Abstract 500: Vitamin D Supplementation Attenuates ADAM-12-mediated Proliferation of Carotid Artery Smooth Muscle Cells of Hypercholesterolemic Swine

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Vikash Kansal ◽  
Eric B Patterson
Keyword(s):  
Vitamin D ◽  
Smooth Muscle ◽  
Carotid Artery ◽  
Protein Expression ◽  
Vitamin D Supplementation ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Tnf Α ◽  
Adam 12

Introduction: Risk of hypertension, peripheral artery disease, myocardial infarction and development of human atherosclerosis has been linked to vitamin D deficiency. Atheromatous cytokines, including IL-6, TNF-α and epidermal growth factor receptor (EGFR) family growth factors are released at the site of atherosclerosis and boost the activity of proteolytic enzymes such as ADAMs (a disintegrin and metalloproteinases). ADAM-12 cleaves proHB-EGF (Heparin-binding EGF-like growth factor) activating EGFR, resulting in increased proliferation of smooth muscle cells (SMCs). The aim of this study was to examine the effect of vitamin D on IL-6 and TNF-α-induced ADAM-12, pEGFR expression, HB-EGF release and SMC proliferation. Methods: Micro-swine were fed with vitamin D-deficient high cholesterol diet, high cholesterol diet containing 900 IU of vitamin D, and high cholesterol diet containing 3000 IU of vitamin D for total of 12 months. After six months, serum cholesterol levels of 500-600 mg/dL were achieved in all the three groups. The protein expression of ADAM-12 & pEGFR, and HB-EGF release, in presence or absence of IL-6, TNF-α and Calcitriol, in SMCs was quantified by western Blot. HB-EGF release was measured by ELISA. The proliferation was assayed by [3H]-Thymidine incorporation and cell counting method. Results: The protein expression of ADAM-12 & pEGFR, HB-EGF release were significantly reduced in carotid artery SMCs isolated from Vitamin D-supplemented swine. IL-6 and TNF-α treatment increased the protein expression of ADAM-12 & pEGFR and HB-EGF release in carotid artery SMCs. Proliferation capacity was higher in SMCs isolated from Vitamin D-deficient swine carotid artery, potentiated by IL-6 and TNF-α. Calcitriol inhibited the ADAM-12, pEGFR expression and HB-EGF released in SMCs of hypercholesterolemic swine. Calcitriol also inhibited the proliferation of carotid artery SMCs isolated from Vit D-deficient, D-sufficient and D-supplemented swine. Conclusion: Together, these results suggest that vitamin D deficiency enhances proliferation of SMCs, which is potentiated by atheromatous cytokines. Whereas, vitamin D supplementation regulates ADAM-12-mediated cleavage of proHB-EGF and activation of EGFR inhibiting SMC proliferation.

Abstract 279: Vitamin D3 Attenuates ADAM-12--Mediated Shedding of EGFR in Carotid Artery Smooth Muscle Cells of Hypercholesterolemic Swine

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Vikash Kansal ◽  
Swastika Sur ◽  
Velidi H Rao ◽  
Devendra K Agrawal
Keyword(s):  
Vitamin D ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Carotid Artery ◽  
Smooth Muscle Cells ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Mrna Transcripts ◽  
Adam 12

