Abstract 276: Systemic Delivery of Microrna-146a Improves Endothelial Function and Ameliorates Atherosclerosis in Apolipoprotein E-deficient Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Shuangtao Ma ◽  
Xiao Yu Tian ◽  
Chaofeng Mu ◽  
Haifa Shen ◽  
Yunrong Zhang ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Apolipoprotein E ◽  
Carotid Arteries ◽  
Treated Group ◽  
Vehicle Group ◽  
Early Event ◽  
Aortic Tissue ◽  
Systemic Delivery ◽  
Plaque Area ◽  
Deficient Mice

Rationale: Endothelial inflammation is an early event in the development of atherosclerosis. The microRNA (miR)-146a showed anti-inflammatory effects in cultured endothelial cells. In this study, we investigated the therapeutic role of miR-146a in endothelial function and atherosclerosis in apolipoprotein E (ApoE)-deficient mice. Methods and Results: The miR-146a was packaged into a multistage vector (MSV) that was conjugated with an E-selectin-targeting thioaptamer (ESTA) to form an ESTA-MSV microparticle. The ApoE-deficient mice were fed with Western diet and injected through tail vein with 15μg of miR-146a loaded ESTA-MSV microparticles or vehicle vectors biweekly for 12 weeks. The expressions of miR-146a in aortic tissue was increased by five times at two weeks after injection. However, the expressions of miR-146a in heart, lung, liver, spleen, kidney, and skeletal muscle were not increased. The acetylcholine-induced endothelium-dependent relaxations in both carotid arteries and aortas were significantly improved in mice from miR-146a treated group compared with vehicle group. In addition, the endothelium-dependent contractions of carotid arteries were also improved by miR-146a treatment. The en face oil red O staining of whole aortas showed the plaque area was decreased in miR-146a-treated mice. Application of miR-146a also decreased the plaque size, macrophages, and T-lymphocytes, but increased the collagen deposition and vascular smooth muscle cells in the sections of aortic roots. The PCR results showed that expressions of chemokine (C-C motif) ligand (CCL)-2, CCL-5, and CCL-8 were decreased by miR-146a. Conclusions: E-selectin-targeting delivery of miR-146a improves endothelial function and inhibits atherosclerosis.

scholarly journals Influence of Lactate Accumulation on Calcium Content of Ischemic and Postischemic Brain

1989 ◽  
Vol 9 (5) ◽  
pp. 640-645 ◽  
Author(s):  
V. MacMillan
Keyword(s):  
Carotid Arteries ◽  
Calcium Content ◽  
Treated Group ◽  
Sampling Time ◽  
Early Event ◽  
Lactate Accumulation ◽  
Vertebral Arteries ◽  
Eeg Abnormalities ◽  
Tissue Calcium

In this study, the cerebral hemisphere content of calcium as well as selected parameters of oxidative metabolism and electrophysiological function were assessed in normoglycemic and hyperglycemic rats that were exposed to ischemia produced by electrocautery of the vertebral arteries and reversible occlusion of the carotid arteries. In hyperglycemic animals, 0.5 h of ischemia was associated with large accumulations of lactate (27 mmol/kg), whereas normoglycemic animals showed lesser lactate accumulation (17 mmol/kg). At this sampling time (0.5 h of ischemia), both groups of ischemic animals showed tissue calcium contents that were unchanged from preischemic control levels. In normoglycemic animals, release of the carotid clamps and recirculation for 1.5–24 h was associated with normalization of lactate, ATP and phosphocreatine, clinical behavior, and EEC During this 24 h of recirculation, cerebral calcium levels showed no changes. Hyperglycemic ischemic animals recirculated for 1.5–24 h showed a persistent lactic acidosis, depressed ATP and phosphocreatine, gross EEG abnormalities, seizures, and a high mortality rate. Again, during this 24 h period, cerebral calcium content showed no changes from preischemic control or from the matched saline-treated group. These data suggest that significant accumulation of calcium in brain tissue is not an early event in ischemic-hyperglycemic brain damage, and thus does not provide support for a role of calcium in the production of this form of ischemic damage.

Selective Estrogen Receptor Modulator Idoxifene Inhibits Smooth Muscle Cell Proliferation, Enhances Reendothelialization, and Inhibits Neointimal Formation In Vivo After Vascular Injury

Circulation ◽  
2000 ◽  
Vol 102 (suppl_3) ◽  
Author(s):  
Tian-Li Yue ◽  
Lynne Vickery-Clark ◽  
Calvert S. Louden ◽  
Juan-Li Gu ◽  
Xin L. Ma ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Smooth Muscle ◽  
Vascular Injury ◽  
Von Willebrand Factor ◽  
Carotid Arteries ◽  
Treated Group ◽  
Vehicle Group ◽  
Receptor Modulator ◽  
Von Willebrand ◽  
Willebrand Factor

