Agents and actions. Supplements最新文献

A variety of in-vitro antiatherosclerotic actions, among them those on vascular smooth muscle cells (mitotic activity, proliferation, extracellular matrix production), have been identified especially for PGE1 and PGI2, and proven in experimental animals. Ex-vivo data in humans are not yet available. We examined the effect of PGE1-, PGI2- and iloprost therapy of various duration (1-4 weeks) on smooth muscle cells (mitosis, proliferation, prostaglandin formation from exogenous and endogenous substrate) derived from vascular surgery samples. In-vivo PG-therapy decreases [3H]-thymidine incorporation as well as [35]S- and [14C]-proline uptake. These effects are dependent on the duration of treatment, PGE1 being trendwise more effective. Arachidonic acid conversion to PGI2 is significantly enhanced in activated smooth muscle cells of the plaque, both in the intima as well as in the media. Due to the activation of the gene for COX-2, the actual synthesis of PGI2 as well as the conversion rate to 6-oxo-PGF1 alpha are increased in activated smooth muscle cells, an effect being abolished by the PG's administered. It can thus be concluded that PG-therapy for advanced atherosclerosis seems to affect vascular smooth muscle cells beneficially, decreasing mitotic and proliferative activity as well as collagen and glycosaminoglycan synthesis. The somewhat less pronounced effect for PGI2 and iloprost could be explained by desensitization at the receptor level as preliminary findings suggest. This could become even more relevant if a long-term administrable stable (oral) analogue becomes available for routine therapy.

Smooth muscle cells (SMC) within atherosclerotic lesions show marked alterations in their differentiated properties as compared to normal medial SMC. This process of de-differentiation of SMC has been referred to as "phenotypic modulation", and is characterized by increased growth responsiveness, altered lipid metabolism, increased matrix production, and loss of contractile proteins, all of which can contribute to the development and/or progression of atherosclerotic disease. As such there has been much interest in understanding mechanisms and factors that control the differentiation of the vascular SMC. This paper reviews the effects of growth factors, growth inhibitors, and other extrinsic factors on differentiation/maturation of SMC, with a particular emphasis on consideration of factors that may contribute to abnormal control of SMC differentiation in vascular disease. In addition, we will briefly summarize what is currently known regarding molecular mechanisms that control the coordinate expression of genes encoding for SMC-selective/specific proteins that are required for the differentiated function of the vascular SMC.

Prostacyclin (PGI2) and nitric oxide (NO) are potent vascular mediators, playing key roles in protecting arterial wall from injury-induced lesions. The key enzyme that catalyzes PGI2 biosynthesis is cyclooxygenase (COX). COX-1 undergoes auto-inactivation, which severely limits PGI2 synthesis. Overexpression of COX-1 in cultured endothelial cells by COX-1 gene transfer was accompanied by a higher capacity for and sustained synthesis of PGI2. Adenovirus-mediated COX-1 gene transfer to angioplasty damaged carotid arteries in pigs augmented PGI2 synthesis and prevents thrombus formation. Transfer of endothelial NO synthase (eNOS) into angioplasty injured, carotid arteries was reported to suppress intimal hyperplasia in rats. Transfer of PGI2 and NO synthetic enzymes restores the vasoprotective properties and represents an exciting new strategy for treating arterial thrombotic disorders.

The development of methods to measure specific isoprostanes affords a unique opportunity to investigate both the role of oxidant stress as a mechanism of disease in vivo and to select rational doses of putative antioxidant drugs and vitamins for evaluation in human disease. The ability to measure these compounds directly in situ at the site of their formation, to immunolocalize them to target cells in atherosclerotic plaque and other tissues (61) and to assess their biosynthesis non-invasively in urine promises to elucidate the role of lipid peroxidation in cardiovascular disease.

Thromboxane A2, a product of activated platelets, is a potent vasoconstrictor and promoter of vascular smooth muscle cell growth. Therefore, thromboxane has the potential to contribute to processes, such as restenosis following coronary angioplasty, characterized by both platelet activation and abnormal vascular smooth muscle growth. This article reviews the effects of thromboxane on growth of cultured vascular smooth muscle cells, discusses the mechanisms by which thromboxane transduces its growth promoting effects in tissue culture with an emphasis on the role of endogenously produced basic fibroblast growth factor, and reviews clinical studies of thromboxane synthesis inhibitors and/or receptor blockers in angioplasty restenosis.

Vasodilatory prostaglandins (PGI2, PGE1) and synthetic prostacyclin mimetics inhibit smooth muscle cell proliferation in vitro after stimulation by growth factors. Similar results are obtained in vivo after endothelial injury, suggesting that vasodilatory prostaglandins might also control smooth muscle cell proliferation in vivo. However, available data from clinical trials are conflicting and currently do not support the concept that these compounds might be successfully used to suppress excessive smooth muscle cell growth in response to tissue injury, specifically restenosis after PTCA. One possible explanation for these different results is an agonist-induced down-regulation of prostacyclin receptors in vascular smooth muscle cells. It is possible that enhanced endogenous prostacyclin biosynthesis, subsequent to induction of COX-2 and/or in relation to the formation of a neointima from media smooth muscle cells, might have a similar effect. There is still uncertainty regarding the cellular signal transduction pathways and their possibly complex interaction, although cAMP-dependent reactions are probably involved. In addition, vasodilatory prostaglandins might also interfere with the generation and action of other growth modulating factors, including PDGF, hepatocyte growth factor and nitric oxide. In conclusion, vasodilatory prostaglandins might be considered as growth modulating endogenous mediators in vascular smooth muscle cells.

Langendorff-perfused rabbit hearts were subjected to 2 h of global, low-flow ischemia followed by 30 min of reperfusion. This resulted in a marked increase of left ventricular enddiastolic pressure and a loss in left ventricular creatine phosphokinase activity. NO formation was significantly reduced in early reperfusion. In the presence of superoxide dismutase (20 U/ml), NO release (oxyhemoglobin technique) was completely normalized, indicating inactivation of NO by superoxide radicals. Treatment with glyceryl trinitrate (GTN; 30 microM) prevented ischemia-induced myocardial tissue injury. SIN-1 (0.3 microM) was ineffective. These data demonstrate a protective effect of GTN but not SIN-1 in myocardial ischemia. It is concluded that the site of NO generation may play an important role in determining the biological activity of NO donating substances.

The thrombin receptor activating peptides with 6 and 14 amino acids (TRAP-6,TRAP-14) caused aggregation of washed platelets as well as of platelets in citrated and hirudin plasma. Stimulation of platelets was associated with an increase in cytosolic Ca2+ and formation of thromboxane. In porcine pulmonary arteries they induced reversible endothelium-dependent relaxation of precontracted vessels via release of endothelium-derived nitric oxide. TRAP-6 and TRAP-14 did not differ in their intrinsic activity. Both peptides possess thrombin-like activity, but their potency is more than three orders of magnitude lower than that of thrombin.

Thrombin (30 nmol/l) as well as the thrombin receptor activating peptide (TRAP), 10 mumol/l) induce a sustained contraction of endothelium-denuded porcine pulmonary arteries. The first phasic component of contraction is associated with the generation of IP3 which precedes the development of contractile force. Since the PKC inhibitor staurosporine (50 nmol/l) completely inhibits the tonic contraction this component of contraction seems to be due to the activation of protein kinase C (PKC). The thrombin- and TRAP-induced vasoconstriction strongly depends on extracellular calcium; the remaining thrombin- or TRAP-induced contraction in Ca(2+)-free medium seems to be attributed to the IP3-mediated release of calcium from intracellular stores.