Hsu Jong-Hau, Liou Shu-Fen, Yang San-Nan, Wu Bin-Nan, Dai Zen-Kong, Chen Ing-Jun, Yeh Jwu-Lai, Wu Jiunn-Ren
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Pediatr Pulmonol. 2014 Aug;49(8):734-44. doi: 10.1002/ppul.22904. Epub 2013 Oct 25.
Pulmonary vascular remodeling, characterized by disordered proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a pathognomonic feature of pulmonary arterial hypertension. Thus, pharmacologic strategy targeting on anti-proliferation and anti-migration of PASMCs may have therapeutic implications for PAH. Here we investigated the effects and underlying mechanisms of B-type natriuretic peptide (BNP) on angiotensin II (Ang II)-induced proliferation and migration of PASMCs. Proliferation and migration of PASMCs cultured from Wistar rats were induced by Ang II, with or without BNP treatment. In addition, potential underlying mechanisms including cell cycle progression, Ca(2+) overload, reactive oxygen species (ROS) production, signal transduction of MAPK and Akt, and the cGMP/PKG pathway were examined. We found that BNP inhibited Ang II-induced PASMCs proliferation and migration dose dependently. BNP could also arrest the cell cycle progression in the G0/G1-phase. In addition, BNP attenuated intracellular calcium overload caused by Ang II. Moreover, Ang II-induced ROS production was mitigated by BNP, with associated down-regulation of NAD(P)H oxidase 1 (Nox1) and reduced mitochondrial ROS production. Finally, Ang II-activated MAPKs and Akt were also counteracted by BNP. Of note, all these effects of BNP were abolished by a PKG inhibitor (Rp-8-Br-PET-cGMPS). In conclusion, BNP inhibits Ang II-induced PASMCs proliferation and migration. These effects are potentially mediated by decreased calcium influx, reduced ROS production by Nox1 and mitochondria, and down-regulation of MAPK and Akt signal transduction, through the cGMP/PKG pathway. Therefore, this study implicates that BNP may have a therapeutic role in pulmonary vascular remodeling.
肺血管重塑以肺动脉平滑肌细胞（PASMCs）增殖和迁移紊乱为特征，是肺动脉高压的标志性特征。因此，针对PASMCs抗增殖和抗迁移的药物策略可能对肺动脉高压具有治疗意义。在此，我们研究了B型利钠肽（BNP）对血管紧张素II（Ang II）诱导的PASMCs增殖和迁移的影响及潜在机制。用Ang II诱导或不诱导Wistar大鼠培养的PASMCs增殖和迁移，并进行BNP处理。此外，还检测了包括细胞周期进程、Ca(2+)超载、活性氧（ROS）生成、MAPK和Akt信号转导以及cGMP/PKG途径等潜在机制。我们发现BNP剂量依赖性地抑制Ang II诱导的PASMCs增殖和迁移。BNP还可使细胞周期进程停滞在G0/G1期。此外，BNP减轻了Ang II引起的细胞内钙超载。而且，BNP减轻了Ang II诱导的ROS生成，同时使NAD(P)H氧化酶1（Nox1）下调，并减少线粒体ROS生成。最后，BNP也抵消了Ang II激活的MAPKs和Akt。值得注意的是，PKG抑制剂（Rp-8-Br-PET-cGMPS）消除了BNP的所有这些作用。总之，BNP抑制Ang II诱导的PASMCs增殖和迁移。这些作用可能是通过cGMP/PKG途径，减少钙内流、降低Nox1和线粒体产生的ROS、下调MAPK和Akt信号转导介导的。因此，本研究表明BNP可能在肺血管重塑中具有治疗作用。
