Soluble form of vascular cell adhesion molecule 1 induces migration and proliferation of vascular smooth muscle cells.
ABSTRACT Serum levels of soluble vascular cell adhesion molecule 1 (sVCAM-1) shed from its membrane-bound form are elevated in hypertension. This study clarified the effects of sVCAM-1 on vascular responses in rat aortic smooth muscle cells (RASMCs).
Boyden chamber, 5-bromo-2'-deoxyuridine incorporation and ex vivo aortic ring assays for migration and proliferation, and Western blot for the kinase activity were used.
Spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were compared functionally. sVCAM-1 increased RASMC migration and proliferation, which were greater in SHR compared with WKY rats. RASMCs expressed the very late antigen 4alpha receptor integrin with no difference between SHR and WKY rats. Inhibitors of phosphoinositide kinase 3 (PI3K) and spleen tyrosine kinase (Syk) and small interference RNA-Syk abolished the sVCAM-1-induced migration, proliferation and phosphorylation of focal adhesion kinase. The phosphorylation of Syk was significantly greater in RASMCs from SHR than from WKY rats. sVCAM-1 increased aortic sprout outgrowth, which was inhibited by inhibitors of PI3K and Syk.
This study suggests that sVCAM-1 promotes the RASMC migration and proliferation via the focal adhesion kinase pathway regulated by Syk and PI3K, and the altered sVCAM-1-induced responses during hypertension are closely associated with the increments in intracellular signal transmission.
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ABSTRACT: Effect of long term cholesterol diet withdrawal on accelerated atherosclerosis in iliac artery of New Zealand White (NZW) rabbits has not been explored so far. Atherosclerosis was thus induced in rabbits by a combination of balloon injury and atherogenic diet (AD) (1% cholesterol and 6% peanut oil) feeding for 8 weeks (baseline) followed by chow diet (CD) feeding for 4, 8, 16, 32, 50 and 64 weeks. The plaque characterization was done using histology, real time RT-PCR and vasoreactivity studies. Significant elevation in plasma lipids with AD feeding was normalized following 16 weeks of CD feeding. However, baseline comparison showed advanced plaque features even after 8 weeks of CD period with significant elevation in intima/media thickness ratio and plaque area later showing reduction at 50 and 64 weeks CD periods. Lesion lipid accumulation and CD68 positivity was maintained till 16 weeks of CD feeding which significantly reduced from 32 to 64 weeks CD periods. Baseline comparison showed significant increase in ground substance, MMP-9 and significant decrease in α-actin and collagen content at 8 weeks CD period indicating features of unstable plaque. These features regressed up to 64 weeks of CD. Partial restoration of functional vasoconstriction and vasorelaxation was seen after 64 weeks of CD feeding. mRNA expression of MCP-1, VCAM-1, collagen type I and III, MMP-9, TIMP-1, IFN-γ, TNF-α, IL-10 and eNOS supported the above findings. The study thus reveals insights into initial plaque instability and subsequent regression on AD withdrawal in this model. These results are suggestive of an appropriate window for drug intervention for plaque stability/regression and restenosis as well as improves understanding of plaque regression phenomenon in this model.PLoS ONE 01/2013; 8(10):e77037. · 3.53 Impact Factor
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ABSTRACT: To identify the new targets for hypertension, we analyzed the protein expression profiles of aortic smooth muscle in spontaneously hypertensive rats (SHR) of various ages during the development of hypertension, as well as in age-matched normotensive Wistar-Kyoto (WKY) rats, using a proteomic analysis. The expressions of seven proteins were altered in SHR compared with WKY rats. Of these proteins, NADH dehydrogenase 1alpha, GSTomega1, peroxi-redoxin I and transgelin were upregulated in SHR compared with WKY rats. On the other hand, the expression of HSP27 and Ran protein decreased in SHR. The diminution of dihydrobiopterin reductase, an enzyme located in the regeneration pathways of tetrahydrobiopterin (BH4), was also prominent in SHR. The results from a PCR analysis revealed that the expression of BH4 biosynthesis enzymes - GTP cyclohydrolase-1 and sepiapterin reductase - decreased and increased, respectively, in SHR compared with WKY rats. The level of BH4 was less in aortic strips from SHR than from WKY rats. Moreover, treatment with BH4 inhibited aortic smooth muscle contraction induced by serotonin. These results suggest that the deficiency in BH4 regeneration produced by diminished dihydrobiopterin reductase expression is involved in vascular disorders in hypertensive rats.Proteomics 10/2009; 9(21):4851-8. · 4.43 Impact Factor
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ABSTRACT: Pustulosis palmaris et plantaris (PPP) is a tonsil-related disease that can be cured with tonsillectomy. Recent immunological studies have shown that hyperactivation of tonsillar T cells is caused by a hyperimmune response to α-streptococci; recruitment of the T cells to lesions may be involved in the pathogenesis of PPP. ß1 integrin, expressed on T cells, not only provides a costimulatory signal for T-cell activation but also facilitates the accumulation of T cells in inflammatory skin lesions. In this study, we found that expression of ß1 integrin on both tonsillar and peripheral blood CD4-positive T cells was higher in PPP patients than in non-PPP patients. In vitro stimulation with α-streptococcal antigen significantly enhanced ß1 integrin expression on tonsillar CD4-positive T cells in PPP patients, but not in non-PPP patients. The chemotactic response of tonsillar CD4-positive T cells to vascular cell adhesion molecule-1, the ß1 integrin ligand, was significantly better in PPP patients than in non-PPP patients. The percentage of ß1 integrin-positive peripheral blood CD4-positive T cells decreased after tonsillectomy in PPP patients. The numbers of ß1 integrin-positive T cells and the expression of vascular cell adhesion molecule-1 were more elevated in plantar PPP skin lesions than in normal skin. These results suggest that ß1 integrin may play a key role in the pathogenesis of PPP.Journal of Clinical Immunology 11/2010; 30(6):861-71. · 3.38 Impact Factor