower [adjusted odds ratio 0.92 (95% confidence interval 0.86-0.98), P = 0.01] compared with those without AAC, after adjusting for demographics, comorbidities and laboratory measurements. Supplemental zinc intake, total zinc intake and serum zinc level were not associated with AAC. CONCLUSIONS: Higher intake of dietary zinc was independently associated with lower odds of having severe AAC among noninstitutionalized US adults.

Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide.

AIMS: Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation. METHODS AND RESULTS: Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation. CONCLUSION: Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.

Green Tea Polyphenol Induced Mg2+-rich Multilayer Conversion Coating: Toward Enhanced Corrosion Resistance and Promoted in Situ Endothelialization of AZ31 for Potential Cardiovascular Applications.

As a promising biodegradable metallic material, magnesium (Mg) and its alloys have attracted special attention in the recent decade. However, challenges still remain due to its high corrosion rate and insufficient biocompatibility after implantation. In this work, we prepare a simple and versatile green tea phenol-metal induced multilayer conversion coating (Mg2+ incorporated epigallocatechin gallate (EGCG) coating) on magnesium alloys' (AZ31) substrate by layer-by-layer (LBL) method. The surface morphology results revealed that, with the incorporation of Mg2+, the as-formed EGCG/Mg coating was rich in phenol-Mg complex and presented more homogeneous and dense morphology, with far less cracks than the pure EGCG coating. The in vitro degradation rate and corrosion resistance were studied by electrochemical corrosion tests and monitoring of the changed pH value and hydrogen evolution, respectively, which revealed that the corrosion rate was effectively decreased compared to that of bare AZ31 after it was protected by EGCG/Mg coating. In vitro and ex vivo thrombogenicity test demonstrated the EGCG/Mg coatings presented an impressive improvement in decreasing the adhesion and activation of platelets and erythrocytes, in activated partial thromboplastin time (APTT), and in antithrombogenicity compared to those of bare AZ31. Owing to the mild degradation rate, in combination with the biological function of EGCG, enhanced endothelial cells' (ECs') adhesion and proliferation, suppressed smooth muscle cells' (SMCs') adhesion/proliferation, and inhibited cytokine release were observed on EGCG/Mg coated AZ31 alloy. Besides, the in vivo subcutaneous embedding experiment suggested that the EGCG/Mg coating performed more mild tissue response due to the improved corrosion resistance to the surrounding microenvironment. Moreover, for in vivo abdominal aorta assay, the EGCG/Mg coated AZ31 wire presented better corrosion resistance and enhanced re-endothelialization compared to bare AZ31 wire. These results suggested the potential of using green tea polyphenol induced Mg2+-rich multilayer conversion coating for enhanced corrosion protection and desired biocompatibility of biodegradable cardiovascular implants.

Fufang-Zhenzhu-Tiaozhi Capsule reduces restenosis via the downregulation of NF-kappaB and inflammatory factors in rabbits.

BACKGROUND: To investigate the effects of a Chinese herbal medicine Fufang-Zhenzhu Tiaozhi Capsule (FTZ) on restenosis and elucidate the mechanism of action. METHODS: A restenosis model was established by balloon rubbing the endothelium of the abdominal aorta followed by high fat diet. Rabbits were divided into blank control group, restenosis group, FTZ group (0.66 mg/kg/day), atorvastatin group (5 mg/kg/day) and FTZ + atorvastatin group (n = 8). Vascular stenosis was analyzed by X-ray. Serum levels of chemokines and cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were measured by ELISA. The levels of NF-κB, IκB-α, P-IκBα, IKK-α, and P-IKKα/ß from injured abdominal arteries were detected by Western blotting. RESULTS: Restenosis was induced successfully via abdominal artery balloon injuries and high fat diet. Restenosis was significantly decreased in FTZ group compared with restenosis group (P < 0.05). FTZ group had markedly reduced serum lipid levels (P < 0.05). In addition, the levels of TNF-α, IL-1, IL-6, IL-8, IL-12, ICAM-1 and MCP-1 decreased by FTZ treatment (P < 0.05). The expression of NF-κB in the atherosclerotic lesions was significantly attenuated in FTZ group (P < 0.05). CONCLUSION: FTZ could reduce restenosis via reducing NF-κB activity and inflammatory factor expression within the atherosclerotic lesion in a rabbit restenosis model. FTZ may be a new therapeutic agent for restenosis.

