細胞老化在好發於老年期的心血管疾病，例如動脈粥狀硬化、高血壓及腹主動脈瘤，扮演重要的角色。目前已知由血管收縮素(Angiotensin II)造成的血管平滑肌細胞老化參與在心血管疾病生成的過程。在此我探討NADPH氧化酶(NADPH oxidase)及 mitogen-activated protein kinases (MAP kinases)成員在血管收縮素造成的人類主動脈平滑肌細胞老化中所扮演的角色。我藉由分析三個已知的細胞老化標誌，senescence-associated β-galactosidase(SA-β-gal)的活性及兩個細胞週期抑制蛋白，p21和p16，的表現量來鑑別細胞老化。血管收縮素刺激48小時造成人類主動脈平滑肌細胞SA-β-gal活性上升及兩個細胞週期抑制蛋白,p16及p21,的表現量增加。我利用藉由螢光染劑carboxy-2’,7’-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA)偵測細胞中氧自由基(reactive oxygen species)的量，發現血管收縮素刺激短時間(2-10分鐘)及長時間(24-48小時)均會刺激細胞中氧自由基的上升。自由基清除劑N-acetyl-L-cysteine(NAC)、過氧化氫酶(catalase)及NADPH氧化酶的抑制劑，apocynin，均完全抑制血管收縮素所誘導的細胞老化。此外，利用干擾RNA來抑制NADPH氧化酶的催化次位元Nox1，亦明顯地抑制血管收縮素誘導的細胞老化。我利用螢光染劑3,3′-dihexyloxacarbocyanine iodide偵測粒線體膜電位的變化，發現血管收縮素刺激粒線體膜電位的去極化。NAC、apocynin及Nox1干擾RNA均會抑制血管收縮素導致的粒線體膜電位的去極化。接著我們更進一步探討MAP kinases在血管收縮素誘導的血管平滑肌細胞老化中所扮演的角色。血管收縮素刺激ERK1/2與p38 MAPK短暫地活化。ERK1/2、p38 MAPK及JNK的抑制劑皆可以抑制血管收縮素造成的血管平滑肌細胞粒線體膜電位的去極化和細胞老化。此外，NAC及apocynin抑制血管收縮素誘導的ERK1/2和JNK的活化，但對p38 MAPK的活化並沒有顯著的影響。由以上這些結果顯示血管收縮素藉由NADPH氧化酶活化的ERK 1/2及JNK及藉由其他途徑活化的p38 MAPK，造成粒線體功能失調且誘導血管平滑肌細胞老化。此外，具有Nox1此異構酶的NADPH 氧化酶是促成粒線體功能損壞與細胞老化的主要因子。

Cellular senescence plays an important role in age-related cardiovascular diseases (CVD) including atherosclerosis and abdominal aortic aneurysm. Angiotensin II (Ang II)-induced cellular senescence of vascular smooth muscle cells (VSMCs) is involved in the pathogenesis of CVD. We investigated the roles of NADPH oxidase and members of the mitogen-activated protein kinases (MAPK) in Ang II-induced cellular senescence of human aortic VSMCs. Cellular senescence was assessed with senescence-associated β-galactosidase (SA-β-gal) activity and the expression of two cell cycle inhibitors p21 and p16, three established biomarkers for cellular senescence. Ang II (10-7 M) treatment for 48 h induced VSMCs senescence assessed with senescence-associated β-galactosidase activity and the expression of two cell cycle inhibitors p21 and p16. Ang II treatment for short term (between 2 and 10 min) and long term (between 24 and 48 h) also stimulated reactive oxygen species (ROS) production detected with a fluorescent probe carboxy-2’,7’-dichlorodihydrofluorescein diacetate (H2DCFDA). ROS scavenging with an antioxidant N-acetyl-L-cysteine (NAC) or a membrane-permeable catalase and inhibiting NADPH oxidase with an inhibitor, apocynin, both abolished Ang II-stimulated cellular senescence. Furthermore, small interfering RNA for NADPH oxidase catalytic subunit isoform Nox1 (Nox1 siRNA, 200 nM) markedly inhibited Ang II–induced cellular senescence. Ang II treatment for 24, 36 or 48 h induced mitochondrial membrane depolarization detected with a fluorescent probe 3,3′-dihexyloxacarbocyanine iodide. NAC, apocynin and Nox1 siRNA inhibited Ang II–induced mitochondrial membrane depolarization. We next examined the involvement of MAPKs in Ang II-induced cellular senescence. Ang II treatment transiently activated extracellular signal-regulated kinases 1/2 (ERK 1/2) and p38 MAPK. Inhibitors for ERK 1/2 activation(U0126), p38 MAPK (SB203580), and c-jun N-terminal kinase (JNK) (SP600125), markedly attenuated Ang II–stimulated mitochondrial membrane depolarization and cellular senescence of VSMCs. Interestingly, NAC and apocynin inhibited Ang II-induced activation of ERK 1/2 and JNK, but not p38 MAPK. These results suggested that Ang II induced cellular senescence of HASMCs via NADPH oxidase-dependent ERK1/2 and JNK activation and NADPH oxidase-independent p38 MAPK activation with both leading to mitochondrial dysfunction. Furthermore, Nox1-dependent NADPH oxidase mediates Ang II-induced mitochondrial dysfunction and cellular senescence.

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