ATRIAL NATRIURETIC POLYPEPTIDE INHIBITS HYPERTROPHY OF VASCULAR SMOOTH-MUSCLE CELLS
ATRIAL NATRIURETIC POLYPEPTIDE INHIBITS HYPERTROPHY OF VASCULAR SMOOTH-MUSCLE CELLS
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DOI：
10.1172/jci114893
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发表时间：
1990-11-01
影响因子：
15.9
通讯作者：
DZAU, VJ
中科院分区：
文献类型：
--
作者：
ITOH, H;PRATT, RE;DZAU, VJ
血管重构是高血压和动脉粥样硬化的病理生理学的中心。最近的证据表明，血管收缩物质，如血管紧张素II（AII），可能作为血管平滑肌生长促进物质。为了探索反调节激素心房钠尿肽（ANP）在这一过程中的作用，我们研究了ANP（α-大鼠ANP [1-28]）对培养的大鼠主动脉平滑肌（RASM）细胞生长特性的影响。ANP（10-7 M）显着抑制1%和5%血清的增殖作用，测定3 H-胸苷掺入和细胞数，证实ANP作为一种抗有丝分裂因子。在静止的RASM细胞中，ANP（10-7，10-6 M）显着抑制基础的~ 3 H-尿苷和亮氨酸的50%和30%，分别。ANP（10-7，10-6 M）也抑制AII诱导的RNA和蛋白质合成（30-40%），伴随着细胞大小的减少。此外，ANP还显著减弱了由转化生长因子-β引起的3 H-尿苷和亮氨酸还原的增加。（4次）10-11，4倍10-10 M），一种强效肥大因子。提示ANP对血管平滑肌细胞具有抗肥大作用。用佛波醇12，13-二丁酸酯处理24小时下调蛋白激酶C并不能抑制ANP诱导的对~ 3 H-尿苷掺入的抑制。基于观察到ANP比ANP的环缺失类似物更有效地抑制3 H-尿苷掺入，我们得出结论，ANP的抑制作用主要通过激活鸟苷酸环化酶连接的ANP受体介导。事实上，8-溴cGMP模仿ANP的抗肥大作用。因此，我们推测，除了其血管舒张和利钠作用，在本研究中观察到的抗肥大作用的ANP可能作为一个额外的代偿机制的ANP在高血压。
Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. Recent evidence suggests that vasoconstrictive substances, such as angiotensin II (AII), may function as a vascular smooth muscle growth promoting substance. To explore the role of the counterregulatory hormone, atrial natriuretic polypeptide (ANP) in this process, we examined the effect of ANP (alpha-rat ANP [1-28]) on the growth characteristics of cultured rat aortic smooth muscle (RASM) cells. ANP (10-7 M) significantly suppressed the proliferative effect of 1% and 5% serum as measured by 3H-thymidine incorporation and cell number, confirming ANP as an antimitogenic factor. In quiescent RASM cells, ANP (10-7, 10-6 M) significantly suppressed the basal incorporations of 3H-uridine and leucine by 50 and 30%, respectively. ANP (10-7, 10-6 M) also suppressed AII-induced RNA and protein syntheses (by 30-40%) with the concomitant reduction of the cell size. Furthermore, ANP also significantly attenuated the increase of 3H-uridine and leucine incorporations caused by transforming growth factor-.beta. (4 .times. 10-11, 4 .times. 10-10 M), a potent hypertrophic factor. These results indicate that ANP possesses an antihypertrophic action on vascular smooth muscle cells. Down-regulation of protein kinase C by 24-h treatment with phorbol 12,13-dibutyrate did not inhibit ANP-induced suppression on 3H-uridine incorporation. Based on the observation that ANP was more potent than a ring-deleted analogue of ANP on inhibiting 3H-uridine incorporation, we conclude that the ANP''s inhibitory effect is primarily mediated via the activation of a guanylate cyclase-linked ANP receptor(s). Indeed 8-bromo cGMP mimicked the antihypertrophic action of ANP. Accordingly, we speculate that in addition to its vasorelaxant and natriuretic effects, the antihypertrophic action of ANP observed in the present study may serve as an additional compensatory mechanism of ANP in hypertension.