Background —Idoxifene (ID) is a tissue-selective estrogen receptor modulator (SERM). The pharmacological profile of ID in animal studies suggests that it behaves like an estrogen receptor (ER) agonist in bone and lipid metabolism while having negligible ER activity on the reproductive system. It is unknown whether ID retains the vascular protective effects of estrogen. Methods and Results —In cultured vascular smooth muscle cells (VSMCs), ID inhibited platelet-derived growth factor–induced DNA synthesis and mitogenesis with IC 50 values of 20.4 and 27.5 nmol/L, respectively. Treatment with ID resulted in S-phase cell cycle arrest in serum-stimulated VSMCs. ID 1 to 100 nmol/L significantly protected endothelial cells from tumor necrosis factor-α (TNF-α)–induced apoptosis in vitro. Virgin Sprague-Dawley rats ovariectomized 1 week before the study were treated with ID (1 mg · kg − 1 · d − 1 ) or vehicle by gavage for 3 days before balloon denudation in carotid artery. The SMC proliferation in injured vessels was determined by immunostaining for proliferating cell nuclear antigen (PCNA). The number of PCNA-positive SMCs was reduced by 69%, 82%, and 86% in the media at days 1, 3 and 7, respectively, and by 78% in the neointima at day 7 after injury in ID- versus vehicle-treated group ( P <0.01). ID significantly enhanced reendothelialization in the injured carotid arteries as determined by Evans blue stain and immunohistochemical analysis for von Willebrand factor. In the former assay, the reendothelialized area in injured vessels was 43% in ID-treated group versus 24% in the vehicle group ( P <0.05); in the latter assay, the numbers of von Willebrand factor–positive cells per cross section increased from 24.8 (vehicle) to 60.5 (ID) ( P <0.01) at day 14 after injury. In addition, the production of nitric oxide from excised carotid arteries was significantly higher in ID-treated than the vehicle group (8.5 versus 2.7 nmol/g, P <0.01). Finally, ID treatment reduced neointimal area and the ratio of intima to media by 45% and 40%, respectively ( P <0.01), at day 14 after balloon angioplasty. Conclusions —The results indicate that ID beneficially modulates the balloon denudation–induced vascular injury response. Inhibition of VSMC proliferation and acceleration of endothelial recovery likely mediate this protective effect of ID.

Abstract 919: Suppression of Abdominal Aortic Aneurysms in the Angiotensin II-infused ApoE Deficient Mice by Treatment with Chymase Inhibitor

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nao Inoue ◽  
Michiko Muramatsu ◽  
Denan Jin ◽  
Shinji Takai ◽  
Tetsuya Hayashi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Treated Group ◽  
Aortic Aneurysms ◽  
Aortic Diameter ◽  
Vehicle Group ◽  
Control Group ◽  
Abdominal Aortic ◽  
Chymase Inhibitor ◽  
Deficient Mice

Chymase promotes not only angiotensin II production but also matrix metalloproteinase (MMP)-9 activation, which have a critical role on development of abdominal aortic aneurysms (AAAs). The purpose of this study is to examine the effects of chymase inhibitor, NK3201, on the MMP-9 activity and development of AAA in the angiotensin II-induced apolipoprotein E (apoE)-deficient mice. Method: Angiotensin II (1000ng/kg/min) (vehicle group) or saline (control group) were infused into 16-week-old male apoE-deficient mice for 4 weeks. To examine the effect of chymase inhibition for AAA, we administered NK3201 (30mg/kg/day) to angiotensin II-infused group (NK3201-treated group) for the same period. At the end of angiotensin II infusion, we measured the diameters of suprarenal and infrarenal aorta. AAA severities were scored using the suprarenal aortic diameter/infrarenal aortic diameter ratio and presence of thrombus formation, i.e. under 2.0 was 0, from 2.0 to 2.5 was 1, from 2.5 to 3.0 was 2, over 3.0 was 3, and presence of thrombus was 4. We also determined the chymase and MMP-9 activities using total aorta. Results: The scores that reflected the progression and severity of AAA were increased in vehicle group compared with control group ( 2.35±0.30 vs. 0.27±0.12, p<0.01). This progression was inhibited in NK3201-treated group compared with vehicle group (1.13±0.35, p<0.05 vs. vehicle group). Chymase activity was significantly increased in vehicle group compared with control group. MMP-9 activity was also increased in vehicle group, however it was decreased significantly in NK3201-treated group.Discussion: We demonstrated that chymase inhibition could reduce AAA progression through inhibition of MMP-9 in angiotensin II-induced apoE-deficient mice. Chymase inhibitor might be a novel strategy for preventing AAAs.

