Protein kinase A (PKA) inhibition reduces human aortic smooth muscle cell calcification stimulated by inflammatory response and inorganic phosphate
Protein kinase A (PKA) inhibition reduces human aortic smooth muscle cell calcification stimulated by inflammatory response and inorganic phosphate
复制标题
DOI：
10.1016/j.lfs.2018.08.051
复制
发表时间：
2018-09
期刊：
影响因子：
6.1
通讯作者：
R. Toita;Kentaro Otani;T. Kawano;S. Fujita;M. Murata;Jeong-Hun Kang
中科院分区：
文献类型：
--
作者：
R. Toita;Kentaro Otani;T. Kawano;S. Fujita;M. Murata;Jeong-Hun Kang
平滑肌细胞（SMC）在中膜血管钙化中起作用，高水平的血清磷酸盐和炎症介质可刺激SMC钙化。本研究的目的是探讨丝裂原活化蛋白激酶（MAPK）（p38 MAPK，ERK 1/2，JNK）和蛋白激酶A（PKA）参与无机磷酸盐（Pi）和炎症反应刺激的SMC钙化。关键发现：与1.5-3.9 mM Pi孵育的HASMC中的Ca水平增加，但与0.9 mM Pi孵育的HASMC相比或与未Pi处理的HASMC相比，Ca水平没有增加。此外，在含有Raw 264.7细胞的培养基中，加入干扰素-γ（IFN-γ）可增加促炎细胞因子[白细胞介素（IL）-1α、IL-6和肿瘤坏死因子-α（TNF-α）]。在含Pi（0.9-2.4 mM）的情况下，与未用IFN-γ处理的培养基相比，在IFN-γ处理的培养基中培养的HASMCs中的Ca水平显著增加。抑制p38 MAPK和PKA可降低Pi和IFN-γ刺激的HASMC钙化，但PKA抑制作用比p38 MAPK抑制作用更明显，提示PKA抑制可有效降低Pi和IFN-γ刺激的SMC钙化。
AimsSmooth muscle cells (SMCs) play a role in medial vascular calcification, which can be stimulated by high levels of serum phosphate and inflammatory mediators. The aim of this study was to investigate whether mitogen-activated protein kinases (MAPKs) (p38 MAPK, ERK1/2, and JNK) and protein kinase A (PKA) can participate in inorganic phosphate (Pi)- and inflammation response-stimulated SMC calcification.Main methodsWe examined the change of Pi- and/or inflammation-stimulated human aortic smooth muscle cell (HASMC) calcification in the presence and absence of inhibitors or small interfering RNAs.Key findingsCa levels were increased in HASMCs incubated with 1.5–3.9 mM Pi, but not with 0.9 mM Pi or compared with non-Pi-treated HASMCs. Furthermore, the addition of interferon-γ (IFN-γ) increased pro-inflammatory cytokines [interleukin (IL)-1α, IL-6, and tumor necrosis factor-α (TNF-α)] in media containing Raw 264.7 cells. Ca levels were significantly increased in HASMCs cultured in IFN-γ-treated medium, compared with non-IFN-γ-treated medium in the presence of Pi (0.9–2.4 mM). The inhibition of p38 MAPK and PKA decreased HASMC calcification stimulated by Pi and IFN-γ-treated medium, though PKA inhibition produced a more significant reduction in calcification than p38 MAPK inhibition.SignificanceThese results indicate that PKA inhibition can efficiently reduce Pi- and inflammation-stimulated SMC calcification.