Deficiency of Vitamin D is linked to an increased risk of hypertension, peripheral artery disease, and myocardial infarction and is a major risk factor for the development of human atherosclerosis. Atheromatous cytokines, including TNF-α, IL-6 and IFN-γ, and EGF receptor family growth factors are released at the site of atherosclerosis and act on proteolytic enzymes, MMPs (matrix metalloproteinases), ADAMs (a disintegrin and metalloproteinases), and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs). ADAM-12 activates EGFR resulting in increased migration and proliferation of smooth muscle cells (SMCs). The aim of this study was to examine the effect of vitamin D on IL-6-induced ADAM-12 expression and SMC migration and proliferation. Micro-swine were fed with either vitamin D-deficient high cholesterol diet or high cholesterol diet containing 900 IU of vitamin D for 6 months. After six months when serum cholesterol levels ranged from 500-600 mg/dL, vitamin D-deficient group continued on the same deficient diet, whereas the other group received supplementation of vitamin D (1,000 IU/d) for 6 months. The mRNA expression of ADAM-12 and EGFR in whole carotid artery and in IL-6-treated SMCs was quantified by qPCR. The proliferation was assayed by CyQuant NF cell proliferation assay. The mRNA transcripts of ADAM-12 and EGFR were significantly increased in carotid arteries from Vitamin D-deficient than in vitamin D- supplemented swine. Treatment of SMCs with IL-6 also increased the mRNA transcripts of ADAM-12 and EGFR in vitamin D-deficient swine SMCs compared to vitamin D-supplemented swine SMCs. The cell proliferation was higher in SMCs isolated from Vitamin D-deficient swine carotid artery compared to vitamin D- supplemented swine carotid artery. Together, these results suggest that Vitamin D regulates ADAM-12-mediated activation of EGFR and vitamin D deficiency further enhances proliferation of SMCs, which is potentiated by atheromatous cytokines.

Abstract 469: Vitamin D Deficiency Potentiates Restenosis Following Coronary Angioplasty in Hypercholesterolemic Swine

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Gaurav K Gupta ◽  
Tanupriya Agrawal ◽  
Michael G Del Core ◽  
William J Hunter ◽  
Devendra K Agrawal
Keyword(s):  
Vitamin D ◽  
Coronary Artery ◽  
Vitamin D Deficiency ◽  
Balloon Angioplasty ◽  
Coronary Intervention ◽  
Vitamin D Supplementation ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Increased Risk

Introduction: Vitamin D is a sectosteroid that functions through vitamin D receptor (VDR), a transcription factor, which regulates various downstream signaling pathways and controls the transcription of many targets genes. Vitamin D deficiency is associated increased risk of incident congestive heart failure, myocardial infarction, and cardiovascular disease mortality. However, most of the studies which identified an association between lower vitamin D intake or lower 25-hydroxyvitamin D and increased risk of cardiovascular disease are observational or cross-sectional studies. There has been no careful study evaluating the effect of vitamin D supplementation on coronary artery disease outcome following coronary intervention. Objective: The purpose of this study was to examine the effect of vitamin D deficiency and vitamin D supplementation on coronary artery restenosis following balloon angioplasty in hypercholesterolemic Yucatan microswine. Methods: Twelve female microswine were fed vitamin D-deficient or vitamin D-sufficient high cholesterol diet. At six months, animals underwent coronary angioplasty. Following coronary intervention swine in the vitamin D-sufficient high cholesterol diet group received supplementation of 1,000 IU or 3,000 IU of vitamin D3. Six months later, angiogram was performed followed by optical coherence tomography to monitor the development of intimal hyperplasia and restenosis. At the end of 12 months animals were euthanized, coronary arteries were harvested and morphological and histological studies were performed. Results: Findings from the optical coherence tomography and histomorphometric studies showed a significant decrease in neointimal hyperplasia, increase in in-segment lumen diameter, and decrease in the intima-media ratio in coronary arteries following balloon angioplasty in swine with vitamin D supplementation compared to the animals with vitamin D-deficient status. In the in-vitro studies, calcitriol inhibited proliferation of coronary artery smooth muscle cells. Conclusion: These data suggest that vitamin D deficiency increases intimal hyperplasia and restenosis following coronary balloon angioplasty in hypercholesterolemic swine. Since vitamin D inhibits smooth muscle cell proliferation, supplementation of non-secosteroidal VDR ligands prior to coronary intervention could help in preventing the neointimal formation and restenosis.

