title: The inhibitory effects of m-nisoldipine on the 5-hydroxytryptamine-induced proliferation of pulmonary artery smooth muscle cells via Ca2+ antagonism and antioxidant mechanisms.
abstract: 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 Ca(2+) 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 Ca(2+) 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 G(0)/G(1) phase. Next, the production of reactive oxygen species and the levels of [Ca(2+)](i) in PASMCs were measured by laser scanning confocal microscopy; m-nisoldipine pretreatment attenuated the [Ca(2+)](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 Ca(2+) antagonistic and antioxidant properties of m-nisoldipine.
authors.affiliation: The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Chen
authors.forename: Huanlong
authors.initials: H
authors.lastname: Liu
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Pan
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Miao
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D015737:Nisoldipine / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D011651:Pulmonary Artery / Q000166:cytology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012701:Serotonin
chemical_list: D000975:Antioxidants; D002121:Calcium Channel Blockers; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012701:Serotonin; D015737:Nisoldipine; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium; D000111:Acetylcysteine