Comparison of efficacy of SHENQI compound and rosiglitazone in the treatment of diabetic vasculopathy analyzing multi-factor mediated disease-causing modules.

Atherosclerosis-predominant vasculopathy is a common complication of diabetes with high morbidity and high mortality, which is ruining the patient's daily life. As is known to all, traditional Chinese medicine (TCM) SHENQI compound and western medicine rosiglitazone play an important role in the treatment of diabetes. In particular, SHENQI compound has a significant inhibitory effect on vascular lesions. Here, to explore and compare the therapeutic mechanism of SHENQI compound and rosiglitazone on diabetic vasculopathy, we first built 7 groups of mouse models. The behavioral, physiological and pathological morphological characteristics of these mice showed that SHENQI compound has a more comprehensive curative effect than rosiglitazone and has a stronger inhibitory effect on vascular lesions. While rosiglitazone has a more effective but no significant effect on hypoglycemic. Further, based on the gene expression of mice in each group, we performed differential expression analysis. The functional enrichment analysis of these differentially expressed genes (DEGs) revealed the potential pathogenesis and treatment mechanisms of diabetic angiopathy. In addition, we found that SHENQI compound mainly exerts comprehensive effects by regulating MCM8, IRF7, CDK7, NEDD4L by pivot regulator analysis, while rosiglitazone can rapidly lower blood glucose levels by targeting PSMD3, UBA52. Except that, we also identified some pivot TFs and ncRNAs for these potential disease-causing DEG modules, which may the mediators bridging drugs and modules. Finally, similar to pivot regulator analysis, we also identified the regulation of some drugs (e.g. bumetanide, disopyramide and glyburide etc.) which have been shown to have a certain effect on diabetes or diabetic angiopathy, proofing the scientific and objectivity of this study. Overall, this study not only provides an in-depth comparison of the efficacy of SHENQI compound and rosiglitazone in the treatment of diabetic vasculopathy, but also provides clinicians and drug designers with valuable theoretical guidance.

Dietary DNA Attenuates the Degradation of Elastin Fibers in the Aortic Wall in Nicotine-Administrated Mice.

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by chronic inflammation in the infrarenal aorta. Epidemiologic data have clearly linked tobacco smoking to aneurysm formation and a faster rate of expansion. It suggested that nicotine, one of the main ingredients of tobacco, has been suggested to be associated with AAA development and rupture. In the condition where no established drugs are available; therefore, an effective approach to prevent the vascular damage from nicotine consumption may be the use of dietary functional food factors. However, little is known about the relationship between dietary components and AAA. In this study, we estimated the effect of dietary deoxyribonucleic acid (DNA) on the vascular wall. After habituation for 5 d, the mice were divided into four groups: control diet and distilled water group (C), DNA-Na diet and distilled water group (DNA), control diet and 0.5 mg/mL nicotine solution group (C-Nic), DNA-Na diet, and 0.5 mg/mL nicotine solution group (DNA-Nic). The dietary DNA attenuated the degradation of elastin fibers induced by nicotine administration. The areas stained positive for MMP-2 in the DNA-Nic group were significantly suppressed compared to C-Nic mice. These data suggest that the dietary DNA may prevent the weakening of the aortic wall via inhibition of the MMP-2-dependent pathway. In conclusion, we have revealed the protective effect of dietary DNA on the vascular pathology of nicotine-administrated mice. A nucleic acid-rich diet might be useful for people who consume nicotine via smoking, chewing tobacco, or nicotine patches.

