Hu R M, Levin E R, Pedram A, Frank H J
Department of Medicine, University of California, Irvine 92717.
J Biol Chem. 1992 Aug 25;267(24):17384-9.
Atrial natriuretic peptide (ANP) and endothelin-1 (ET-1) are vasoactive peptides produced in cells of the cardiovascular system. We examined the effects of ANP on ET-1 transcription, production (translation), and secretion in cultured bovine aortic endothelial cells (BAEC). ANP and C-ANP 4-23 (a specific ligand for the C or non-guanylate cyclase receptor) equipotently inhibited the synthesis of prepro-ET-1 and ET-1 proteins in BAEC by at least 50%. Both of these forms of ANP and another C receptor specific ligand, nanopiperazine ANP (11-15)-NH2, inhibited ET-1 secretion by as much as 55%. LY 83583, an inhibitor of ANP-induced cGMP generation, failed to reverse the ANP-induced inhibition of ET-1 secretion. This further indicated that the guanylate cyclase-linked B receptor is not involved. The decreased ET-1 secretion caused by C-ANP 4-23 was reversed by 8-bromo-cAMP or amiloride, which prevents ANP-induced inhibition of cAMP. We also found that ANP and C-ANP 4-23 augmented ET-1 mRNA levels in BAEC by prolonging the mRNA half-life. ANP or cycloheximide comparably inhibited ET-1 translation while increasing ET-1 mRNA levels, suggesting that the two events are related. These results indicate that ANP inhibits ET-1 protein production and secretion while stabilizing the ET-1 mRNA. The effects of ANP are mediated through the C receptor and are probably the result of ANP inhibiting the generation of cAMP. These findings suggest a potentially important new function for this receptor to mediate, in part, the interactions of ANP and ET in the vasculature.
心房利钠肽（ANP）和内皮素-1（ET-1）是在心血管系统细胞中产生的血管活性肽。我们研究了ANP对培养的牛主动脉内皮细胞（BAEC）中ET-1转录、产生（翻译）和分泌的影响。ANP和C-ANP 4-23（C或非鸟苷酸环化酶受体的特异性配体）等效地抑制BAEC中前原ET-1和ET-1蛋白的合成至少50%。这两种形式的ANP以及另一种C受体特异性配体纳米哌嗪ANP（11-15）-NH2，可将ET-1分泌抑制多达55%。LY 83583是一种ANP诱导的cGMP生成抑制剂，未能逆转ANP诱导的ET-1分泌抑制。这进一步表明与鸟苷酸环化酶相关的B受体不参与其中。C-ANP 4-23引起的ET-1分泌减少可被8-溴-cAMP或阿米洛利逆转，后者可防止ANP诱导的cAMP抑制。我们还发现ANP和C-ANP 4-23通过延长mRNA半衰期来提高BAEC中ET-1 mRNA水平。ANP或环己酰亚胺在增加ET-1 mRNA水平的同时，同等程度地抑制ET-1翻译，表明这两个事件相关。这些结果表明，ANP抑制ET-1蛋白的产生和分泌，同时稳定ET-1 mRNA。ANP的作用是通过C受体介导的，可能是ANP抑制cAMP生成的结果。这些发现提示该受体可能具有一项潜在的重要新功能，即部分介导血管系统中ANP和ET的相互作用。
