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      Rhein Inhibits TNF-α-Induced Human Aortic Smooth Muscle Cell Proliferation via Mitochondrial-Dependent Apoptosis

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          Background: Vascular smooth-muscle cell proliferation plays an important role in atherosclerosis and restenosis. Rhein is an active component extracted from rhubarb. In this study, rhein was found to exert potent inhibitory effects against tumor necrosis factor (TNF)-α-induced human aortic smooth-muscle cells (HASMCs) proliferation. Method: These effects were associated with induced apoptosis, including the induction of Annexin V-positive cells, the cleavage of poly(ADP-ribose)polymerase (PARP), and caspases 3, 8 and 9. Results: Inhibitors of caspases 3, 8 and 9 were efficiently blocked by rhein-induced apoptosis in TNF-α-treated HASMCs. In addition, treatment with rhein resulted in the release of cytochrome c into the cytosol, a loss of mitochondrial membrane potential (ΔΨ<sub>m</sub>), a decrease in Bcl-2 and Bcl-xL and an increase in Bax and Bak expression. However, rhein-mediated apoptosis was blocked by a mitochondrial membrane depolarization inhibitor. These findings indicate that rhein-induced apoptosis occurred via a mitochondrial pathway. Furthermore, the inhibition of mitochondrial membrane depolarization was efficiently blocked by rhein-induced caspase-9 activity, which indicates that the rhein-induced caspase activation signal was downstream of the mitochondrial pathway. Taken together, the results of this study show that rhein inhibits TNF-α-induced HASMC proliferation via mitochondria-dependent apoptosis and that rhein has the potential to act as an anti-atherosclerosis agent.

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          Most cited references 16

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          Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.

          Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.
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            Biochemical pathways of caspase activation during apoptosis.

            Caspase activation plays a central role in the execution of apoptosis. The key components of the biochemical pathways of caspase activation have been recently elucidated. In this review, we focus on the two most well-studied pathways of caspase activation: the cell surface death receptor pathway and the mitochondria-initiated pathway. In the cell surface death receptor pathway, activation of caspase-8 following its recruitment to the death-inducing signaling complex (DISC) is the critical event that transmits the death signal. This event is regulated at several different levels by various viral and mammalian proteins. Activated caspase-8 can activate downstream caspases by direct cleavage or indirectly by cleaving Bid and inducing cytochrome c release from the mitochondria. In the mitochondrial-initiated pathway, caspase activation is triggered by the formation of a multimeric Apaf-1/cytochrome c complex that is fully functional in recruiting and activating procaspase-9. Activated caspase-9 will then cleave and activate downstream caspases such as caspase-3, -6, and -7. This pathway is regulated at several steps, including the release of cytochrome c from the mitochondria, the binding and hydrolysis of dATP/ATP by Apaf-1, and the inhibition of caspase activation by the proteins that belong to the inhibitors of apoptosis (IAP).
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              Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL.

              A growing body of evidence supports a role for mitochondria and mitochondria-derived factors in the cell death process. In particular, much attention has focused on cytochrome c, a key component of the electron transport chain, that has been reported to translocate from the mitochondria to the cytosol in cells undergoing apoptosis. The mechanism for this release is, as yet, unknown. Here we report that ectopic expression of Bax induces apoptosis with an early release of cytochrome c preceding many apoptosis-associated morphological alterations as well as caspase activation and subsequent substrate proteolysis. A loss of mitochondrial transmembrane potential was detected in vivo, although no mitochondrial swelling or loss of transmembrane potential was observed in isolated mitochondria treated with Bax in vitro. Caspase inhibitors, such as endogenous XIAP and synthetic peptide benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk), although capable of altering the kinetics and perhaps mode of cell death, had no influence on this release, suggesting that if cytochrome c plays a role in caspase activation it must precede this step in the apoptotic process. Mitochondrial permeability transition was also shown to be significantly prevented by caspase inhibition, indicating that the translocation of cytochrome c from mitochondria to cytosol is not a consequence of events requiring mitochondrial membrane depolarization. In contrast, Bcl-xL was capable of preventing cytochrome c release while also significantly inhibiting cell death. It would therefore appear that the mitochondrial release of factors such as cytochrome c represents a critical step in committing a cell to death, and this release is independent of permeability transition and caspase activation but is inhibited by Bcl-xL.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                June 2009
                10 January 2009
                : 46
                : 4
                : 375-386
                Cardiovascular Medical Research Center and Department of Prescriptionology, University of Dongguk, Gyeongju City, Republic of Korea
                189798 J Vasc Res 2009;46:375–386
                © 2009 S. Karger AG, Basel

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                Page count
                Figures: 7, References: 39, Pages: 12
                Research Paper


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