Tamsulosin attenuates abdominal aortic aneurysm growth.

BACKGROUND: Tamsulosin, an α1A-adrenergic receptor inhibitor, is prescribed to treat benign prostatic hyperplasia in men >60 years of age, the same demographic most susceptible to abdominal aortic aneurysm. The goal of this study was to investigate the effect of tamsulosin on abdominal aortic aneurysm pathogenesis. METHODS: Abdominal aortic aneurysms were induced in WT C57BL/6 male mice (n = 9-18/group), using an established topical elastase abdominal aortic aneurysm model. Osmotic pumps were implanted in mice 5 days before operation to create the model, administering either low dose (0.125 µg/day tamsulosin), high dose (0.250µg/day tamsulosin), or vehicle treatments with and without topical application of elastase. Blood pressures were measured preoperatively and on postoperative days 0, 3, 7, and 14. On postoperative day 14, aortic diameter was measured before harvest. Sample aortas were prepared for histology and cytokine analysis. RESULTS: Measurements of systolic blood pressure did not differ between groups. Mice treated with the low dose of tamsulosin and with the high dose of tamsulosin showed decreased aortic diameter compared with vehicle-treated control (93% ± 24 versus 94% ± 30 versus 132% ± 24, respectively; P = .0003, P = .0003). Cytokine analysis demonstrated downregulation of pro-inflammatory cytokines in both treatment groups compared with the control (P < .05). Histology exhibited preservation of elastin in both low- and high-dose tamsulosin-treated groups (P = .0041 and P = .0018, respectively). CONCLUSION: Tamsulosin attenuates abdominal aortic aneurysm formation with increased preservation of elastin and decreased production of pro-inflammatory cytokines. Further studies are necessary to elucidate the mechanism by which tamsulosin attenuates abdominal aortic aneurysm pathogenesis.

Supplementation with camelina oil prevents negative changes in the artery in orchidectomized rats.

The aim of the research was to examine the influence of orchidectomy on the elasticity and wall structure of the abdominal aorta in male rats and to check whether camelina oil treatment has an effect on aorta wall characteristics in orchidectomized rats. Forty 2-month-old male Wistar rats were used in the experiment: 10 animals underwent a sham testis repositioning operation (SHO) and 30 rats were orchidectomized (ORX). After the convalescence period, the SHO and ORX1 rats were given physiological saline intragastrically for 8 weeks; simultaneously, the other rats received camelina oil at the dose of 5 g/kg/b.w. (ORX2) or 9 g/kg/b.w. (ORX3) once a day. At the end of experiment, the animals were euthanized and fragments of the aorta were sampled for elasticity measurement and for histomorphometric and immunohistochemistry analysis. Orchidectomy caused a significant increase in the thickness of the total wall and its particular layers, mean intensity of elastin fluorescence in the tunica intima-media, and the volume of collagen I in tunica adventitia of the abdominal aorta in comparison to the other groups. The mean intensity of collagen I fluorescence in the tunica adventitia and tunica intima-media was significantly lower in the aorta of the orchidectomized rats. The values of the histomorphometric parameters of animals receiving camelina oil were lower than in the ORX1 group and higher than in the SHO rats. The values of the other parameters analyzed after the camelina oil treatment were similar to those in the SHO rats. In conclusion, our study showed that orchidectomy induced changes in the abdominal aorta wall characteristic for aging. Supplementation with camelina oil prevents negative consequences in the vessel wall structure in males with impaired endocrine function.

Role of myeloperoxidase in abdominal aortic aneurysm formation: mitigation by taurine.

