Aortic Media Thickness Research Articles

Irisin in Adolescent Type 1 Diabetic Patients and its Relation to Diabetes Control and Atherosclerosis

AIM: The objective of this was to determine the role of irisin in adolescent type 1 diabetes (T1D) patients.
 METHODS: This study was conducted on 65 patients with T1D and 50 healthy individuals as control group. Serum irisin, glycosylated hemoglobin (HbA1c), lipid profile, oxidized low-density lipoprotein (OxLDL), urinary albumin/creatinine ratio; carotid intimal medial thickness (cIMT), and aortic intimal medial thickness (aIMT) were evaluated for all participant.
 RESULTS: HbA1c, lipid profile, albumin/creatinine ratio, OxLDL, irisin, aIMT and cIMT were significantly higher in diabetic patients. Irisin had a positive correlation with age of diabetic patients, onset of diabetes, mid arm circumference, waist/height ratio, body mass index, HbA1c, and cIMT.
 CONCLUSION: Irisin is a marker for detection of diabetes control and early detection of subclinical atherosclerosis. Irisin had a relation with obesity.

Abstract 14780: Developing a Model for Abdominal Aortic Aneurysm in Swine

Introduction: Abdominal aortic aneurysms (AAA) are responsible for over 150,000 deaths worldwide annually. Attempts at producing a reliable large-animal model of AAA have proven challenging. We sought to create a reproducible swine model of AAA using enzymatic degradation of the aortic wall. Methods: A total of 9 male Yorkshire swine received periadventitial injections of type 1 collagenase (23.5 mg) and porcine pancreatic elastase (500 mg) into a 4 cm segment of infrarenal aorta. Aortic diameter growth was monitored at POD 7 and 14 using ultrasound. The animals were euthanized on POD 21, and the suprarenal (control) and infrarenal (treated) aorta was harvested for analysis, after gross measurement of aortic diameter under physiologic blood pressure. Sections of control and treated aorta were used to obtain tensile strength using a tensiometer. Additional segments of the aorta were collected for histopathological analysis (H&E, elastin, alpha smooth muscle actin). PCR of matrix metalloproteinases (MMP9) was conducted. Groups were compared with paired t-tests, or ANOVA for repeated measures, where appropriate. Results: Average percent growth of aortic diameter at POD 21 for treated segments was 27% +/- 16.5% versus 4.5% +/- 4% for control tissue. The average difference in aortic growth by subject, was 26.7% [14.6%-38.8%]; (p<0.001). Aortic medial thickness was decreased in treated tissue; 235 um +/- 208 um versus 645 um +/- 191 um (p<0.0001). Quantity of both medial elastin fibers, and vascular smooth muscles cells was decreased in treated tissue; 1.8% +/- 3.16%, compared to 9.9% +/- 6.85% (p<0.0001), and 24% +/- 6.8% versus 37.4% +/- 6.9%, respectively. Tensile strength was also decreased in treated tissue; 16.7 MPa +/- 7 MPa versus 29.5 MPa +/- 10.7 MPa (p=0.0002). A 12-fold increase in expression of MMP9 mRNA was also demonstrated in aneurysmal tissue (p=0.002) Conclusion: A reproducible, large-animal model of AAA, with anatomical, histopathological, and biomechanical properties that are clinically translatable, can be achieved with extraluminal enzymatic degradation.

Abstract P078: Sex Differences In Aortic Stiffness Following Simulated Microgravity In Middle Aged Rats

Men and women have different cardiovascular responses to spaceflight. We determined sex differences in arterial stiffness, an independent risk factor for cardiovascular dysfunction, in rats after the exposure to 14-days of simulated weightlessness via hindlimb unloading (HLU). Male and female Sprague-Dawley rats at 20 weeks of age were either tail suspended via HLU or remained full-weight bearing in similar cages. Female control rats had lower body weight compared with males. There was no significant effect of HLU on body weight in either male or female rats. Our data demonstrate that HLU increased aortic pulse wave velocity, an index of arterial stiffness, in female rats (2.7 fold vs. control female- adjusted for body weight, n=5-6), but not in males. HLU had no effect on the levels of structural proteins (alpha smooth muscle actin or myosin) in either female or male rats. The levels of G-protein-coupled estrogen receptor 1 (GPER) were lower in the thoracic aorta of female rats exposed to HLU compared with female controls (0.3±0.02 vs. 0.39±0.01 relative density, p<0.05, n=6-7); lower aortic GPER levels were associated with greater aortic media thickness (110.5±4.2 vs. 97.1±3.1 μm, p<0.05, n=5) and lower COX-2 protein levels (0.47±0.04 vs. 0.61±0.02 relative density, p<0.05, n=3-4). However, no differences in GPER, aortic media thickness, or COX-2 were observed in the aortas of male rats after HLU versus male controls. The administration of GPER agonist, G1 (400 ug/kg/day) prevented the increase in aortic pulse wave velocity in the intact females following HLU (2.2±0.2 vs. 9.7±1.8, p<0.05, n=4). Our data demonstrate sex differences in aortic stiffness in response to simulated microgravity. Since GPER has many protective actions in the cardiovascular system, a dysregulation of estrogen signaling may attenuate the protection of females from cardiovascular dysfunction following the exposure to spaceflight stressors.

