.-Phosphatidylinositol 3-kinase (PI3K) is required for smooth muscle cell (SMC) proliferation. This study reports that inhibitors of PI3K also prevent SMC migration and block neointimal hyperplasia in an organ culture model of restenosis. Inhibition of neointimal formation by LY-294002 was concentration and time dependent, with 10 M yielding the maximal effect. Continuous exposure for at least the first 4 -7 days of culture was essential for significant inhibition. To assess the role of matrix metalloproteinases (MMPs) in this process, we monitored MMP secretion by injured vessels in culture. Treatment with LY-294002 selectively reduced active MMP-2 in media samples according to zymography and Western blot analysis without concomitant changes in latent MMP-2. Parallel results with wortmannin indicate that MMP-2 activation is PI3K dependent. Previous research has shown a role for both furin and membrane-type 1 (MT1)-MMP (MMP-14) in the activation of MMP-2. The furin inhibitor decanoylArg-Val-Lys-Arg-chloromethylketone did not prevent MMP-2 activation after balloon angioplasty. In contrast, balloon angioplasty induced a significant increase in the levels of MT1-MMP, which was suppressed by LY-294002. No change in MT1-MMP mRNA was observed with LY-294002, because equivalent amounts of this mRNA were present in both injured and noninjured vessels. These results implicate PI3K-dependent regulation of MT1-MMP protein synthesis and subsequent activation of latent MMP-2 as critical events in neointimal hyperplasia after vascular injury. matrix metalloproteinase; LY-294002; wortmannin; furin; restenosis PHOSPHATIDYLINOSITOL 3-KINASE (PI3K) is a heteromeric protein consisting of an 85-kDa (p85) regulatory subunit and a 110-kDa (p110) catalytic subunit. PI3K functions as a lipid kinase and phosphorylates phosphoinositides on the 3Ј position of the inositol ring. The biological functions of PI3K can be grouped into four distinct categories: mitogenic signaling, inhibition of apoptosis, cell adherence and motility, and intracellular vesicle trafficking (5). A role in cell motility and cell adherence was indicated by evidence showing PDGF-dependent membrane ruffling and chemotaxis requires an interaction between PI3K and the PDGF receptor (25,55). In addition, PI3K is involved in microtubule reassembly in response to both insulin and PDGF (21) and actin rearrangement by PDGF (59). The involvement of PI3K in growth factor regulation of integrins and cell adherence has also been established (16,23). In particular, PI3K has been shown to associate with focal adhesion kinase (FAK) as well as participate in PDGF-mediated phosphorylation of both FAK and paxillin (40). A recent study (41) has also demonstrated that PI3K promotes cell migration on fibronectin by facilitating the binding of FAK to Src and p130Cas
IntroductionGoal-directed therapy (GDT) has been shown in numerous studies to decrease perioperative morbidity and mortality. The mechanism of benefit of GDT, however, has not been clearly elucidated. Targeted resuscitation of the vascular endothelium with GDT might alter the postoperative inflammatory response and be responsible for the decreased complications with this therapy.MethodsThis trial was registered at ClinicalTrials.gov as NCT01681251. Forty patients undergoing elective open repair of their abdominal aortic aneurysm, 18 years of age and older, were randomized to an interventional arm with GDT targeting stroke volume variation with an arterial pulse contour cardiac output monitor, or control, where fluid therapy was administered at the discretion of the attending anesthesiologist. We measured levels of several inflammatory cytokines (C-reactive protein, Pentraxin 3, suppressor of tumorgenicity--2, interleukin-1 receptor antagonist, and tumor necrosis factor receptor-III) preoperatively and at several postoperative time points to determine if there was a difference in inflammatory response. We also assessed each group for a composite of postoperative complications.ResultsTwenty patients were randomized to GDT and twenty were randomized to control. Length of stay was not different between groups. Intervention patients received less crystalloid and more colloid. At the end of the study, intervention patients had a higher cardiac index (3.4 ± 0.5 vs. 2.5 ± 0.7 l/minute per m2, p < 0.01) and stroke volume index (50.1 ± 7.4 vs. 38.1 ± 9.8 ml/m2, p < 0.01) than controls. There were significantly fewer complications in the intervention than control group (28 vs. 12, p = 0.02). The length of hospital and ICU stay did not differ between groups. There was no difference in the levels of inflammatory cytokines between groups.ConclusionsDespite being associated with fewer complications and improved hemodynamics, there was no difference in the inflammatory response of patients treated with GDT. This suggests that the clinical benefit of GDT occurs in spite of a similar inflammatory burden. Further work needs to be performed to delineate the mechanism of benefit of GDT.Trial registrationClinicalTrials.gov Identifier: NCT01681251. Registered 18 May 2011.
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