Valsartan, a selective angiotensin II type 1 receptor (AT1R) blocker, lowers blood pressure by causing vascular smooth muscle cell relaxation and nitric oxide (NO) production in endothelium. However, the underlying mechanisms of valsartan on NO production are not fully understood. In this study, we sought to investigate the molecular mechanism of valsartan in activation of endothelial nitric oxide synthase (eNOS) in bovine aortic endothelial cells (BAECs). Treatment with valsartan increased NO production in a dose‐ and time‐dependent manner, while the protein level of eNOS was not affected. Furthermore, valsartan increased the phosphorylated levels of Akt and eNOS proteins. Specific inhibitors were utilized to clarify the critical kinases involved in valsartan‐mediated eNOS activation. Our results showed that LY294002, a PI3 kinase antagonist and SU6656, a Src kinase family antagonist markedly suppressed valsartan‐induced eNOS phosphorylation and NO production. On the other hand, we also found valsartan treatment increased phosphorylation of AT1R on tyrosine residues and reduced association of eNOS and AT1R. Pretreatment with SU6656, but not LY294002 reversed this dissociation between eNOS and AT1R, implying the requirement of tyrosine phosphorylation on AT1R for valsartan‐mediated reduction of eNOS‐AT1R interaction. Take together, our findings suggest that valsartan induced eNOS activation through Src/PI3/Akt signaling pathway and regulation on AT1R‐eNOS interaction.

We studied the cellular mechanisms underlying the acceleration effect of resistin on macrophage foam cell formation. In vivo studies demonstrated that resistin levels were elevated in atherosclerotic aortas of apolipoprotein E deficient mice compared with wildtype counterparts. In vitro studies showed that resistin increased lipid accumulation in rat macrophages treated with oxidized low‐density lipoprotein (oxLDL), as compared to control cells. Resistin also increased levels of mRNA and proteins of scavenger receptor class A (SR‐A) and CD36 (two types of SRs for internalization of oxLDL) and decreased protein level, but not mRNA level, of ATP‐binding cassette transporter‐A1 (ABCA1; a type of cholesterol exporter). The up‐regulations of SR‐A and CD36 by resistin were due to activation of AP‐1 and PPARγ, respectively, as evidenced by increased nuclear levels of these two transcriptional factors and by their preventions after pharmacological inhibition of AP‐1 (curcumin or SP600125) or PPARγ (GW9662). The down‐regulation of ABCA1 by resistin resulted from a more rapid degradation of protein via proteasome pathway, as revealed by its abolition after pharmacological inhibition (calpeptin or MG‐132) of the pathway. In conclusion, resistin may promote foam cell formation via dsyregulation of SR‐A, CD36 and ABCA1. SR‐A and CD36 are up‐regulated through transcription regulation, whereas ABCA1 is down‐regulated through proteasome‐mediated protein degradation.

ObjectiveAccumulation of foam cells in intima is the hallmark of early stage atherosclerotic lesion. Ginkgo Biloba extract (EGb761) has been reported to exert excellent anti‐oxidative and anti‐inflammatory properties in the development of atherosclerosis, yet the effect and the molecular mechanisms of EGb on the formation of macrophage foam cells are not fully understood.Methods and resultsTreatment with EGb761 resulted in a dose‐dependent decrease in oxLDL‐mediated cholesterol accumulation in macrophages, a result that was due to a decrease in cholesterol uptake and an increase in cholesterol efflux. Additionally, EGb treatment significantly decreased the mRNA and protein expression of class A scavenger receptor (SR‐A), while EGb had no effect on the expression of CD36, SR‐BI or ATP‐binding cassette (ABC) transporter G1. Furthermore, EGb increased the protein stability of ABCA1 by reducing calpain activity without affecting ABCA1 mRNA expression. Moreover, small interfering RNA (siRNA) targeting heme oxygenase‐1 (HO‐1) abolished the EGb‐induced protective effects on the expression of SR‐A and ABCA1 and calpain activity. Consistently, EGb‐mediated suppression on lipid accumulation in foam cells was also abrogated by HO‐1 siRNA.ConclusionEGb confers the protection from the formation of foam cells by an HO‐1‐dependent regulation on cholesterol homeostasis in macrophages.