The Histological Alteration of Proximal Part of Aorta Exposed to (MSG) and Protective Effect of an a Lipoic Acid (ALA) in Male Rabbits

Background. Monosodium Glutamate is one of the most world’s most widely used food additives. Its toxic effect have been shown in numerous animal studies, in which study MSG effects on cardiovascular system, therefore, This study was aimed to investigate the effect of alpha lipoic acid(ALA) on the damage in the large blood vessels induce by Mono sodium glutamate. Thirty two male rabbits was divided equally and randomly into four groups as following. Control group in which rabbits where fed with normal diet without supplementation, second group was gived MSG orally (8mg/kg.BW), While animals of third group were given ALA orally (60mg/kg.BW) while animal in fourth group were given orally (MSG 8mg/kg.bw and ALA 60mg/kg.bw), all treatment are extended to 8 weeks. The outcomes of research revealed a significant increased (p<0.05) in aortic medial layer thickness in animals administration of MSG in a comparesion with control and groups treated and distortion structure of laminar fibers, endothelial cells lost normal squamous. In addition, there is a significant decreased (p<0.05) in medial tunica thicken in animals used ALA combination with MSG, so we noted return the disarranged of architecture tissue near.

Effects of hydrogen sulphide on oxidative stress, inflammatory cytokines, and vascular remodelling in l-NAME-induced hypertension.

This study was designed to evaluate the protective effects of hydrogen sulphide (H2 S) against NG-Nitro l-Arginine Methyl Ester (l-NAME)-induced hypertension and its possible effects on the inflammatory process, oxidative stress, and vascular remodelling in rats. Forty male Wistar Albino rats were assigned to four equal groups: the control group, the H2 S control group, the hypertensive group, and the treated group, which received concomitant treatment with sodium hydrosulphide (NaHS) and l-NAME. Systolic blood pressure (SBP) was measured weekly. Serum levels of nitric oxide (NO), total peroxide, and total antioxidant capacity (TAC) were measured and the oxidative stress index (OSI) was calculated. Aortic weight and length were measured and the aortic weight/length ratio determined. Aortic fold expression of interferon-γ (IFN-γ) and vascular cell adhesion molecule-1 (VCAM-1) mRNA was measured using qPCR. Aortic media thickness and elastin content were measured morphometrically. l-NAME administration increased SBP, serum levels of total peroxide and OSI, but reduced serum levels of NO and TAC. Aortic fold expression of IFN-γ and VCAM-1 mRNA, aortic weight, aortic weight/length ratio, aortic media thickness, and elastin area percentage were increased in the hypertensive group. Concurrent administration of l-NAME and H2 S attenuated these changes. Thus, H2 S could attenuate the increase in ABP through restoration of the NO level, reduction in the oxidative state, and attenuation of the inflammatory process, thereby reduced vascular remodelling.

Copeptin as a Biomarker of Atherosclerosis in Type 1 Diabetic Patients.

AIM:To evaluate copeptin as an early marker of atherosclerosis in adolescent type 1 diabetics.METHODS:Sixty-two type 1 diabetic patients and 50 healthy volunteers were enrolled in the study. Serum copeptin, glycosylated haemoglobin (HbA1c), lipid profile, oxidised low-density lipoprotein (OxLDL), urinary albumin/creatinine ratio, carotid intimal medial thickness (cIMT), aortic intimal medial thickness (aIMT) and resistivity index were assessed for all participants in the study.RESULTS:HbA1c, albumin/creatinine ratio, lipid profile, OxlDL, copeptin, cIMT and aIMT were significantly higher in diabetic patients. Copeptin was higher in patients with positive cIMT and aIMT. Copeptin correlated with cIMT and aIMT. Stepwise multiple regression analysis found that copeptin correlated with aIMT. ROC curve showed that copeptin had 100 % specificity with aIMT and cIMT and 95.2 and 60,7 sensitivity with aIMT and cIMT respectively.CONCLUSION:Copeptin can be used as a marker for early detection of atherosclerosis of type 1 diabetic patients.

Osteopontin for Early Detection of Microvascular and Macrovascular Type 1 Diabetic Complication.