SHORT TERM HIGH CHOLESTEROL DIET CAUSES CHANGES IN MEGAKARYOCYTE SIZE AND IN VASCULAR ULTRASTRUCTURE

1987 ◽  
Author(s):  
S Dalby Kristensen ◽  
K M Roberts ◽  
J Lawry ◽  
J F Martin
Keyword(s):  
Smooth Muscle ◽  
Normal Diet ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Short Term ◽  
Transmission Electron ◽  
Perfusion Fixation ◽  
And Migration ◽  
Proliferation And Migration

Platelets produced by megakaryocytes (MK) have a role in atherogenesis. Six pairs of male litter mate rabbits were randomised to feeding with either 2g of cholesterol daily in addition to their normal diet or normal diet alone. After seven days the animals were killed and serum cholesterol, platelet count, MK total, cytoplasmic and nuclear area (microscopic planimetry) and MK DNA content cell distribution (fluorescent activated cell sorting) were measured and compared between the two groups. The results are given in the table as medians with range values in brackets.After perfusion-fixation the aortas were examined by transmission electron microscopy. In the aortas from the animals on high cholesterol diet cells with ultrastructural features resembling smooth muscle cells were found in the intima. Changes in megakaryocyte size are associated with the occurrence of smooth muscle cell proliferation and migration. The platelet-megakaryocyte axis may be activated in early atherogenesis.

Effects of low-dose ketanserin on atherosclerosis in rats and rabbits

2010 ◽  
Vol 88 (11) ◽  
pp. 1054-1060 ◽  
Author(s):  
Yong-Sheng Yu ◽  
He-Hui Xie ◽  
Ling Li ◽  
Shu-Wei Song ◽  
Ping Han ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vitamin D ◽  
New Zealand ◽  
Treatment Group ◽  
Low Dose ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
New Zealand White Rabbits

The present study was designed to test the hypothesis that a small dose of ketanserin, which enhances baroreflex activity, prevents the early lesions of atherosclerosis. In experiment 1, baroreflex sensitivity (BRS) was measured in 31 spontaneously hypertensive rats (SHRs) in a conscious state using a computerized blood pressure monitoring system. Four weeks later, the rats were administered vitamin D3 and fed a high-cholesterol diet for 8 weeks to induce atherosclerosis. Then their hearts and aortae were removed for pathological examination. A negative correlation was found between BRS and the scores of coronary (r = –0.460, P < 0.01) and aortic atherosclerosis (r = –0.448, P < 0.05) in SHR. In experiment 2, SHRs were divided into 3 groups (n = 10 in each group) and received a dose of ketanserin of 0.3, 1.0, and 3.0 mg/kg (i.g.), respectively. At the smallest dose (0.3 mg/kg), ketanserin did not lower blood pressure but enhanced BRS. In experiment 3, SHRs were administered vitamin D3, fed a high-cholesterol diet, and simultaneously treated with low-dose ketanserin. The atherosclerosis scores of the treatment group were significantly lower than those of the control group (coronary score: 0.90 ± 0.14 vs. 1.76 ± 0.27, P < 0.05; aortic scores: 1.00 ± 0.39 vs. 2.18 ± 0.41, P < 0.05). In experiment 4, male New Zealand White rabbits were fed a high-cholesterol diet and treated with low-dose ketanserin at the same time. The atherosclerosis scores of the treatment group were significantly lower than those of the control group (aortic scores: 0.26 ± 0.20 vs. 0.60 ± 0.31, P < 0.05). In conclusion, the present study demonstrated, for the first time, that low-dose ketanserin prevented the development of atherosclerosis independent of its blood pressure lowering action in SHRs and New Zealand White rabbits at least in part via enhancement of arterial baroreflex function.

scholarly journals Oxidized Low-Density Lipoprotein-Deteriorated Psoriasis Is Associated with the Upregulation of Lox-1 Receptor and Il-23 Expression In Vivo and In Vitro

2018 ◽  
Vol 19 (9) ◽  
pp. 2610 ◽  
Author(s):  
Chun-Ming Shih ◽  
Chien-Yu Huang ◽  
Kuo-Hsien Wang ◽  
Chun-Yao Huang ◽  
Po-Li Wei ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Cholesterol Diet ◽  
Low Density ◽  
Hacat Cells ◽  
Cholesterol Diet ◽  
Oxidized Low Density Lipoprotein ◽  
High Cholesterol ◽  
Tnf Α

