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      Adenovirus-Encoded Hammerhead Ribozyme to PDGF A-Chain mRNA Inhibits Neointima Formation after Arterial Injury

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          To develop a strategy for gene therapy of restenosis following coronary angioplasty, we examined the effects of a recombinant adenovirus vector encoding a hammerhead ribozyme specific for rat platelet-derived growth factor (PDGF) A-chain mRNA (Ad.Ribozyme) and a control recombinant adenovirus vector encoding the Escherichia coli LacZ gene (Ad.LacZ) on neointima formation in rat carotid artery after balloon injury. Ad.Ribozyme (10<sup>8</sup> PFU/ml) markedly reduced the increased expression of PDGF A-chain mRNA and protein. Ad.Ribozyme significantly decreased the intima/media ratio (68%) of the injured artery, whereas Ad.LacZ had no effect on the intima/media ratio. Most carotid arteries developed thrombi by 14 days after balloon injury, whereas Ad.Ribozyme completely inhibited thrombus formation. Expression of thromboxane A<sub>2</sub> (TXA<sub>2</sub>) receptor mRNA was significantly increased after balloon injury. Ad.Ribozyme significantly decreased the levels of TXA<sub>2</sub> receptor. Expression of prostaglandin I<sub>2</sub> (PGI<sub>2</sub>) synthase mRNA was significantly decreased after balloon injury. Ad.Ribozyme significantly increased levels of PGI<sub>2</sub> synthase mRNA after balloon injury. The observation that adenovirus-encoded ribozyme to PDGF A-chain inhibits neointima formation may serve as a novel strategy to prevent restenosis after coronary angioplasty. Inhibition of growth factors by genetic approaches may yield new insights into the mechanisms underlying responses to vascular injury and lead to new therapeutic applications.

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          Most cited references 26

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          Role of prostacyclin in the cardiovascular response to thromboxane A2.

          Thromboxane (Tx) A2 is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA2 formation by platelet cyclooxygenase (COX-1). Prostacyclin (PGI2) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor (IP) but are depressed in mice genetically deficient in the TxA2 receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TxA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI2 but not TxA2.
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            Ribozymes as potential anti-HIV-1 therapeutic agents.

            Certain RNA molecules, called ribozymes, possess enzymatic, self-cleaving activity. The cleavage reaction is catalytic and no energy source is required. Ribozymes of the "hammerhead" motif were identified in plant RNA pathogens. These ribozymes possess unique secondary (and possibly tertiary) structures critical for their cleavage ability. The present study shows precise cleavage of human immunodeficiency virus type 1 (HIV-1) sequences in a cell-free system by hammerhead ribozymes. In addition to the cell-free studies, human cells stably expressing a hammerhead ribozyme targeted to HIV-1 gag transcripts have been constructed. When these cells were challenged with HIV-1, a substantial reduction in the level of HIV-1 gag RNA relative to that in nonribozyme-expressing cells, was observed. The reduction in gag RNA was reflected in a reduction in antigen p24 levels. These results suggest the feasibility of developing ribozymes as therapeutic agents against human pathogens such as HIV-1.
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              Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture.

              The purpose of this study was to determine whether different components of human atherosclerotic plaques exposed to flowing blood resulted in different degrees of thrombus formation. It is likely that the nature of the substrate exposed after spontaneous or angioplasty-induced plaque rupture is one factor determining whether an unstable plaque proceeds rapidly to an occlusive thrombus or persists as a nonocclusive mural thrombus. Although observational data show that plaque rupture is a potent stimulus for thrombosis, and exposed collagen is suggested to have a predominant role in thrombosis, the relative thrombogenicity of different components of human atherosclerotic plaques is not well established. We investigated thrombus formation on foam cell-rich matrix (obtained from fatty streaks), collagen-rich matrix (from sclerotic plaques), collagen-poor matrix without cholesterol crystals (from fibrolipid plaques), atheromatous core with abundant cholesterol crystals (from atheromatous plaques) and segments of normal intima derived from human aortas at necropsy. Specimens were mounted in a tubular chamber placed within an ex vivo extracorporeal perfusion system and exposed to heparinized porcine blood (mean [+/- SEM] activated partial thromboplastin time ratio 1.5 +/- 0.04) for 5 min under high shear rate conditions (1,690 s-1). Thrombus was quantitated by measurement of indium-labeled platelets and morphometric analysis. Under similar conditions, substrates were perfused with heparinized human blood (2 IU/ml) in an in vitro system, and thrombus formation was similarly evaluated. Thrombus formation on atheromatous core was up to sixfold greater than that on other substrates, including collagen-rich matrix (p = 0.0001) in both heterologous and homologous systems. Although the atheromatous core had a more irregular exposed surface and thrombus formation tended to increase with increasing roughness, the atheromatous core remained the most thrombogenic substrate when the substrates were normalized by the degree of irregularity as defined by the roughness index (p = 0.002). The atheromatous core is the most thrombogenic component of human atherosclerotic plaques. Therefore, plaques with a large atheromatous core content are at high risk of leading to acute coronary syndromes after spontaneous or mechanically induced rupture because of the increased thrombogenicity of their content.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                August 2004
                30 September 2004
                : 41
                : 4
                : 305-313
                aSecond Department of Internal Medicine, Nihon University School of Medicine, and bDepartment of Advanced Medicine, Division of Cell Regeneration and Transplantation, Nihon University School of Medicine, Tokyo, Japan
                78928 J Vasc Res 2004;41:305–313
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 39, Pages: 9
                Research Paper


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