AIM:To evaluate the relationship between osteopontin and diabetes complication in type 1 diabetic patient.PATIENTS AND METHODS:Seventy types 1 diabetic and 60 healthy volunteers were studied. Full history, examination, laboratory tests of glycosylated haemoglobin (HbA1c), serum lipids {cholesterol, triglyceride (Tg), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein – cholesterol (LDL-c)}, oxidised low-density lipoprotein (OxLDL), Osteopontin and urinary microalbuminuria (albumin/creatinine ratio) were done. Image study in the form of a carotid intimal medial thickness (cIMT) and aortic intimal medial thickness (aIMT), renal doppler for resistivity index was also done for all participant included in the study.RESULTS:Urinary albumin/creatinine ratio, lipid profile, osteopontin, cIMT and aIMT were higher in people with diabetes. Osteopontin was higher in people with diabetes with positive microalbuminuria and cIMT. Systolic blood pressure, microalbuminuria and cIMT had a positive correlation with osteopontin in people with diabetes. Stepwise multiple regression analysis showed that osteopontin had a significant correlation with cIMT. Receiver operating characteristic (ROC) curve showed that the cut off value of Osteopontin for detection of cIMT was > 60 with a specificity of 100% and sensitivity 80.5%, while that of albumin/creatinine ratio was > 64 with a specificity of 66.7 and sensitivity of 92.3.CONCLUSION:Osteopontin is higher in type 1 diabetics and is useful for early detection of diabetic microvascular and macrovascular complication.

Dietary Ethanolic Extract of Mangosteen pericarp Reduces VCAM-1, Perivascular Adipose Tissue and Aortic Intimal Medial Thickness in Hypercholesterolemic Rat Model.

BACKGROUND:High-fat diet (HFD) is associated with dyslipidemia which is a risk factor for atherosclerosis. Dyslipidemia causes oxidative stress which induces vascular cell adhesion molecule-1 (VCAM-1). Oxidative stress also triggers the thickening of tunica intima-media (IMT) and Perivascular Adipose Tissue (PVAT). Xanthone compound in ethanolic extract of Mangosteen pericarp (EEMP) has an antioxidant property to overcome the oxidative stress.AIM:The objective of this study is to investigate the effect of dietary EEMP administration on the expression of VCAM-1 and thickness of PVAT and IMT in atherosclerotic rat model fed with HFD.METHODS:This experimental laboratory study uses 25 Wistar strain Rattus norvegicus which were divided into 5 study groups. Negative Control group (GT1) was given a normal diet, Positive Control group (GT2) was treated with HFD, and three treatment groups were each treated with HFD with Mangosteen pericarp extract of 200 mg/kg BW (GT3), 400 mg/kg BW (GT4), and 800 mg/kg BW (GT5). Measurements of VCAM-1 expression were performed using immunofluorescence. PVAT and IMT measurements were performed on rat aortic preparations.RESULTS:One-way ANOVA test showed the addition of dietary EEMP significantly (p < 0.05) decreased the expression of VCAM-1 and decreased the thickness of PVAT and IMT in treatment groups as compared with both negative and positive controls. Tukey HSD test showed a dose of 800 mg/kg BW was the most effective dose for decreasing VCAM-1 level, PVAT and IMT.CONCLUSION:Dietary EEMP significantly decreases the expression of VCAM-1, as well as the thickness of PVAT and IMT in Wistar strain Rattus norvegicus treated with HFD.

Angiotensin II-Induced vascular remodeling and hypertension involves cathepsin L/V- MEK/ERK mediated mechanism

The development of hypertension involves extensive arterial wall remodeling, in which cysteine proteases play an essential role. Cathepsin L/V has been reported to be a cysteine protease that is closely intertwined with the tissue inflammatory response and extracellular matrix accumulation, allowing it to regulate arterial remodeling. The aim of this study was to determine the role of cathepsin L/V and its regulatory pathway in vascular remodeling in hypertension. We showed that cathepsin L/V and its endogenous inhibitor cystatin C, as well as mitogen-activated protein kinase (MEK) phosphorylation, were upregulated in the mesenteric arteries and serum of hypertensive patients. Using a model of angiotensin II-induced hypertension, we observed an increase in aortic artery media thickness, cathepsin L activity, blood pressure and MEK phosphorylation. Treatment with the cathepsin L inhibitor Z-FF-FMK or the genetic deletion of cathepsin L significantly attenuated angiotensin II-induced hypertension, arterial remodeling, cathepsin L activation and MEK phosphorylation. In addition, siRNA-cathepsin V significantly blocked angiotensin II-induced MEK and extracellular signal–regulated kinase (ERK) phosphorylation but not cell proliferation in human aortic smooth muscle cells (HASMCs). Further treatment with the ERK phosphorylation inhibitor U0126 also blocked angiotensin II-induced HASMCs proliferation. The results indicate that the inhibition of cathepsin L prevents arterial remodeling and hypertension, in part by inhibiting the MEK-ERK signaling-mediated regulation of smooth muscle cell proliferation in the vessel wall.

