Statins inhibit high glucose-mediated neutrophil–endothelial cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating production of endothelial nitric oxide

Omi, Hitoshi; Okayama, Naotsuka; Shimizu, Manabu; Fukutomi, Tatsuya; Imaeda, Kazuo; Okouchi, Masahiro; Itoh, Makoto

doi:10.1016/s0026-2862(02)00033-x

Cited by 41 publications

(24 citation statements)

References 32 publications

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“…Enhanced expression of adhesion molecules within the contusion area facilitates migration of leukocytes through brain parenchyma (Knoblach and Faden, 2002). Statin therapy has been shown to attenuate leukocyteendothelium interactions in hypercholesterolemic animals (Li et al, 2005) and to inhibit expression of endothelial adhesion molecules in stimulated endothelial cells (Omi et al, 2003) and monocytes (Niwa et al, 1996). Statins also interfere with multiple steps of leukocyte recruitment and migration into the CNS, either by suppressing cell surface receptors and adhesion molecule expression or by binding to leukocyte functionassociated antigen(s) (Weitz-Schmidt et al, 2001;Youssef et al, 2002;Daimon et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury

et al. 2007

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“…n=4 per group. Asterisks p<0.05 vs SD, section marks p<0.05 vs STZ + atorvastatin cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating the production of endothelial nitric oxide [45]; and (3) RHOA kinase inhibitors lead to increased eNOS levels and reduction of oxidative stress [13].…”

Section: Effect Of Atorvastatin On Lipid Profilementioning

confidence: 99%

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

et al. 2007

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Aims/hypothesis Emerging evidence suggests that statins exert beneficial effects beyond those predicted by their cholesterollowering actions. We investigated whether atorvastatin influences the development of left ventricular (LV) dysfunction, independently of cholesterol-lowering, in an experimental model of type 1 diabetes mellitus cardiomyopathy. Methods Streptozotocin-induced diabetic rats were treated with atorvastatin (50 mg/kg daily, orally) or with vehicle for 6 weeks. LV function was analysed using tip-catheter measurements. Cardiac stainings of TNF-α, IL-1β, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, CD11a/lymphocyte-associated antigen-1, CD11b/ macrophage antigen alpha, CD18/β2-integrin, ED1/CD68, collagen I and III, and Sirius Red were assessed by digital image analysis. Ras-related C3 botulinum toxin substrate (RAC1) and ras homologue gene family, member A (RHOA) activities were determined by RAC1 glutathione-S-transferasep21-activated kinase and rhotekin pull-down assays, respectively. Cardiac lipid peroxides were measured by a colorimetric assay. The phosphorylation state of p38 mitogen-activated protein kinase (MAPK) and endothelial nitric oxide synthase (eNOS) protein production were analysed by western blot. Results Diabetes was associated with induced cardiac stainings of TNF-α, IL-1β, cellular adhesion molecules, increased leucocyte infiltration, macrophage residence and cardiac collagen content. In contrast, atorvastatin reduced both intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function. This effect was paralleled with a normalisation of diabetes-induced RAC1 and RHOA activity, in the absence of LDL-cholesterol lowering. In addition, atorvastatin decreased diabetesinduced cardiac lipid peroxide levels and p38 MAPK phosphorylation by 1.3-fold (p<0.05) and 3.2-fold (p<0.0005), respectively, and normalised the reduced eNOS production caused by diabetes. Conclusions/interpretation These data indicate that atorvastatin, independently of its LDL-cholesterol-lowering capacity, reduces intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function in an experimental model of diabetic cardiomyopathy.

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“…Among its many roles, PKC activity is necessary for leukocyte recruitment 9 and free radical production by endothelial cells in diabetic atherosclerosis, 10 and mediates ICAM-1 upregulation. 11 PKC is a family of serine/threonine kinases which have been divided into 3 classes of isozymes based on their domain structure and activity profiles.…”

mentioning

confidence: 99%

Endothelial Protein Kinase C Isoform Identity and Differential Activity of PKCζ in an Athero-Susceptible Region of Porcine Aorta

Magid

Davies

2005

Circulation Research

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Abstract-Endothelial protein kinase C (PKC) signaling was investigated in different regions of normal porcine aorta. The locations map to differential atherosclerotic susceptibility and correlate with sites of disturbed (DF) or undisturbed (UF) local flow profiles. Endothelial lysates were isolated from the inner curvature of the aortic arch (DF; athero-susceptible) and a nearby UF region of the descending thoracic aorta (UF; athero-protected), and in some experiments a distant athero-protected UF site, the common carotid artery. Total endothelial PKC activity in the DF regions was 145% to 240% of that in both UF locations (PϽ0.05), whereas the UF regions were not significantly different from each other. PKC protein isoforms ␣, ␤, ⑀, , , and were expressed in similar proportions in both aortic regions, suggesting that differences of kinase activity were not directly attributable to expression levels. Inhibition of members of the "conventional" and "novel" PKC families had no differential effect on regional kinase activity. However, inhibition of PKC, a member of the "atypical" PKC family, reduced the DF lysate kinase activity to that of UF levels (NS Pϭ0.35). Differential phosphorylation of PKC Thr410 and Thr560, along with increased levels of PKC degradation products in UF endothelial lysates, suggested posttranslational modification of PKC as the basis for site-specific differences in vivo. Steady-state regional heterogeneity of an important family of regulatory proteins in intact arterial endothelium in vivo may link localized athero-susceptibility and the associated hemodynamic environment. (Circ Res. 2005;97:443-449.)Key Words: endothelial phenotypic heterogeneity Ⅲ site-specific PKC activity Ⅲ flow disturbance Ⅲ hemodynamics I n regions of the arterial vasculature that exhibit complex hemodynamics associated with laminar flow separations and transient turbulence (collectively "disturbed flow", DF), there is a predilection for the development of atherosclerotic lesions. 1 The regulation of endothelial biology by hemodynamic forces, particularly shear stress, is well established, 2 as is the link between endothelial functional changes, and by implication phenotype, to the focal initiation and development of lesions. 3 We have proposed that endothelial phenotypic heterogeneity within arteries over relatively short length scales accounts for localized athero-susceptibility while adjacent regions are protected. 4 The diversity of endothelial phenotype from different vascular beds persists in tissue culture as demonstrated by transcript profiles of cultured endothelial cells isolated from distinct anatomic locations. 5 Functional heterogeneity, demonstrated by variations in lymphocyte recruitment, has also been shown in endothelial cells cultured from different organs. 6 Investigations over a narrower spatial scale and conducted on endothelium directly isolated from fresh arteries has recently revealed differential transcriptional regulation of athero-protective and athero-susceptible pathways in discrete aortic...

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Statins inhibit high glucose-mediated neutrophil–endothelial cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating production of endothelial nitric oxide

Cited by 41 publications

References 32 publications

Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury

Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

Endothelial Protein Kinase C Isoform Identity and Differential Activity of PKCζ in an Athero-Susceptible Region of Porcine Aorta

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