Oxidative stress plays a fundamental role in abdominal aortic aneurysm (AAA) formation. Activated polymorphonuclear leukocytes (or neutrophils) are associated with AAA and express myeloperoxidase (MPO), which promotes inflammation, matrix degradation, and other pathological features of AAA, including enhanced oxidative stress through generation of reactive oxygen species. Both plasma and aortic MPO levels are elevated in patients with AAA, but the role of MPO in AAA pathogenesis has, heretofore, never been investigated. Here, we show that MPO gene deletion attenuates AAA formation in two animal models: ANG II infusion in apolipoprotein E-deficient mice and elastase perfusion in C57BL/6 mice. Oral administration of taurine [1% or 4% (wt/vol) in drinking water], an amino acid known to react rapidly with MPO-generated oxidants like hypochlorous acid, also prevented AAA formation in the ANG II and elastase models as well as the CaCl2 application model of AAA formation while reducing aortic peroxidase activity and aortic protein-bound dityrosine levels, an oxidative cross link formed by MPO. Both MPO gene deletion and taurine supplementation blunted aortic macrophage accumulation, elastin fragmentation, and matrix metalloproteinase activation, key features of AAA pathogenesis. Moreover, MPO gene deletion and taurine administration significantly attenuated the induction of serum amyloid A, which promotes ANG II-induced AAAs. These data implicate MPO in AAA pathogenesis and suggest that studies exploring whether taurine can serve as a potential therapeutic for the prevention or treatment of AAA in patients merit consideration.NEW & NOTEWORTHY Neutrophils are abundant in abdominal aortic aneurysm (AAA), and myeloperoxidase (MPO), prominently expressed in neutrophils, is associated with AAA in humans. This study demonstrates that MPO gene deletion or supplementation with the natural product taurine, which can scavenge MPO-generated oxidants, can prevent AAA formation, suggesting an attractive potential therapeutic strategy for AAA.

Increased galectin-3 levels are associated with abdominal aortic aneurysm progression and inhibition of galectin-3 decreases elastase-induced AAA development.

Abdominal aortic aneurysm (AAA) evolution is unpredictable and no specific treatment exists for AAA, except surgery to prevent aortic rupture. Galectin-3 has been previously associated with CVD, but its potential role in AAA has not been addressed. Galectin-3 levels were increased in the plasma of AAA patients (n=225) compared with the control group (n=100). In addition, galectin-3 concentrations were associated with the need for surgical repair, independently of potential confounding factors. Galectin-3 mRNA and protein expression were increased in human AAA samples compared with healthy aortas. Experimental AAA in mice was induced via aortic elastase perfusion. Mice were treated intravenously with the galectin-3 inhibitor modified citrus pectin (MCP, 10 mg/kg, every other day) or saline. Similar to humans, galectin-3 serum and aortic mRNA levels were also increased in elastase-induced AAA mice compared with control mice. Mice treated with MCP showed decreased aortic dilation, as well as elastin degradation, vascular smooth muscle cell (VSMC) loss, and macrophage content at day 14 postelastase perfusion compared with control mice. The underlying mechanism(s) of the protective effect of MCP was associated with a decrease in galectin-3 and cytokine (mainly CCL5) mRNA and protein expression. Interestingly, galectin-3 induced CCL5 expression by a mechanism involving STAT3 activation in VSMC. Accordingly, MCP treatment decreased STAT3 phosphorylation in elastase-induced AAA. In conclusion, increased galectin-3 levels are associated with AAA progression, while galectin-3 inhibition decreased experimental AAA development. Our data suggest the potential role of galectin-3 as a therapeutic target in AAA.

Improvement in erectile function in a rat model of high cholesterol diet-induced atherosclerosis by atorvastatin in a manner that is independent of its lipid-lowering property.

