1. CRP CRP increased p22phox
   1. CRP--a predictor of cardiovascular events, localizes in atherosclerotic arteries and exerts proinflammatory effects on vascular cells
   2. CRP inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by producing superoxide from NAD(P)H oxidase, which facilitate the intiation of numerous cardiovascular diseases.
      1. In the presence of TEMPOL (a membrane-permeable superoxide scavenger), the impairment of serotonin-induced NO-mediated vasodilation by CRP (7ug/ml) was prevented. This preventive effect was also found in the vewwels treated with NAD(P)H oxidase inhibitor apocynin.
2. ROS
   1. generated by the mitochondrial electron transport chain
   2. cyclooxygenase
   3. lipoxygenase
   4. xanthine oxidase
   5. NADH/NADPH oxidase
      1. gp91phox
      2. p22phox
         1. RFK binds to both the TNFR1 to NADPH oxidase.
            1. TNF, through the activation of RFK, enhances the incorporation of FAD in NADPH oxidase enzymes, a critical step for the assembly and activation of NADPH oxidase.
         2. expressed in inflammatory cells
         3. smooth muscle cells
         4. endothelial cells
         5. adventitial fibroblasts in atherosclerotic coronary arteries
         6. a critical component of the superoxide-generating vascular NADH/NADPH oxidase expression increased with the progression of coronary atherosclerosis; the upreglated p22phox was associated with the production of intracellular ROS
         7. the product of the CYBA gene
      3. p67phox
      4. p47phox
      5. p40 phox
      6. the small G protein rac
3. CYBA
   1. contains 6 exons spans 8.5 kb 16q24
      1. C242T (rs4673)
         1. causing a his72-to tyr change（Y72H）
            1. 242T polymorphism was associated with reduced risk of coronary artery disease (CAD) in Japanese. Inoue et al. (1998)
            2. The prevalence of the 242T allele was not different in 149 patients with CAD compared to 103 patients with angiographically normal coronary arteries. 252 U.S patients (83% Caucasian） Li et al. (1999)
            3. One haplotype (214T-C, 521T-C, and the 3-prime UTR 24G-A (640A-G) SNPs), showing markedly reduced ROS generation compared to other haplotypes. Bedard et al. (2009）
      2. tyr121-to-his (Y121H) mutation in the Cyba gene
         1. homozygous mutant mice showed chronic granulomatous disease characterized by absence of superoxide production in phagocytes and complete absence of NADPH oxidase activity. Nakano et al. (2008)
      3. 10-KB DEL
         1. CGD
      4. 1-BP DEL, 272C
         1. CGD
         2. 慢性肉芽肿病（chronic granulomatous disease,CGD）是以皮肤、肺及淋巴结广泛肉芽肿性损害为特点的遗传性粒细胞杀菌功能缺陷病。多数病人的男性，X-连锁隐性遗传；少数为常染色体隐性遗传，两性均可发病。主要缺陷是宿主吞噬细胞系统产生的过氧化氢不足，不能杀灭过氧化氢酶阳性菌，致感染广泛播散。肉芽肿是对比化脓性感染的一种反应，常有色素性类脂组织细胞浸润和包绕。
      5. ARG90GLN
         1. CGD
      6. ......
      7. 98G-A transition in exon 2 of the CYBA gene
         1. resulting in a gly24-to-arg (G24R) substitution. 2 unrelated Japanese patients with mild cytochrome b-negative CGD
            1. maybe a common mutation in the Japanese population. Yamada et al. (2000)
4. The production of superoxide anion has been implicated in the pathogenesis of both hypertension and atherosclerosis. Superoxide anions produced by NAD(P)H oxidase are responsible for the detrimental effect of CRP.
5. Topic
6. Topic
7. The downregulation of p22phox, a component of the active Nox4 complex, not only inhibited the CRP-induced ROS generation but also reduced the degree of AP-1 and NF-kB activation, the production of MCP-1, IL-6, and ET-1, and the apoptotic changes of VSMCs in response to CRP.
   1. VSMCs mainly express NADPH oxidase 4 isoform (Nox4)