Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, No. 95, Wenchang Rd., Taipei 111, Taiwan.
School of Medicine, Fu-Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist, New Taipei City 242, Taiwan.
Int J Mol Sci. 2017 Nov 27;18(12):2545. doi: 10.3390/ijms18122545.
Abnormal proliferation of vascular smooth muscle cells (VSMCs) gives rise to major pathological processes involved in the development of cardiovascular diseases. The use of anti-proliferative agents for VSMCs offers potential for the treatment of vascular disorders. Intravenous anesthetics are firmly established to have direct effects on VSMCs, resulting in modulation of blood pressure. Ketamine has been used for many years in the intensive care unit (ICU) for sedation, and has recently been considered for adjunctive therapy. In the present study, we investigated the effects of ketamine on platelet-derived growth factor BB (PDGF-BB)-induced VSMC proliferation and the associated mechanism. Ketamine concentration-dependently inhibited PDGF-BB-induced VSMC proliferation without cytotoxicity, and phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated protein kinase (ERK) inhibitors, LY294002 and PD98059, respectively, have similar inhibitory effects. Ketamine was shown to attenuate PI3K, Akt, and ERK1/2 phosphorylation induced by PDGF-BB. Okadaic acid, a selective protein phosphatase 2A (PP2A) inhibitor, significantly reversed ketamine-mediated PDGF-BB-induced PI3K, Akt, and ERK1/2 phosphorylation; a transfected protein phosphatse 2a ( siRNA reversed Akt and ERK1/2 phosphorylation; and 3-O-Methyl-sphingomyeline (3-OME), an inhibitor of sphingomyelinase, also significantly reversed ERK1/2 phosphorylation. Moreover, ketamine alone significantly inhibited tyrosine phosphorylation and demethylation of PP2A in a concentration-dependent manner. In addition, the siRNA potently reversed the ketamine-activated catalytic subunit (PP2A-C) of PP2A. These results provide evidence of an anti-proliferating effect of ketamine in VSMCs, showing activation of PP2A blocks PI3K, Akt, and ERK phosphorylation that subsequently inhibits the proliferation of VSMCs. Thus, ketamine may be considered a potential effective therapeutic agent for reducing atherosclerotic process by blocking the proliferation of VSMCs.
血管平滑肌细胞（VSMCs）的异常增殖导致心血管疾病发展中涉及的主要病理过程。抗增殖剂在 VSMCs 中的应用为血管疾病的治疗提供了潜力。静脉内麻醉剂已被牢固确立为对 VSMCs 具有直接作用，导致血压调节。氯胺酮多年来一直被用于重症监护病房（ICU）的镇静，最近被考虑作为辅助治疗。在本研究中，我们研究了氯胺酮对血小板衍生生长因子 BB（PDGF-BB）诱导的 VSMC 增殖的影响及其相关机制。氯胺酮浓度依赖性地抑制 PDGF-BB 诱导的 VSMC 增殖而无细胞毒性，并且磷脂酰肌醇 3-激酶（PI3K）和细胞外信号调节蛋白激酶（ERK）抑制剂，LY294002 和 PD98059，分别具有相似的抑制作用。氯胺酮被证明可减弱 PDGF-BB 诱导的 PI3K、Akt 和 ERK1/2 磷酸化。选择性蛋白磷酸酶 2A（PP2A）抑制剂 okadaic 酸显着逆转了氯胺酮介导的 PDGF-BB 诱导的 PI3K、Akt 和 ERK1/2 磷酸化；转染的蛋白磷酸酶 2a（siRNA 逆转了 Akt 和 ERK1/2 磷酸化；和鞘氨醇酶抑制剂 3-O-甲基神经酰胺（3-OME）也显着逆转了 ERK1/2 磷酸化。此外，氯胺酮本身以浓度依赖性方式显着抑制 PP2A 的酪氨酸磷酸化和脱甲基化。此外，siRNA 有力地逆转了氯胺酮激活的 PP2A 的催化亚基（PP2A-C）。这些结果提供了氯胺酮在 VSMCs 中具有抗增殖作用的证据，表明激活的 PP2A 阻断了 PI3K、Akt 和 ERK 磷酸化，随后抑制了 VSMCs 的增殖。因此，氯胺酮可被认为是一种通过阻断 VSMCs 增殖来减少动脉粥样硬化过程的潜在有效治疗剂。