IL-10 deficiency increases superoxide and endothelial dysfunction during inflammation

2000 ◽  
Vol 279 (4) ◽  
pp. H1555-H1562 ◽  
Author(s):  
Carol A. Gunnett ◽  
Donald D. Heistad ◽  
Daniel J. Berg ◽  
Frank M. Faraci
Keyword(s):  
Endothelial Function ◽  
Xanthine Oxidase ◽  
Carotid Arteries ◽  
Interleukin 10 ◽  
Vehicle Injection ◽  
Endothelium Dependent Relaxation ◽  
Deficient Mice ◽  
Lps Treatment

Little is known about the role of interleukin-10 (IL-10), an anti-inflammatory cytokine, in blood vessels. We used IL-10-deficient mice (IL-10 −/−) to examine the hypothesis that IL-10 protects endothelial function after lipopolysaccharide (LPS) treatment. The responses of carotid arteries were studied in vitro 6 h after injection of a relatively low dose of LPS (10 μg ip). In IL-10 −/− mice, the maximum relaxation to ACh (3 μM) was 56 ± 6% (means ± SE) after LPS injection and 84 ± 4% after vehicle injection ( P < 0.05). Thus endothelium-dependent relaxation was impaired in carotid arteries from IL-10 −/− mice after LPS injection. In contrast, this dose of LPS did not alter relaxation to ACh in vessels from wild-type (IL-10 +/+) mice. Relaxation to nitroprusside and papaverine was similar in arteries from both IL-10 −/− and IL-10 +/+ mice after vehicle or LPS injection. Because inflammation is associated with increased levels of reactive oxygen species, we also tested the hypothesis that superoxide contributes to the impairment of endothelial function by LPS in the absence of IL-10. Results using confocal microscopy and hydroethidine indicated that levels of superoxide are elevated in carotid arteries from IL-10 −/− mice compared with IL-10 +/+ mice after LPS injection. The impaired relaxation of arteries from IL-10 −/− mice after LPS injection was restored to normal by polyethylene glycol-suspended superoxide dismutase (50 U/ml) or allopurinol (1 mM), an inhibitor of xanthine oxidase. These data provide direct evidence that IL-10 protects endothelial function after an acute inflammatory stimulus by limiting local increases in superoxide. The source of superoxide in this model may be xanthine oxidase.

scholarly journals Moxibustion at CV4 alleviates atherosclerotic lesions through activation of the LXRα/ABCA1 pathway in apolipoprotein-E-deficient mice

2019 ◽  
Vol 37 (4) ◽  
pp. 237-243 ◽  
Author(s):  
Yingxue Cui ◽  
Juntian Liu ◽  
Chang Huang ◽  
Baixiao Zhao
Keyword(s):  
Apolipoprotein E ◽  
Thoracic Aorta ◽  
Serum Lipids ◽  
Plaque Area ◽  
Atherosclerotic Lesions ◽  
Liver X Receptor Α ◽  
Moxa Stick ◽  
And Control ◽  
Area Percentage ◽  
Deficient Mice

Objectives: To investigate the anti-atherogenic effect of moxibustion and whether it is mediated through the reverse cholesterol transport process. Methods: 8-week-old male apolipoprotein E deficient (ApoE−/− knockout) mice were randomly divided into two groups (n=10 per group): atherosclerosis (AS) and AS plus moxibustion (AS+M). C57BL/6J mice of the same background (n=10) were selected as controls. Mice in the AS+M group received indirect moxibustion with an ignited moxa stick held over CV4. Mice of the AS and control groups were restrained in the same holder with an unlit moxa stick held over CV4. All treatments were performed for 20 min per day, 6 days per week for 12 weeks. After the treatment, the mice were euthanased and their serum lipids were measured. The aortic roots and thoracic aortas were collected for haematoxylin and eosin and red oil O staining, respectively, to analyse the atherosclerotic lesions. Expression of adenosine triphosphate binding cassette (ABCA)A1/G1 and liver X receptor α (LXRα) in the thoracic aorta were examined with Western blotting. Results: The moxibustion-treated (AS+M) mice showed a significantly lower plaque area percentage in the aortic root and thoracic aorta, and higher expression of LXRα and ABCA1 in the thoracic aorta compared with the AS mice. No significant differences were found in average lipid area percentage in the thoracic aorta, or ABCG1 expression in the thoracic aorta, between mice in the AS+M and AS groups. Conclusion: Moxibustion treatment at CV4 suppressed the progression of atherosclerotic lesions in ApoE−/− mice. The anti-atherogenic effect of moxibustion may be achieved by: (1) regulation of lipid metabolism, and thus prevention of lipid accumulation; and (2) upregulation of LXRα- and ABCA1-mediated cholesterol efflux in the lesion area.

Arterial Injury Increases Expression of Inflammatory Adhesion Molecules in the Carotid Arteries of Apolipoprotein-E-Deficient Mice1

1999 ◽  
Vol 36 (5) ◽  
pp. 372-378 ◽  
Author(s):  
David R. Manka ◽  
Peter Wiegman ◽  
Salah Din ◽  
John M. Sanders ◽  
Samuel A. Green ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Adhesion Molecules ◽  
Carotid Arteries ◽  
Arterial Injury ◽  
Deficient Mice
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