Abstract P3052: A Muscadine Grape Extract Improves Hypertension-Induced Aortic Damage in Conjunction With a Reduction in Fibrosis, Oxidative Stress, and Inflammation

Hypertension-induced arterial stiffness contributes to both reduced vascular and cardiac function. While the pathophysiology of aortic stiffness is not completely understood, significant vascular remodeling occurs in response to stimuli such as vascular stress and Ang II. The goal of this study was to determine whether a polyphenol-enriched muscadine grape skin and seed extract (MGE) improves Ang II-induced aortic remodeling. Sprague-Dawley rats (male, 8 weeks old) received normal drinking water (Control), 0.2 mg total phenolics/mL in their drinking water (MGE), 24 μg/kg/h of Ang II via osmotic minipump (Ang II), or both Ang II and MGE (Ang II/MGE, pre-treated with MGE for 1 week prior to Ang II treatment). MGE had no effect on systolic blood pressure, measured by tail cuff plethysmography, in normotensive or Ang II-treated rats. Aortic stiffness, determined by echocardiographic pulse wave velocity, was increased 2.5-fold in Ang II-treated animals but was significantly improved by co-administration of MGE. MGE prevented the Ang II-induced increase in aortic media thickness (Control: 95.8 ± 2.1 μm, Ang II: 135.1 ± 3.7 μm, and Ang II/MGE: 118.2 ± 2.9 μm) and lumen diameter (Control: 2.7 ± 0.2, Ang II: 2.1 ± 0.1 mm, and Ang II/MGE: 2.6 ± 0.1 mm). Nuclear phosphorylated ERK (pERK) in aortic medial cells was increased by 131% in Ang II-treated rats compared to Controls (p &lt; 0.05); MGE co-administration prevented this by 83% (p &lt; 0.001). Ang II-induced aortic fibrosis, measured by total collagen and collagen III, was significantly attenuated in hypertensive animals treated with MGE, in association with reduced pSMAD2 and CTGF. 4-HNE, a marker of lipid peroxidation, and subunits of NADPH oxidases--Nox1, Nox2, p-p47phox--were significantly upregulated by Ang II and normalized with MGE. The inflammatory markers IL-6 and NF-κB were also increased in Ang II-treated aortas (8.9- and 12.7-fold, respectively) and attenuated by MGE. This study is the first to demonstrate that Ang II-induced vascular remodeling is prevented by co-administration of MGE. MGE reduced aortic stiffness, in association with a decrease in fibrotic, oxidative stress, and inflammatory signaling, suggesting that MGE supplementation may improve vascular function in hypertensive patients.

Curcumin attenuates migration of vascular smooth muscle cells via inhibiting NFκB-mediated NLRP3 expression in spontaneously hypertensive rats

Migration of vascular smooth muscle cell (VSMC) plays a critical role in the pathophysiology of hypertension and several other vascular diseases. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a bioactive constituent from Curcuma longa, is commonly used as a spice, food additive or dietary pigment. It has several health benefits including antioxidant, anti-inflammatory and anticancer properties. This study examined the roles of curcumin in VSMC migration in hypertension and underlying mechanism. VSMC was isolated and prepared from thoracic aorta of Wistar–Kyoto rats and spontaneously hypertensive rats (SHR). VSMC migration was evaluated with Boyden chamber assay and wound-healing assay. Curcumin attenuated VSMC migration, inhibited nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression and reduced interleukin (IL)-1β concentration in VSMC of SHR, which were similar to the effects of NLRP3 knockdown on IL-1β concentration and VSMC migration. Curcumin inhibited NFκB activation in VSMC of SHR, which was similar to the effects of NFκB inhibitor BAY11-7082 on NFκB activation. In another in vitro model of rat VSMC migration, curcumin also inhibited angiotensin II-induced VSMC migration, NFκB activation, NLRP3 expression and IL-1β production. Intragastric administration of curcumin in SHR attenuated hypertension and reduced NFκB activation, NLRP3 and matrix metalloproteinase-9 expressions and aortic media thickness. These results indicate that curcumin inhibits VSMC migration via inhibiting NFκB-mediated NLRP3 expression in VSMC of SHR or in angiotensin II-treated VSMC. Curcumin attenuates hypertension, vascular inflammation and vascular remodeling in SHR.

Dietary Cocoa Prevents Aortic Remodeling and Vascular Oxidative Stress in Diabetic Rats.

The aim of the present study is to investigate the potential protective effect of a cocoa-rich diet on functional and structural vascular alterations in diabetes and the mechanism involved. Male Zucker diabetic fatty (ZDF) rats are fed on a standard (ZDF-C) or cocoa-rich diet (ZDF-Co) from week 10 to 20 of life. Diabetic ZDF-C rats showed increased blood pressure and enhanced aortic stiffness, as demonstrated by the increased pulse pressure and the augmented aortic medial thickness with loss and disruption of elastic fibres. Interestingly, cocoa intake strongly avoided all these adverse effects and reduced aortic oxidative stress. Mechanistically, cocoa diet prevented sirtuin-1 (SIRT-1) depletion and increased NADPH oxidases (NOXs) and reactive oxygen species production as well as reduced active nuclear factor E2 related factor 2 (Nrf2) and their antioxidant products. The results demonstrate for the first time that a cocoa-rich diet strongly prevents aortic stiffening and remodeling in diabetic animals and avoids aortic oxidative stress. It is suggested that this effect could be mediated via its effects on SIRT-1, NOXs, and Nrf2.