The purpose of the present study is to explore the effects of a lipid-lowering drug atorvastatin, a three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in the treatment of erectile dysfunction (ED) in a rat model of atherosclerosis (AS) and the possible mechanisms underneath. A high-cholesterol diet was administrated to Sprague-Dawley rats in an attempt to induce an ASED model, which was later confirmed by abdominal aorta histopathology and erectile function evaluation. ASED rats were further assigned to non-treatment group, atorvastatin low-dose treatment group (5 mg kg-1  day-1 ), high-dose group (10 mg kg-1  day-1 ) and sildenafil (1.5 mg kg-1  day-1 ) treatment group. Lipid profile, erectile function, oxidative stress biochemical markers, endothelial nitric oxide synthase (eNOS) and extracellular superoxide dismutase (SODEX ) mRNA expression were evaluated after 8-week treatment duration. Erectile function was impaired in AS rat model, which was preserved in atorvastatin and sildenafil intervention groups. The oxidative stress biochemical markers were attenuated, while eNOS and SODEX mRNA expression were restored in atorvastatin and sildenafil groups, which were found to be involved in ED pathogenesis. However, the lipid profile remained unaltered in the treatment group, and it was elevated in ASED rats. This kind of lipid-lowering agent, or atorvastatin, has the utilisation potential in ASED treatment, even before lipid profiles altered. This effect on erectile function preservation of atorvastatin was attributed to its preservation of endothelial function, possibly through amelioration of oxidative stress and improvement in eNOS expression.

Comparison of the Protective Effects of Individual Components of Particulated trans-Sialidase (PTCTS), PTC and TS, against High Cholesterol Diet-Induced Atherosclerosis in Rabbits.

Previous studies showed the presence of Mycoplasma pneumoniae (M. pneumoniae) and membrane-shed microparticles (MPs) in vulnerable atherosclerotic plaques. H&S Science and Biotechnology developed PTCTS, composed by natural particles from medicinal plants (PTC) combined with trans-Sialidase (TS), to combat MPs and Mycoplasma pneumoniae. Our aim was to determine the effects of the different components of PTCTS in a rabbit model of atherosclerosis. Rabbits were fed with high cholesterol diet for 12 weeks and treated during the last 6 weeks with either vehicle, PTC, TS, or PTCTS. Lipid profile and quantification of MPs positive for Mycoplasma pneumoniae and oxidized LDL antigens were carried out. Aortas and organs were then histologically analyzed. PTCTS reduced circulating MPs positive for Mycoplasma pneumoniae and oxidized LDL antigens, reduced the plaque area in the abdominal aorta, and caused positive remodeling of the ascendant aorta. PTC caused positive remodeling and reduced plaque area in the abdominal aorta; however, TS had a lipid lowering effect. PTCTS components combined were more effective against atherosclerosis than individual components. Our data reinforce the infectious theory of atherosclerosis and underscore the potential role of circulating MPs. Therefore, the removal of Mycoplasma-derived MPs could be a new therapeutic approach in the treatment of atherosclerosis.

Prevention of abdominal aortic aneurysm progression by oral administration of green tea polyphenol in a rat model.

OBJECTIVE: Inflammation-mediated elastin destruction in the aortic medial layer is related to progression of abdominal aortic aneurysm (AAA). Epigallocatechin-3-gallate (EGCG), a major component of green tea polyphenols, reportedly increases elastin synthesis in vitro and may possess anti-inflammatory effects. We used a rat model to investigate whether EGCG could prevent AAA progression. METHODS: AAA was induced with administration of intraluminal elastase and extraluminal CaCl2 in male rats. Rats were randomly divided into a control group (n = 30) and an EGCG group (n = 30). In the EGCG group, an EGCG solution (20 mg/d) was administered orally to each rat from 2 weeks before AAA induction and continued 4 weeks beyond induction. RESULTS: The abdominal aortic diameter was significantly smaller in the EGCG group than in the control group on day 28 (2.9 ± 0.2 vs 2.3 ± 0.1 mm; P < .0001). The medial layer wall thickness and elastin content were significantly greater in the EGCG group than in the control group on day 28 (68.4 ± 13.6 vs 46.7 ± 13.4 µm [P < .001] and 20.3 ± 4.6 vs 9.5 ± 3.6% [P < .0001], respectively). Gene expression levels of tropoelastin and lysyl oxidase were significantly higher in the EGCG group immediately before AAA induction, indicating promoted elastoregeneration by EGCG administration (tropoelastin: 0.59 ± 0.36 control vs 1.24 ± 0.36 EGCG [P < .05], lysyl oxidase: 0.77 ± 0.45 control vs 1.34 ± 0.4 EGCG [P < .05]) (fold increase). Gene expression levels of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, were significantly downregulated in the EGCG group (1.82 ± 0.71 vs 0.97 ± 0.59 [P < .05] and 3.91 ± 3.24 vs 0.89 ± 0.59 [P < .05], respectively). On day 7, gene expression levels and gelatinolytic activity of matrix metalloproteinase 9 were significantly lower in the EGCG group (1.41 ± 0.86 vs 0.51 ± 0.42 [P < .05] and 1.00 ± 0.17 vs 0.29 ± 0.12 [P < .0001], respectively), whereas gene expression levels of tissue inhibitors of metalloproteinase-1 were significantly higher in the EGCG group (0.96 ± 0.11 vs 1.14 ± 0.09; P < .05). CONCLUSIONS: EGCG attenuated AAA progression in a rat model by preserving the aortic thickness and elastin content of the medial layer through regeneration of elastin, as mediated by anti-inflammatory effects, and subsequent reduction of matrix metalloproteinase activity.

