| Budget Amount *help |
¥7,600,000 (Direct Cost: ¥7,600,000)
Fiscal Year 1990: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1989: ¥3,800,000 (Direct Cost: ¥3,800,000)
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| Research Abstract |
In order to elucidate the cellular mechanism of endothelin (ET) its receptors and signal transduction, as well as the synthetic and secretory mechanism of ET, we studied primarily using cultured vascular smooth muscle and endothelial cells and nonvascular epithelial cells. Using specific radioimmunoassay for ET-1, we also studied the changes of ET-1-like immunoreactivity (LI) levels in human biological fuids under various pathological states. Vascular smooth muscle cells have specific ET-1 receptor, through which ET-1 stimulates phosphatidylinositol (PI) response and increase intracellular Ca^<2+> levels, thereby leading to smooth muscle contraction. Structure and activity study revealed the importance of two intramolecular disulfide bonds and C-terminal hydrophobic residues, especially Trp^<21> residue, for interacting with ET-1 receptor and expression of its biological effects. Vascular endothelial cells have specific ET-3 receptor functionally coupled to pertussis toxin-sensitive GT
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P-binding proteins, through which ET-3 induces PI response and increase intracellular Ca^<2+> levels, thereby leading to synthesis of prostacyclin and endothelium-derived relaxing factor. These data suggest that ET-1 directly contracts vascular smooth muscle, while ET-3 relaxes via endothelium-dependent mechanism, thus interacting with each other to regulate vascular tonus. Production and release of ET-1 by vascular endothelial cells are stimulated by angiotensin and vasopressin, whose intracellular mechanism involves increase in intracellular Ca^<2+> level and activation of protein kinase C, resulting from receptor-mediated PI response. In addition to endothelial cells, nonvascular cells including renal mesangial cells, tubular epithelialcells, certain carcinoma cells, express mRNA for ET-1 precursor gene, produce and secrete ET-1 and related peptides. It is suggested that ET-1 functions not only as a vasoconstrictor, but also as autocrine/paracrine growth factor. Plasma ET-1-LI levels were elevated in certain cardiovascular diseases (hypertension, arterial spasm, vasculitis, etc.), which may partly contribute to the development and progression of the lesions. ET-1-LI is also present in human urine and cerebrospinal fluid, of which physiological and pathophysiological functions remain to be determined. Less
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