The protective effect of dronedarone on the structure and mechanical properties of the aorta in hypertensive rats by decreasing the concentration of symmetric dimethylarginine (SDMA).

Background and aimsDronedarone is a new multichannel-blocking antiarrhythmic for the treatment of patients with atrial fibrillation. Our group has demonstrated that dronedarone produces regression of cardiac remodeling; however, its effect on the remodeling of the elastic arteries has not yet been reported. We aim to assess the effects of dronedarone on the regression of thoracic aortic remodeling in spontaneously hypertensive rats (SHRs).MethodTen-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where the animals received dronedarone treatment (100 mg/kg), to a control group (SHR) where rats were given vehicle, or to a group (SHR-A) where they were given amiodarone. A fourth group of normotensive control rats (Wistar-Kyoto rats, WKY) was also added. After two weeks of treatment, we studied the structure, the elastic fiber content of the thoracic aorta using histological techniques and confocal microscopy, and the vascular mechanical properties using an organ bath and isometric tension analysis. A mass spectrometric determination of symmetric dimethylarginine (SDMA) concentrations was performed.ResultsSHR group developed the classic remodeling expected from the experimental model: outward hypertrophic remodeling, increased elastic fiber content and wall stiffness. However, the SHR-D group showed statistically significantly lower values for aortic tunica media thickness, wall to lumen ratio, external diameter, cross-sectional area, volume density of the elastic fibers, wall stiffness, and aortic SDMA concentration when compared to the SHR group. These parameters were similar in the SHR and SHR-A groups. Interestingly, the values for tunica media thickness, volume density of the elastic fibers, wall stiffness, and SDMA concentration obtained from the SHR-D group were similar to those measured in the WKY group.ConclusionThese results suggest that dronedarone improves the structure and passive mechanical properties of the thoracic aorta in hypertensive rats, and that this protective effect could be associated with a reduction in the concentration of aortic SDMA.

Rabbit aortic aneurysm model with enlarging diameter capable of better mimicking human aortic aneurysm disease.

The self-healing phenomenon can be found in the elastase-induced abdominal aortic aneurysm (AAA) model, and an enlarging AAA model was successfully induced by coarctation. Unfortunately, aortic coarctation in these enlarging models is generally not found in human AAA disease. This study aimed to create an experiment model of enlarging AAA in rabbits to better mimic human aortic aneurysm disease. Eighty-four male New Zealand white rabbits were randomly divided into three equal groups: two aneurysm groups (A and B) and a SHAM group. Aneurysm group rabbits underwent extrinsic aortic stenosis below the right renal artery and received a 10-minute incubation of 60 μl elastase (1 unit/μl). Absorbable suture was used in Group A and nonabsorbable cotton thread was used in Group B. A sham operation was performed in the SHAM group. Aortic diameter was measured after 1, 3, 7, and 15 weeks; thereafter animals were sacrificed for histopathological, immunohistochemical and quantitative studies. Two rabbits died at 29 and 48 days, respectively, after operation in Group B. All aneurysms formed and enlarged progressively by 3 weeks in the Aneurysm groups. However, diameter enlargement in Group A was significantly lower than that in Group B at 7 weeks. Aneurysm groups developed intimal hyperplasia; intima-media thickness (IMT) increased significantly by week 7, and aortic media thickness and intima-media ratio (IMR) increased significantly by week 15. Marked destruction of elastin fibers and smooth muscle cells (SMCs) occurred 1 week later and increased progressively thereafter. Intimal hyperplasia and SMCs content in Group A increased significantly by week 15 compared with Group B. Aneurysm groups exhibited strong expression of matrix metalloproteinases 2 and 9 and RAM11 by week 1, and decreased progressively thereafter. In conclusion, this novel rabbit AAA model enlarges progressively without coarctation and is capable of better mimicking human aortic aneurysm disease.

