Different Effects of Amlodipine and Enalapril on the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase–Extracellular Signal-Regulated Kinase Pathway for Induction of Vascular Smooth Muscle Cell Differentiation In Vivo
Different Effects of Amlodipine and Enalapril on the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase–Extracellular Signal-Regulated Kinase Pathway for Induction of Vascular Smooth Muscle Cell Differentiation In Vivo
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DOI：
10.1291/hypres.29.179
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发表时间：
2006-03
影响因子：
5.4
通讯作者：
S. Umemoto;S. Kawahara;Ryo Hashimoto;Kyoko Umeji;Susumu Matsuda;Masakazu Tanaka;M. Kubo;M. Matsuzaki
中科院分区：
文献类型：
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作者：
S. Umemoto;S. Kawahara;Ryo Hashimoto;Kyoko Umeji;Susumu Matsuda;Masakazu Tanaka;M. Kubo;M. Matsuzaki
虽然最近的临床试验表明，芦荟发挥抗动脉粥样硬化的作用，这些作用的机制仍然未知。本研究的目的是检查的信号转导途径可能是重要的抗动脉粥样硬化的财产，作为评估的主动脉平滑肌细胞（SMC）表型在体内高血压。易卒中的自发性高血压大鼠（SHRSP）随机接受溶媒、依那普利或依那普利治疗，而作为对照的Wistar-Kyoto大鼠（WKY）仅接受溶媒治疗。两种药物在降低收缩压和抑制主动脉重塑和纤维化进展方面与溶媒治疗的SHRSP相同。在赋形剂处理的SHRSP的腹主动脉中，与WKY腹主动脉中的那些相比，收缩型平滑肌（SM）肌球蛋白重链（MHC）SM 2的水平显著降低，而合成型MHC NMHC-B/SMemb的水平显著升高。与溶剂处理的SHRSP组相比，两种药物通过降低NMHC-B/SMemb和增加SM 2，显著且同等地使SHRSP中的主动脉SMC表型向分化状态转移。溶剂处理的SHRSP中MKK 6、p38 MAPK、MEK 1和p-42/44 ERK的水平显着高于WKY。两种药物均显著降低了SHRSP主动脉中的这些值。此外，MEK 1和p-42/44 ERK的水平在依那普利治疗的SHRSP组中显著低于依那普利治疗的SHRSP组，而依那普利在增加SHRSP动脉中的p-Akt和内皮NO合酶方面比依那普利更有效，而在SHRSP组中，这一水平显著低于WKY组。因此，MEK-ERK通路可能是体内高血压治疗激活主动脉SMC表型的关键决定因素之一。
Although recent clinical trials have shown that amlodipine exerts antiatherogenic effects, the mechanism of these effects remains unknown. This study was designed to examine which signal transduction pathway might be important for the antiatherogenic property of amlodipine, as assessed by aortic smooth muscle cell (SMC) phenotypes in hypertension in vivo. Stroke-prone spontaneously hypertensive rats (SHRSP) were randomly treated with a vehicle, amlodipine, or enalapril while Wistar-Kyoto rats (WKY) used as controls were treated with only the vehicle. Both drugs were equally effective at reducing systolic blood pressure, and inhibiting the progression of aortic remodeling and fibrosis in comparison to those of vehicle-treated SHRSP. In the aortas of vehicle-treated SHRSP, the level of contractile-type smooth muscle (SM) myosin heavy chain (MHC) SM2 was significantly lower, whereas the level of synthetic-type MHC NMHC-B/SMemb was significantly higher compared with those in the WKY aortas. Compared to the vehicle-treated SHRSP group, both drugs significantly and equally shifted the aortic SMC phenotype in SHRSP toward the differentiated state by reducing NMHC-B/SMemb and increasing SM2. The levels of MKK6, p38 MAPK, MEK1 and p-42/44 ERK were significantly higher in the vehicle-treated SHRSP than in the WKY. Both drugs significantly reduced these values in the SHRSP aorta. Furthermore, the levels of MEK1 and p-42/44 ERK were significantly lower in the amlodipine- than in the enalapril-treated SHRSP group, whereas enalapril was more effective than amlodipine at increasing p-Akt and endothelial NO synthase in SHRSP aortas, which were significantly lower in the vehicle SHRSP group than in the WKY group. Thus, the MEK-ERK pathway might be one of the crucial determinants of the aortic SMC phenotype activated by amlodipine treatment of hypertension in vivo.