The inhibitory effects of m-nisoldipine on the 5-hydroxytryptamine-induced proliferation of pulmonary artery smooth muscle cells via Ca²⁺ antagonism and antioxidant mechanisms

详细信息	查看全文 | 推荐本文 |

• 作者：Xueyan Chen^a ; ^b ; ^c ; ¹ ; Huanlong Liu^d ; ¹ ; Zhenhua Pan^a ; ^b ; ^c ; Qingfeng Miao^a ; ^b ; ^c ; Yongjian Zhang^a ; ^b ; ^c ; ^{zhangyjtougao@126.com}
• 关键词：Pulmonary artery smooth muscle cells ; Proliferation ; Reactive oxygen species ; Calcium ; M-nisoldipine
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：5 July, 2012
• 卷：686
• 期：1-3
• 页码：32-40
• 文件大小：1425 K

摘要

The excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) plays a critical role in the development of pulmonary arterial hypertension. Recent studies indicate that Ca²⁺ and reactive oxygen species are critically involved in the process of smooth muscle cell proliferation stimulated by mitogens, such as 5-hydroxytryptamine (5-HT). Because m-nisoldipine, a Ca²⁺ channel blocker of the dihydropyridine class, possesses some calcium antagonistic and antioxidant properties, we investigated the effect of m-nisoldipine on PASMC proliferation. The results indicated that m-nisoldipine inhibited 5-HT-induced PASMC proliferation, evaluated by BrdU incorporation and the MTT assay, and this effect was associated with a decreased expression of proliferating cell nuclear antigen (PCNA). Flow cytometry analysis showed that m-nisoldipine blocked 5-HT-induced cell-cycle progression by arresting the cells in the G₀/G₁ phase. Next, the production of reactive oxygen species and the levels of [Ca²⁺]_i in PASMCs were measured by laser scanning confocal microscopy; m-nisoldipine pretreatment attenuated the [Ca²⁺]_i elevation and the production of reactive oxygen species induced by 5-HT. In addition, m-nisoldipine significantly decreased the 5-HT-induced activation of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) and the subsequent c-fos and c-jun mRNA expression. Meanwhile, results also showed that N-acetylcysteine (a reactive oxygen species scavenger) suppressed the proliferation and the ERK1/2 and JNK activation induced by 5-HT. In summary, this study demonstrated that m-nisoldipine effectively suppressed the 5-HT-induced PASMC proliferation, ERK1/2 and JNK activation and subsequent c-fos and c-jun mRNA expression, all of which might be associated with the Ca²⁺ antagonistic and antioxidant properties of m-nisoldipine.