| Research Abstract |
1. We constructed non-replicating adenovirus expressing C-type natriuretic peptide (CNP), a novel endothelium-derived relaxing peptide (Ad.CNP). Ad.CNP-infected vascular smooth muscle cells (VSMC) produced CNP,1000 times higher than endothelial cells (EC) and were growth-arrested at G_1 phase by elevation of cGMP.
2. We elucidated that the gene expression of Gax (growth arrest-specific homeobox), a novel cardiovascular specific homeobox-type transcriptional factor, was down-regulated by anigotensin II,which promotes VSMC growth and was up-regulated by CNP,a VSMC growth inhibitor.
The blockade of Gax expression by the antisense oligonucleotide directed against Gax mRNA almost completely reserved the growth inhibitory action of cGMP,indicating the involvement of Gax in CNP/cGMP-induced growth inhibition.
3. Shear stress augmented the gene expression of CNP as well as adrenomedullin, which is another endothelium-derived relaxing peptide and was originally isolated from pheochromocytoma. Endothelial expression of CNP in human coronary atherosclerotic lesion, in which shear stress is reduced, was demonstrated to be decreased.
4. We cloned human cGMP-dependent protein kinase (cGK) type Ialpha cDNA,which is the major mediator of cGNP cascade. Over-expression of cGK cDNA in VSMC inhibited migration and proliferation of VSMC.We generated cGK transgenic mice in which cGK expression was enhanced in cardiovascular system.
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