Psoriasis is a chronic inflammatory skin disease. Even though scientists predict that abnormalities in lipid metabolism play an important role in the pathogenesis of psoriasis, the actual underlying mechanisms are still unclear. Therefore, understanding the possible relationship between mechanisms of the occurrence of psoriasis and dyslipidemia is an important issue that may lead to the development of effective therapies. Under this principle, we investigated the influences of hyperlipidemia in imiquimod (IMQ)-induced psoriasis-like B6.129S2-Apoetm1Unc/J mice and oxidized low-density lipoprotein (oxLDL) in tumor necrosis factor (TNF)-α-stimulated Hacat cells. In our study, we showed that a high-cholesterol diet aggravated psoriasis-like phenomena in IMQ-treated B6.129S2-Apoetm1Unc/J mice. In vitro analysis showed that oxLDL increased keratinocyte migration and lectin-type oxLDL receptor 1 (LOX-1) expression. Evidence suggested that interleukin (IL)-23 was a main cytokine in the pathogenesis of psoriasis. High-cholesterol diet aggravated IL-23 expression in IMQ-treated B6.129S2-Apoetm1Unc/J mice, and oxLDL induced IL-23 expression mediated by LOX-1 in TNF-α-stimulated Hacat cells. Therefore, it will be interesting to investigate the factors for the oxLDL induction of LOX-1 in psoriasis. LOX-1 receptor expression may be another novel treatment option for psoriasis and might represent the most promising strategy.

Abstract 12315: Four-and-a-Half LIM Domain Protein-2 Absence Reduces Atherogenesis in Apolipoprotein E-deficient Mice: Role of Monocytic Immune Cells

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Talin Ebrahimian ◽  
David Simon ◽  
Stefania Simeone ◽  
Catherine A Lemarié ◽  
Maryam Heidari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Smooth Muscle ◽  
Apolipoprotein E ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
Lim Domain ◽  
High Cholesterol ◽  
High Fat ◽  
Lim Domain Protein ◽  
Domain Protein

Background: Four-and-a-half LIM domain protein-2 (FHL2) is expressed in endothelial and vascular smooth muscle cells. It negatively regulates endothelial cell survival and migration, but its role in atherogenesis is unknown. Methods and Results: FHL2-deficient (FHL2-/-) mice were crossed with apolipoprotein E-deficient (ApoE-/-) mice to generate ApoE/FHL2-/- mice. After high-fat, high-cholesterol diet, ApoE/FHL2-/- mice displayed significantly smaller atherosclerotic plaques than ApoE-/- mice in the aortic sinus, the brachiocephalic artery and the aorta. This was associated with significantly enhanced collagen and smooth muscle cell contents and a significant 2-fold reduction of macrophage content within the plaques of ApoE/FHL-2-/- vs ApoE-/- mice. There was a significant reduction in aortic ICAM-1 mRNA and VCAM-1 protein expression in the plaques of ApoE/FHL2-/- mice. Aortic gene expression of CX3CL1 and CCL5 was significantly increased in ApoE/FHL2-/- vs ApoE-/- mice. Peritoneal thioglycollate injection elicited equivalent numbers of monocytes and macrophages in both groups, but a significantly lower number of pro-inflammatory Ly6C-high monocytes were recruited in ApoE/FHL2-/- vs ApoE-/- mice. Furthermore, mRNA levels of CX3CR1 were 2-fold higher in monocytes from ApoE/FHL2-/- vs ApoE-/- mice. Finally, we investigated the potential importance of myeloid cell FHL2 deficiency in atherosclerosis. After being irradiated, ApoE-/- or ApoE/FHL2-/- mice were transplanted with ApoE-/- or ApoE/FHL2-/- bone marrow. After high-fat, high-cholesterol diet, both chimeric groups developed significantly smaller plaques than ApoE-/- mice transplanted with ApoE-/- bone marrow. Conclusion: These results suggest that FHL2 in both myeloid and vascular cells may play an important role in atherogenesis by promoting pro-inflammatory chemokine production, adhesion molecule expression, and pro-inflammatory monocyte recruitment.

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