| 摘要 |
A cDNA clone encoding the human prohormone convertase PC5 was isolated from human adrenal gland messenger RNA. The deduced protein sequene would encode a 915 amino acid prepro PC5 which shares a very high degree of homology with the previously cloned rat and mouse homologues. PC5 mRNA is detected in multiple human tissues, including the brain, adrenal and thyroid glands, heart, placenta, lung and testes. PC5 mRNA was undetectable in the liver and is present at lower levels in skeletal muscle, kidney, pancreas, small intestine and stomach. Co-transfection of human PC5 and human prorenin expression vectors in cultured GH4Cl cells leads to secretion of active renin. The activation of human prorenin by PC5 is dependent on a pair of basic amino acids at positions 42 and 43 of the prorenin prosegment and occurs only in cells containing dense core secretory granules. Human PC5 was co-localized with renin by immunohistochemistry in the zona glomerulosa of the adrenal gland suggesting that it could participate in the activation of a local renin-angiotensin system in the human adrenal cortex. PC5 is overexpressed in atherosclerotic coronary blood vessels. Silencing PC5 expression with a specific antisense oligonucleotide efficiently inhibited the proliferation of smooth muscle cells in culture. Furthermore, the antisense inhibited carotid stenosis in a carotoid injury model. These results indicate that silencing PC5 applies to the prevention of restenosis. PCs could be targets of choice for treating any proliferative diseases involving their action on a given growth factor. Finally, the antisense oligonucleotide PC5 is to be used for silencing the activity of this enzyme towards HIV gp160, since both coexist in CD4<+> T lymphocytes and the viral glycoprotein is cleavable by PC5. |
