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Proprotein convertase subtilisin/kexin 9 (PCSK9), a member of the protein-converting enzyme family, is highly expressed in adult hepatocytes and small intestinal enterocytes. To our knowledge, in this study, we demonstrate for the first time that PCSK9 is upregulated in a dose-dependent manner via oxidized low-density lipoprotein (oxLDL) stimulation in THP-1-derived macrophages. PCSK9 small interfering RNA (siRNA) suppresses the oxLDL-induced inflammatory cytokine expression in THP-1-derived macrophages. The exposure of macrophages to oxLDL markedly increased the expression of NF-κB protein in the nucleus. However, this effect was significantly attenuated by PCSK9 siRNA. These findings indicate that PCSK9 expression is induced by oxLDL, and that PCSK9 siRNA protects against inflammation via the inhibition of NF-κB activation in oxLDL-stimulated THP-1-derived macrophages. Our results suggest that PCSK9 may be used as a therapeutic target for the treatment of atherosclerosis since PCSK9 siRNA suppresses oxLDL-induced IκB-α degradation and NF-κB nuclear translocation into THP-1-derived macrophages.

This paper investigated the effects of ox-LDL on PCSK9, and the molecular mechanisms of PCSK9 siRNA-inhibited apoptosis induced by ox-LDL in human umbilical vein endothelial cells (HUVECs), to clarify the role of PCSK9 in atherosclerogenesis. HUVECs were incubated with ox-LDL for 24 h. The apoptosis was observed by Hoechst 33258 staining. The expression of PCSK9, LOX-1 mRNAs and proteins was detected by RT-PCR, western blot, respectively. The PCSK9 siRNAs labeled with fluorescence were transfected into HUVECs by Lipofectamine 2000. After transfection for 24 h, cells were treated with ox-LDL for 24 h, HUVECs apoptosis transfected siRNA was detected by Hoechst 33258 staining and flow cytometer. The expression of Bcl-2, Bax, caspase3, 8, 9 was detected by western blot. The activity of caspase3, 9 was detected by kits. Our results showed that apoptosis of HUVECs and the expressions of PCSK9 and LOX-1 were upregulated secondary to induction by ox-LDL in a concentration-dependent manner. However, ox-LDL-induced HUVEC apoptosis and PCSK9 expression, but not LOX-1 expression, were significantly reduced by PCSK9 siRNA. These results demonstrate a linkage between HUVEC apoptosis and PCSK9 expression. Furthermore, we detected the possible pathway involved in apoptotic regulation by PCSK9 siRNA; our results showed that the expression of Bcl-2 decreased, whereas that of Bax increased. In addition, ox-LDL enhanced the activity of caspase9 and then caspase3. Pretreatment of HUVECs with PCSK9 siRNA blocked these effects of ox-LDL. These findings suggest that ox-LDL-induced HUVECs apoptosis could be inhibited by PCSK9 siRNA, in which Bcl/Bax-caspase9-caspase3 pathway maybe was involved through reducing the Bcl-2/Bax ratio and inhibited the activation of both caspase9 and 3.

Hydrogen sulfide (H 2 S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide. It is physiologically generated by cystathionine-␥-lyase, cystathionine-␤-synthase, and 3-mercaptopyruvate sulfurtransferase. H 2 S has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems. Substantial evidence shows that H 2 S is involved in aging by inhibiting free-radical reactions, activating SIRT1, and probably interacting with the age-related gene Klotho. Moreover, H 2 S has been shown to have therapeutic potential in age-associated diseases. This article provides an overview of the physiological functions and effects of H 2 S in aging and age-associated diseases, and proposes the potential health and therapeutic benefits of H 2 S.

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