The transcriptional factor nuclear factor-kappaB (NFkappaB) plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes that might be involved in myocardial damage after ischemia and reperfusion. Therefore, we hypothesized that synthetic double-stranded DNA with high affinity for NFkappaB could be introduced in vivo as "decoy" cis elements to bind the transcriptional factor and to block the activation of genes mediating myocardial infarction, thus providing effective therapy for myocardial infarction. Treatment before and after infarction by transfection of NFkappaB decoy, but not scrambled decoy, oligodeoxynucleotides before coronary artery occlusion or immediately after reperfusion had a significant inhibitory effect on the area of infarction. Here, we report the first successful in vivo transfer of NFkappaB decoy oligodeoxynucleotides to reduce the extent of myocardial infarction following reperfusion, providing a new therapeutic strategy for myocardial infarction.
Klotho is a senescence suppressor protein that, when overexpressed, extends the lifespan of mice. Klotho-disrupted mice exhibit atherosclerosis and endothelial dysfunction, which led us to investigate the effect of the Klotho protein on vascular inflammation, particularly adhesion molecule expression. In this study, human umbilical vein endothelial cells (HUVECs) were preincubated with Klotho protein and then exposed to tumor necrosis factor-alpha (TNF-alpha) or vehicle. Reverse transcription-PCR and Western blot analyses revealed that Klotho suppressed TNF-alpha-induced expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). NF-kappaB activation, IkappaB phosphorylation induced by TNF-alpha were also attenuated by Klotho protein administration. The inhibition of eNOS phosphorylation by TNF-alpha was reversed by Klotho. Furthermore, Klotho inhibited TNF-alpha-induced monocyte adhesion to HUVECs and suppressed adhesion molecule expression in an organ culture of the rat aorta. These results suggest that Klotho suppresses TNF-alpha-induced expression of adhesion molecules and NF-kappaB activation. Klotho may have a role in the modulation of endothelial inflammation.
The feasibility of a novel therapeutic strategy using angiogenic growth factors to expedite and/or augment collateral artery development has recently entered the realm of treatment of ischemic diseases. Hepatocyte growth factor (HGF) is a novel member of endothelium-specific growth factors whose mitogenic activity on endothelial cells is very potent. Although it has been demonstrated that HGF is a potential angiogenic growth factor in in vitro culture systems, there is no direct in vivo evidence for the angiogenic activity of HGF in physiological conditions. In this study, we hypothesized that transfection of HGF gene into infarcted myocardium could induce angiogenesis, potentially resulting in a beneficial response to hypoxia. Human HGF gene or control vector driven by the SR␣ promoter was transfected into rat myocardium by the HVJ-liposome method. Four days after in vivo transfection of human HGF gene, there was a marked increase in human immunoreactive HGF as compared with control vector (P Ͻ 0.01). In myocardium transfected with HGF vector, a significant increase in PCNA-positive endothelial cells was observed, while few PCNA-positive endothelial cells were detected in both control-vector-transfected and untreated myocardium. The number of vessels around
Abstract-Adiponectin is emerging as an important molecule in obesity, the metabolic syndrome, and cardiovascular disease. On the other hand, smoking habit is well known to be related to cardiovascular disease and hypertension. To examine the association between adiponectin concentration and smoking habit, we performed an epidemiological survey and an acute exposure test in humans and an experiment in adipocytes to elucidate the mechanism underlying the association between adiponectin and smoking. In the epidemiological study, we enrolled a total of 331 male subjects to examine chronic smoking exposure. Plasma adiponectin was significantly lower (Pϭ0.01) in current smokers (5.3Ϯ0.3 g/mL) than in never-smokers (6.5Ϯ0.4 g/mL). A significant association between smoking and low adiponectin level was also confirmed in multiple regression analysis including age, body mass index, hypertension, diabetes, hyperlipidemia, and creatinine clearance (never-smokers 6.5Ϯ0.4 g/mL; past smokers 5.6Ϯ0.3 g/mL; current smokers 5.2Ϯ0.4 g/mL; Fϭ4.52; Pϭ0.01). To examine the acute effect of smoking on adiponectin concentration for 12 hours, we measured plasma adiponectin level in 5 male never-smokers before smoking and 3, 6, and 12 hours after smoking, with the result that adiponectin showed a significant decrease after smoking (12 hours; Ϫ14.5Ϯ0.6%; PϽ0.01). In cultured mouse 3T3-L1 adipocytes, H 2 O 2 and nicotine reduced the mRNA expression and secretion of adiponectin in a dose-dependent manner. Smoking habit is associated with adiponectin concentration in men, and its suppressive effect is mediated in part through direct inhibition of smoking on adiponectin expression in adipocytes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.