ANTI-INFLAMMATORY FACTOR DEL-1 PROTECTS FROM ANGIOTENSIN II-DEPENDENT VASCULAR REMODELING AND HYPERTENSION

Objective: Hypertension is the leading cause of mortality worldwide. Critical contributor to pathophysiology of hypertension is vascular remodeling, which is mediated by angiotensin II (ANGII) driven T-cell inflammation and production of interleukin 17 (IL-17). Thus, anti-inflammatory approaches have been proposed as a potential therapeutic strategy. We tested the role of an endogenous anti-inflammatory factor, developmental endothelial locus-1 (Del-1), in prevention of ANGII-induced vascular remodeling and hypertension. Design and method: Mice overexpressing endothelial Del-1 (Del1 Tg) and WT mice which were repetitively injected with soluble Del-1 (50 μg/per injection) were used. Hypertension and vascular remodeling were induced with ANGII infusion using osmotic minipumps (Alzet®) for 4-weeks. Systolic blood pressure (SBP) was measured via tail-cuff method. Aortic remodeling was assessed by quantification of adventitial fibrosis, elastin and medial thickness. Aortic inflammatory cells were quantified with flow cytometry, whereas endothelial dysfunction was assessed using Mulvany myography. Results: After 4-weeks of ANGII infusion, Del-1 Tg mice had lower (P < 0.01) SBP compared to WT littermates. Del-1 Tg mice had less (P < 0.01) aortic medial thickness, less adventitial collagen (P < 0.01) and more elastin (P < 0.01) area compared to WT mice. MMP2 activity was significantly (P < 0.01) less in Del-1 Tg mice than in WT. Endothelium-dependent relaxation of aorta was stronger (P < 0.01) in Del-1 Tg mice than in WT. Del-1 Tg mice had less (P < 0.05) CD45+ leukocytes, TCRβ+ T-cells, as well as CD4+ T-helper and CD8+ T-cytotoxic cells in aorta compared to WT mice. TCRβ+/IL-17+ double positive T-cell count was also less (P < 0.05) in Del-1 Tg than in WT mice. Injections of soluble Del-1 in WT completely protected from ANGII-induced development of hypertension and aortic remodeling. Del-1 injected mice had lower (P < 0.05) SBP compared to vehicle treated mice. Del-1 injections resulted in less aortic medial thickness (P < 0.05) and adventitial collagen area (P < 0.05), as well as lower MMP2 (P < 0.05) activity. Endothelium-dependent relaxation was stronger (P < 0.01) in Del-1 injected mice. Conclusions: Our findings demonstrate that Del-1 protects from ANGII-dependent development of hypertension and vascular remodeling via limitation of inflammation and maintaining of endothelial function. Its proof of efficacy via exogenous injections presents Del-1 as a potential therapeutic agent.

Leptin Restores Endothelial Function, Reduces Vascular Inflammation But Not Vascular Remodeling In Mouse Models Of Congenital And Acquired Lipodystrophy Via Anti‐Oxidant Properties.

Lipodystrophy is a metabolic disease characterized by a loss of adipose tissue and a major cause of vascular disease. A key feature of lipodystrophy is a decrease in the levels of the adipokine leptin, which can exerts both deleterious and beneficial cardiovascular actions. We tested the hypothesis that leptin replacement therapy, the treatment currently offered to lipodystrophic patients, restores endothelial function via direct mechanisms in lipodystrophic mice. Constitutive and inducible deletion of Berardinelli‐Seip gene (Bscl2) was employed to generate mouse models of congenital (gBscl2−/−) and acquired (iBscl2) lipodystrophy. Constitutive (gBscl2−/−) and 8 weeks of Bscl2 deletion in iBscl2−/− markedly reduced adipose mass [% of fat: wild‐type (WT): 8.6 ± 0.3 vs gBscl2−/−: 2.4 ± 0.1* vs iBscl2−/−: 4.2 ± 0.2* (*P&lt;0.05 vs WT)] and leptin levels [ng/mL: WT: 4.0 ± 0.3 vs gBscl2−/−: 0.3 ± 0.1* vs iBscl2−/−: 1.4 ± 0.5* (*P&lt;0.05 vs WT)], and impaired aortic endothelium‐dependent but not independent relaxation. Deletion of Bscl2 for a week in iBscl2−/− mice did not reduce adipose mass nor impaired endothelial function indicating that loss of adipose mass is a pre‐requisite to endothelial dysfunction. ROS scavenging via tempol (100 μmol/l) or NOX1/4 inhibition (GKT137831, 10 μmol/l) restored endothelial function in aortic rings from both gBscl2−/− and iBscl2 mice. Contribution of ROS to endothelial function was further supported by increases in vascular −O2, H2O2 and Nox1 expression in aortic rings and in endothelial cells from gBscl2−/− mice. Despite no increase in blood pressure, gBscl2−/− mice exhibit increased aortic media thickness and elevated TGF‐β and collagen 1 and 3α1 expression. In addition, aortas from gBscl2−/− shown increases in TNF‐α, IL‐1β, IL‐18 and Caspase‐1, characteristic of vascular inflammation. A week leptin supplementation lowered blood glucose, fully restored endothelial function, decreased vascular inflammation and reduced ROS and Nox1 expression in aortas and in endothelial cells from gBscl2−/− mice, without increasing blood pressure. However, one week of leptin treatment did not reduce aortic media thickness nor TGF‐β and collagen 1 and 3α1 gene expression. Treatment of gBscl2−/− mice with the sodium/glucose cotransporter 2 inhibitor (dapagliflozin) reduced glucose levels similarly to leptin but did not restore endothelial function in gBscl2−/− mice. Our data demonstrate that leptin replacement therapy restores endothelial function and reduces vascular inflammation in mouse models of congenital lipodystrophy, via reducing expression Nox1‐derived ROS and independent of improvement of metabolic function. Our data also show the physiological role of leptin in the homeostasis of metabolic and vascular function and may present leptin replacement therapy as a therapeutic approach for the treatment of other metabolic disease associated with a reduced fat mass.Support or Funding InformationWork supported by 17POST33410363 to TBN and 16IRG27770047 and 1R01HL13030101 to EJ.BdC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The intervention of enalapril maleate and folic acid tablet on the expressions of the GRP78 and CHOP and vascular remodeling in the vascular smooth muscle cells of H-hypertensive rats with homocysteine.

