Shen Ying H, Zhang Lin, Utama Budi, Wang Jian, Gan Yehua, Wang Xinwen, Wang Jing, Chen Li, Vercellotti Greg M, Coselli Joseph S, Mehta Jawahar L, Wang Xing Li
Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Adult Cardiac Services, Texas Heart Institute, St Luke's Episcopal Hospital, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cardiovasc Res. 2006 Feb 1;69(2):502-11. doi: 10.1016/j.cardiores.2005.10.007. Epub 2005 Nov 28.
Atherosclerosis is the leading cause of death in the United States, and human cytomegalovirus (HCMV) infection may play a role in the development of this disease. Diminished expression and/or activity of endothelial nitric oxide synthase (eNOS) are an early event in atherogenesis. In the current study, we investigated the effects of HCMV infection on eNOS activation in human aortic endothelial cells (HAECs).
We found that HCMV inhibited eNOS phosphorylation/activation in HAECs. The signaling upstream of eNOS involving Akt and PDK1 were also suppressed by the HCMV infection. Moreover, HCMV infection increased the expression of PTEN (phosphatase and tensin homolog deleted on chromosome 10). Silencing PTEN expression with specific siRNA reversed the inhibitory effects on eNOS activation in HCMV-infected cells indicating the involvement of PTEN in mediating HCMV's inhibitory effects. Next we observed that the activation of p38 MAPK stress signaling pathway mediates HCMV's effects on PTEN up-regulation and eNOS inactivation.
In summary, our findings suggest that inhibition of eNOS leading to endothelial dysfunction may be a basis of the pro-atherogenic effects of HCMV. Importantly, upregulation of PTEN and activation of stress signal p38 MAPK are involved in HCMV's inhibitory effects on eNOS activation.
动脉粥样硬化是美国主要的死亡原因，而人巨细胞病毒（HCMV）感染可能在该疾病的发展中起作用。内皮型一氧化氮合酶（eNOS）表达和/或活性降低是动脉粥样硬化发生的早期事件。在本研究中，我们调查了HCMV感染对人主动脉内皮细胞（HAECs）中eNOS激活的影响。
我们发现HCMV抑制HAECs中eNOS的磷酸化/激活。涉及Akt和PDK1的eNOS上游信号传导也受到HCMV感染的抑制。此外，HCMV感染增加了10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）的表达。用特异性小干扰RNA沉默PTEN表达可逆转对HCMV感染细胞中eNOS激活的抑制作用，表明PTEN参与介导HCMV的抑制作用。接下来我们观察到p38丝裂原活化蛋白激酶（MAPK）应激信号通路的激活介导了HCMV对PTEN上调和eNOS失活的影响。
总之，我们的研究结果表明，抑制eNOS导致内皮功能障碍可能是HCMV促动脉粥样硬化作用的基础。重要的是，PTEN的上调和应激信号p38 MAPK的激活参与了HCMV对eNOS激活的抑制作用。
