Abstract
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 (pp2a) 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 pp2a 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.
Highlights
Cardiovascular diseases (CVDs) are the most common causes of death
In harmony with the above evidence, this study found that increased phosphatidylinositol 3-kinase (PI3K), Akt, and ERK1/2 phosphorylation stimulated by platelet-derived growth factor BB (PDGF-BB) was potently inhibited by ketamine
These results indicate that inhibiting platelet-derived growth factor (PDGF)-BB-induced activation of the PI3K, Akt, and ERK1/2 signaling pathway may have contributed to the inhibition of vascular smooth muscle cells (VSMCs) proliferation exerted by ketamine
Summary
Cardiovascular diseases (CVDs) are the most common causes of death. Atherosclerosis, a chronic inflammatory disease of the vessel wall, is the principal underlying pathology of CVD [1]. In the development of vascular disease, VSMCs contribute a vital role; the abnormal proliferation of VSMCs has a central role in the progress of atherosclerosis and restenosis [3]. Different cytokines and growth factors, such as platelet-derived growth factor (PDGF), tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β induce the proliferation of VSMC [4]. PDGF is a major growth factor and is known to contribute to the development of atherosclerosis through the induction of abnormal VSMC phenotypes [5]. Various intracellular signaling molecules, such as extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and protein kinase C (PKC) are associated with PDGF-BB-induced rat aortic VSMC migration [6]. The regulation of expression and function of specific PP2A in VSMCs remain largely unknown
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