Abstract-Diabetes mellitus (DM) is a primary risk factor for cardiovascular disease. Although recent studies have demonstrated an important role for extracellular matrix metalloproteinases (MMPs) in atherosclerosis, little is known about the effects of hyperglycemia on MMP regulation in vascular cells. Gelatin zymography and Western blot analysis revealed that the activity and expression of 92-kDa (MMP-9) gelatinase, but not of 72 kDa (MMP-2) gelatinase, were significantly increased in vascular tissue and plasma of two distinct rodent models of DM. Bovine aortic endothelial cells (BAECs) grown in culture did not express MMP-9 constitutively; however, chronic (2-week) incubation with high glucose medium induced MMP-9 promoter activity, mRNA and protein expression, and gelatinase activity in BAECs.On the other hand, high glucose culture did not change MMP-9 activity from vascular smooth muscle cells or macrophages. Electron paramagnetic resonance studies indicate that BAECs chronically grown in high glucose conditions produce 70% more ROS than do control cells. Enhanced MMP-9 activity was significantly reduced by treatment with the antioxidants polyethylene glycol-superoxide dismutase and N-acetyl-L-cysteine but not by inhibitors of protein kinase C. In conclusion, vascular MMP-9 activity is increased in DM, in part because of enhanced elaboration from vascular endothelial cells, and oxidative stress plays an important role. This novel mechanism of redox-sensitive MMP-9 expression by hyperglycemia may provide a rationale for antioxidant therapy to modulate diabetic vascular complications. (Circ Res. 2001;88:1291-1298.)Key Words: endothelium Ⅲ atherosclerosis Ⅲ gelatinase Ⅲ oxidative stress Ⅲ remodeling C ardiovascular complications are the leading cause of morbidity and mortality in patients with diabetes mellitus (DM). 1,2 Because the onset and progression of complications are delayed in patients with good glycemic control, 3 hyperglycemia is thought to be an important regulator of vascular lesion development. Recent studies indicate that elevated glucose concentrations can induce dysfunction of several intracellular signal transduction cascades, including modulation of protein kinase C (PKC), activation of mitogenactivated protein kinase, generation of reactive oxygen species (ROS), and accumulation of advanced glycation end products (AGEs). 4,5 However, the underlying mechanisms between hyperglycemia and vascular disease remain unclear.Matrix metalloproteinases (MMPs) are members of a family of Zn 2ϩ -and Ca 2ϩ -dependent endopeptidases, which are essential for cellular migration and tissue remodeling in both physiological and pathological conditions. 6 MMPs are secreted by many types of cells as proenzymes. On activation by proteolytic cleavage, activated enzymes are capable of degrading many extracellular matrix components. Because MMPs appear to be involved in monocyte invasion and vascular smooth muscle cell migration, derangement of MMP regulation is considered to be a critical factor in the development of...

Abstract-Advanced age is associated with endothelial dysfunction and increased risk for atherosclerosis. However, the mechanisms for these observed effects are not clear. To clarify the association between aging and loss of endothelial function, young human aortic endothelial cells (HAECs), senescent HAECs transfected with control vector, and immortalized HAECs containing human telomerase reverse transcriptase (hTERT) were compared for expression of endothelial nitric oxide synthase (eNOS) and production of NO. To investigate a specific function modulated by endothelial NO, adhesion of monocytes under basal conditions as well as after exposure to TNF-␣ was assessed. A decrease in eNOS mRNA, protein, and activity was observed in endothelial cells at senescence as compared with young HAEC; this effect was blunted in hTERT cells. In all cells, shear stress induced a greater increase in the expression of eNOS protein with the final result being higher levels in hTERT compared with senescent cells. Basal monocyte binding was significantly elevated on aged endothelial cells compared with parental and hTERT cells. Exposure of TNF-␣ resulted in a 2-fold increase in monocyte adhesion in senescent cells, whereas this effect was reduced in cells transfected with hTERT. Prior exposure to fluid flow significantly reduced subsequent monocyte adhesion in all groups. These studies demonstrate that replicative aging results in decreased endothelial expression of eNOS accompanied by enhanced monocyte binding. Key Words: aging Ⅲ telomerase Ⅲ atherosclerosis Ⅲ nitric oxide Ⅲ shear stress V ascular endothelial cells play an important role in maintaining normal vascular homeostasis by producing a balance of paracrine factors such as nitric oxide (NO) and angiotensin II. Many of these factors are known not only to play an important role in the regulation of vessel tone, but also have dramatic effects on vascular structure. Nitric oxide, for example, is not only a potent vasodilator, but it also inhibits platelet adhesion and reactivity, smooth muscle proliferation, and leukocyte adhesion. 1 Because each of these processes is thought to be important in the development of atherosclerosis, nitric oxide is hypothesized to be an important endogenous antiatherogenic molecule.Nitric oxide is produced from the conversion of L-arginine to L-citrulline by the enzyme nitric oxide synthase (NOS). 2 In endothelial cells, the constitutive isoform, eNOS (NOSIII) is responsible for endothelium-derived NO production. In vivo, the predominant physiological stimulus for NO is wall shear stress. 3 NO is produced in response to not only the specific level of shear but also to acute changes in blood flow.Interestingly, eNOS expression is also shear responsive with increasing levels of laminar shear stress resulting in enhanced eNOS mRNA and protein. 4 Because NO has important regulatory function in atherogenesis, increased eNOS expression by laminar shear stress has been hypothesized to be a factor in the resistance of specific vascular segments to atheros...

We described perfluorocarbon encapsulated in mesoporous silica nanoparticles which enabled dual modal imaging (NIR/19F MRI) and drug delivery.