Effects of Labisia pumila var alata extracts on the lipid profile, serum antioxidant status and abdominal aorta of high-cholesterol diet rats.

BACKGROUND: Previous studies on Labisia pumila var. alata (LPva) have showed that it could inhibit low-density lipoprotein (LDL) oxidation and provide protection on myocardial infarction in rats. HYPOTHESIS/PURPOSE: We hypothesized that LPva extracts can modulate the lipid profiles and serum antioxidant status of hypercholesterolemic rats. In the present study, we investigated the effects of aqueous and 80% ethanol extracts of LPva on atherogenic and serum antioxidant parameters as well as changes in abdominal aorta of high-cholesterol diet rats. METHODS: The major components of the extracts, gallic acid, flavonoids and alkyl resorcinols were analyzed by using a validated reversed phase HPLC method. The rats were induced to hypercholesterolemic status with daily intake of 2% cholesterol for a duration of 8 weeks. Three different doses (100, 200 and 400mg/kg) of the extracts were administered daily on the 4th week onwards. The rats were then sacrificed and the blood was collected via abdominal aorta and serum was separated by centrifugation for biochemical analysis. Part of the aorta tissues were excised immediately for histopathological examination. RESULTS: The serum of LPva treated rats showed significant reduction in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels and the abdominal aorta showed a significant decrease of atheroma lesions in treated rats. Serum lipid profiles of treated rats showed a decrease in total cholesterol, total triglycerides and low-density lipoprotein (LDL) levels as compared to control group. The atherogenic indices in treated rats were significantly improved along with an increasing level of serum high-density lipoprotein (HDL). The extracts also exhibited significant increase of antioxidant enzymes and decrease of MDA as a product of lipid peroxidation. CONCLUSION: LPva extracts can reduce the risk of dyslipidemia by improving the serum lipid profiles and modulating serum antioxidants.

Chinese Herbal Cardiotonic Pill Stabilizes Vulnerable Plaques in Rabbits by Decreasing the Expression of Adhesion Molecules.

The cardiotonic pill (CP), consisting of a mixture of Radix Salviae Miltiorrhizae, Radix Notoginseng, and Borneolum Syntheticum, has been widely used in the prevention and treatment of cardiovascular disease. Adhesion molecules, including intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, are involved in the development of vulnerable plaque. We investigated the effect of the CP in a rabbit model of vulnerable plaque established by local transfection with p53 gene. Compared with the control group, rabbits with vulnerable plaque showed a significantly lower intima-media thickness and plaque burden after CP treatment for 12 weeks. Moreover, the reduction in rate of plaque rupture and vulnerability index was similar. On enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry analysis, the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 was inhibited with CP treatment. CP treatment could postpone atherosclerotic plaque development and stabilize vulnerable plaque by inhibiting the expression of adhesion molecules in treatment of cardiovascular disease.