GRP78 and CHOP play essential roles in endoplasmic reticulum stress (ERS) of the vascular smooth muscle cells. We aim to investigate the effect of enalapril maleate and folic acid tablet on the expressions of GRP78 and CHOP and vascular remodeling in a homocysteine (HCY)-treated hypertensive rat model. The hypertensive rat model was established with the technique of coarctation in the abdominal aorta, and the blood pressure of the rat was measured with the non-destructive tail-cuff method two weeks after operation. Thirty-six rats with hypertension were randomly divided into 3 groups (n=12 in each group). The control group received common diet and double distilled water, methionine group received 30 g/L methionine diet and double distilled water, while enalapril maleate and folic acid tablet group received 30 g/L methionine diet and 0.2 mg.kg-1.d-1 solution of enalapril maleate and folic acid tablet. Samples were collected at week 4 and week 8 for analysis. The plasma homocysteine was measured by homocysteine detector; MAP was detected through carotid artery incubation and aortic media thickness was determined by image analyses software. The expression of GRP78 and CHOP in the vascular smooth muscle cells were identified by immunohistochemistry and Western blot. Compared with the control group, the concentration of HCY in the serum of rats in methionine group was increased significantly after 4 weeks (p < 0.01), and even more significant after 8 weeks (p < 0.01). Compared with that of methionine group, the level of HCY in enalapril maleate and folic acid tablet group rats was significantly decreased (p < 0.01). The level of MAP in methionine group was increased significantly after 8 weeks compared with that of control group (p < 0.05). However, the MAP in enalapril maleate and folic acid tablet group was decreased significantly compared with that of methionine group. Compared with control group, the media thickness of vascular smooth muscle of rats in the methionine group was increased significantly (p < 0.05) while was statistically reduced in the enalapril maleate and folic acid tablet group (p < 0.05). The expressions of GRP78 and CHOP in methionine group were significantly elevated compared to that of control in a time dependent manner (p < 0.05), which were remarkably down regulated in enalapril maleate and folic acid tablet group compared with that in methionine group. The administration of enalapril maleate and folic acid tablet can maintain the normal state of cells via the alleviation of ERS and vascular damages, reduction of HCY and the thickness of arterial media as well as the improvement of vascular remodeling.

Effects of Herbal-cake-separated Moxibustion on Blood Lipid Protein Levels and Expression of Toll-like Receptor and Nuclear Factor Genes in Atherosclerotic Plaques in Hyperglycemia Rabbits

