PubMed · 14853019
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E J MOEYS, A van der VALK. 1951-06-02. [Aortography].. https://pubmed.ncbi.nlm.nih.gov/14853019/
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Resveratrol-mediated heme oxygenase-1 (HO-1) induction has been shown to occur in primary neuronal cultures and is thought to have potential neuroprotective action. Further, antioxidant properties of resveratrol have been reported to protect against coronary heart disease. We attempted to examine resveratrol's HO-1 inducing potency and its induction regulation in human aortic smooth muscle cells (HASMC). We showed that resveratrol-mediated HO-1 induction occurred in concentration- and time-dependent manners, but only at low concentrations (1-10 microM), and that it was modulated at both the transcription and translation levels. Additionally, the results of our study showed that nuclear factor-kappa B (NF-kappaB) inhibitors eliminated resveratrol-mediated HO-1 induction and promoter activity, and that deletion of NF-kappaB binding sites in the HO-1 promoter region strongly reduced promoter activity, suggesting involvement of the NF-kappaB pathway in HO-1 induction by resveratrol. Suppression of NF-kappaB activity by resveratrol at high concentrations (> or =20 microM) has been reported to be attributed to its anti-inflammatory and anti-oxidative properties. Likewise, we showed that resveratrol at concentrations of > or =20 microM blocked the activity of NF-kappaB through suppression of I kappa-B alpha (IkappaBalpha) phosphorylation, which caused inhibition of HO-1 induction. Conversely, resveratrol in a range of 1-10 microM enhanced the phosphorylation and degradation of IkappaBalpha, a key step in NF-kappaB activation, resulting in HO-1 induction. Collectively, we suggest that resveratrol-mediated HO-1 expression occurs, at least in part, through the NF-kappaB pathway, which might contribute to resveratrol's vascular-protective effect at physiological concentrations after moderate red wine consumption.
C-reactive protein (CRP) is significantly associated with the risk of ischemic cardiovascular disease in epidemiological studies. To explore if CRP has a functional role, we investigated its effect on the gene expression profile of vascular endothelial cells. Human vascular endothelial cells (human umbilical vein endothelial cells and human aortic endothelial cells) were incubated with CRP at various concentrations (0-10 mug/ml). Microarray analysis showed that a total of 11 genes increased (IL-8, core promoter element binding protein, activin A, monocyte chemoattractant protein 1, Exostoses 1, Cbp/p300-interacting transactivator with Glu/Asp-rich COOH-terminal domain 2, plasminogen activator inhibitor 1, fibronectin-1, gravin, connexin43, and sortilin-related receptor-1) and 6 genes decreased (methionine adenosyltransferase 2A, tryptophan-rich basic protein, reticulocalbin 1, membrane-associated RING-CH protein VI, cytoplasmic dynein1, and annexin A(1)) by more than twofold for their mRNA levels. IL-8 was the most significantly upregulated gene (13.6-fold), which demonstrated a clear dose- and time-dependent pattern revealed by quantitative real-time PCR. Cell adhesion assay showed that CRP enhanced the monocyte adhesion to endothelial cell monolayer by 2-fold (P < 0.01), which was partially blocked by an anti-IL-8 antibody (34.2% inhibition, P < 0.01). Inhibition of ERK MAPK pathway using U0126 prevented CRP-induced IL-8 upregulation, and Western blot analysis revealed a rapid activation of ERK1/2 after CRP stimulation. These data showed that CRP can significantly influence gene expressions in vascular endothelium. The CRP-responsive genes suggested that CRP may have a broad functional role in cell growth and differentiation, vascular remodeling and solid tumor development.
Hyperglycemia increases expression of platelet-derived growth factor (PDGF)-beta receptor and potentiates chemotaxis to PDGF-BB in human aortic vascular smooth muscle cells (VSMCs) via PI3K and ERK/MAPK signaling pathways. The purpose of this study was to determine whether increased activation of protein kinase C (PKC) isoforms had a modulatory effect on the PI3K and ERK/MAPK pathways, control of cell adhesiveness, and movement. All known PKC isoforms were assessed but only PKCalpha and PKCbetaII levels were increased in 25 mmol/L glucose. However, only PKCbetaII inhibition affected (decreased) PI3K pathway and MAPK pathway activities and inhibited PDGF-beta receptor upregulation in raised glucose, and specific MAPK inhibition was required to completely block the effect of glucose. In raised glucose conditions, activity of the ERK/MAPK pathway, PI3K pathway, and PKCbetaII were all sensitive to aldose reductase inhibition. Chemotaxis to PDGF-BB (360 pmol/L), absent in 5 mmol/L glucose, was present in raised glucose and could be blocked by PKCbetaII inhibition. Formation of lamellipodia was dependent on PI3K activation and filopodia on MAPK activation; both lamellipodia and filopodia were eliminated when PKCbetaII was inhibited. FAK phosphorylation and cell adhesion were reduced by PI3K inhibition, and although MAPK inhibition prevented chemotaxis, it did not affect FAK phosphorylation or cell adhesiveness. In conclusion, chemotaxis to PDGF-BB in 25 mmol/L glucose is PKCbetaII-dependent and requires activation of both the PI3K and MAPK pathways. Changes in cell adhesion and migration speed are mediated mainly through the PI3K pathway.