To observe the effect of herbal cake-separated moxibustion on blood lipid-apoprotein levels and the expression of Toll-like receptor 2 (TLR 2), TLR 4 and nuclear factor kappa B(NF-κB) mRNAs in atherosclerotic (AS) vulnerable plaques of hyperglycemia rabbits, so as to explore its mechanism underlying improvement of atherosclerosis. Sixty New Zealand rabbits were randomly divided into 5 groups: control, model, direct moxibustion, herbal-cake-separated moxibustion and medication groups(n＝12 rabbits in each group). The AS vulnerable plaque model was established by high-fat forage feeding plus balloon-induced abdominal aorta injury and gene transfection of Ad 5-p 53 recombinant vector. Direct moxibustion or herbal-cake-separated moxibustion was applied to "Juque" (CV 14) and bilateral "Tianshu" (ST 25), "Fenglong" (ST 40), or bilateral "Xinshu" (BL 15), "Pishu" (BL 20) and "Ganshu" (BL 18) for 15－20 min every time. The medication group was treated by feeding Atorvastatin. All the treatments were conducted once daily for 8 weeks. Plasma total cholesterol(TC) and triglyceri-de(TG) contents were detected by enzyme method, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) contents detected by colorimetric determination, and plasma apolipoprotein A(Apo-A) and apolipoprotein B(Apo-B) levels determined by electrophoretic method. The pathological changes of vulnerable plaque and the aortic intima and media thickness were observed under light microscope after H．E. staining. The expression levels of TLR 2, TLR 4 and NF-κB mRNAs in AS plaques were determined by quantitative real-time PCR. After modeling, the levels of plasma TC, TG, LDL and Apo-B in the model group were remarkably increased (P<0.01), and Apo-A and HDL/LDL were significantly decreased in comparison with the control group (P<0.01). Additionally, the aortic intima and media thickness and the expression levels of TLR 2, TLR 4 and NF-κB mRNAs in AS plaques were significantly increased (P<0.01). After the treatment, the elevated levels of plasma TC, TG, LDL and Apo-B, the aortic intima thickness and media thickness, and the expression levels of TLR 2, TLR 4 and NF-κB mRNAs in the 3 treatment groups were significantly down-regulated in comparison with the model group (P<0.05, P<0.01), while the decreased levels of Apo-A and HDL/LDL were considerably increased (P<0.01). Comparison among the 3 treatment groups showed that the therapeutic effects of the herbal-cake-separated moxibustion and medication were significantly superior to those of the direct moxibustion in down-regulating the levels of TC, TG, LDL, Apo-B, TLR 2 mRNA, TLR 4 mRNA and NF-κB mRNA, and reducing the thickness of the aortic intima and media, as well as in up-regulating the levels of Apo-A and HDL/LDL (P<0.05, P<0.01). No significant differences were found between the herbal-cake-separated moxibustion and medication groups in the above-mentioned indexes (P>0.05). Herbal-cake-separated moxibustion has a positive role in stabilizing AS vulnerable plaque in hyperglycemia rabbits, which may be associated with its effects in regulating blood lipid-apolipoprotein levels and inhibiting the expression of TLR 2, TLR 4 and NF-κB mRNAs in vulnerable plaques.

Preventive effect of Eucommia leaf extract on aortic media hypertrophy in Wistar-Kyoto rats fed a high-fat diet.

Eucommia ulmoides Oliver leaf extract (ELE) has been shown to have anti-hypertensive and anti-obesity effects in rats that are fed a high-fat diet (HFD). To explore the effects of chronic administration of ELE on body weight, blood pressure and aortic media thickness, 7-week-old male Wistar-Kyoto (WKY) rats were orally administered a normal diet, a 30% HFD, or a 5% ELE plus HFD ad libitum for 10 weeks. The HFD treatment caused mild obesity and hypertension in the normotensive rats, while rats receiving both ELE and the HFD had significantly lower body weights, less visceral and perirenal fat, lower blood pressure and thinner aortic media than the control rats receiving the HFD only. The plasma adiponectin/leptin ratio also improved in ELE-treated rats. Although plasma leptin levels were elevated in all HFD rats, adiponectin levels increased only in the ELE-treated rats. Anti-hypertensive and anti-obesity effects may be caused by the geniposidic acid (GEA) and/or asperuloside present in ELE. These findings suggest that chronic ELE administration prevents aortic media hypertrophy in early-stage obesity with hypertension. Long-term administration of ELE might inhibit the development of arteriosclerosis.

Puerarin protects against endothelial dysfunction and end-organ damage in Ang II-induced hypertension

ABSTRACTPuerarin, a major isoflavonoid compound from Chinese herb Kudzu roots, has been widely used for the treatment of hypertensive and cardiovascular diseases in China. Here, we investigated puerarin’s beneficial effects on the cardiovascular system in angiotensin (Ang) II-induced hypertensive rats. Sprague–Dawley rats were treated with Ang II for 5 days or with puerarin for 10 days followed by Ang II and puerarin for 5 days. Endothelium-dependent relaxation (EDR) to acetylcholine was determined using an organ chamber bath. Ang II increased the systolic blood pressure (SBP: 178 ± 5 mmHg vs. 112 ± 3 mmHg in control, p < 0.05), aortic (30%, p < 0.05), and left ventricular (LV) weight (23%); puerarin reduced SBP (160 ± 2 mmHg, p < 0.05), aortic, and left ventricular weight in Ang II-infused rats. Puerarin also reduced aortic medial thickness and myocardial cell surface area in Ang II-infused rats. Compared with control rats, Ang II infused rats exhibited an impaired EDR with reduction in the protein expression of phosphor-eNOS at Ser 1177 and an increase in the expression of gp91phox (85%), p22phox (113%), transforming growth factor β1 (145%) and vascular cell adhesion molecule 1 (82%). Puerarin improved EDR and reversed the changes in Ang II-induced protein expression of above molecules. Our results demonstrate that in Ang II-induced hypertensive rats, puerarin protects against endothelial dysfunction and end organ damage with a mild reduction in SBP, and that the cardiovascular beneficial effects of puerarin may be in part attributed to its anti-oxidant and upregulation of phosphor-eNOS.