日前，教育部新世纪人才、北京市科技新星、北京大学第一医院儿科金红芳副教授课题组揭示了二氧化硫（SO2）调控血管平滑肌细胞增殖的新机制，即SO2通过cAMP/PKA信号介导的Erk/MAPK通路调控血管平滑肌细胞增殖。研究论文近日发表于国际生物学领域著名杂志Cell Death Disease (《细胞死亡与疾病》)（2014），金红芳为该文的通讯作者。

为了揭示SO2对血管平滑肌细胞增殖的调控机制，杜军保教授、金红芳副教授带领课题组成员多年来潜心研究，发现以往被称为废气的SO2可在心血管系统内源性生成，并且具有重要的心血管生理学意义和心血管病理生理学意义，提出内源性SO2是心血管调节的又一新型气体信号分子，对整个心血管疾病发病机制的调节作用具有普遍性意义。课题组的系列研究极大地推动了气体分子调控理论与心血管疾病发病理论的进步，得到国内外科学家的高度评价和关注。

近日，课题组在《细胞死亡与疾病》刊出的文章中，进一步揭示SO2抑制血管平滑肌细胞增殖的分子机制，即SO2可提高血管平滑肌细胞内腺苷酸环化酶活性，从而增加了胞内cAMP含量，激活PKA信号分子，导致c-Raf分子的抑制性位点Ser259磷酸化水平增高，进而抑制c-Raf激酶活性，导致由PDGF-BB诱导活化的Erk/MAPK信号通路的失活，通过影响细胞周期G1期向S期的进展，最终发挥对大鼠胸主动脉平滑肌细胞的增殖抑制作用。

上述研究是血管平滑肌细胞的“自卫性修复过度”的异常生理机制的可能过程，为“自卫性修复过度”的防治提供有力理论依据，而且对深入认识SO2的分子细胞学调控机制提供了重要的科学依据，具有重要的科学价值。

长期以来，在唐朝枢教授、卜定方教授的指导下，杜军保教授、金红芳副教授及其团队成员围绕气体信号分子等小分子活性物质展开了系列创新性研究工作，取得了突出的学术成绩，先后主持国家“973课题”（2项）、国家自然科学基金重点项目（2项）、国家杰出青年科学基金、北京市自然科学基金重点项目、教育部****奖励计划等多项国家级及部委级课题项目，相关工作荣获教育部自然科学奖一等奖、高等学校科学研究优秀成果二等奖；并主办首届（2007）、第二届（2010）及第三届（2013）全国气体信号分子硫化氢学术会议，广泛交流研究成果，引领国际该领域的学术前沿。课题组曾在J Biol Chem、Antioxid Redox Signal (IF=7.189)、Arterioscler Thromb Vasc Biol (IF=6.338)及J Am Coll Cardiol (IF=14.086)等国际权威杂志上发表大量学术论文，被广泛引用，受到了科学界的广泛关注，其团队对本领域的研究贡献在国际学术界具有重要影响。

原文摘要：

Sulfur dioxide inhibits vascular smooth muscle cell proliferation via suppressing the Erk/MAP kinase pathway mediated by cAMP/PKA signaling

The present study was designed to investigate the role of endogenous sulfur dioxide (SO2) in vascular smooth muscle cell (VSMC) proliferation, and explore the possible role of cross-talk between cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk)/mitogen-activated protein kinase (MAPK) pathways in this action. By cell counting, growth curve depict, flow cytometry and bromodeoxyuridine (BrdU) labeling assays, we found that SO2 inhibited VSMC proliferation by preventing cell cycle progression from G1 to S phase and by reducing DNA synthesis. SO2 synthase aspartate aminotransferase (AAT1 and AAT2) overexpression significantly inhibited serum-induced proliferating cell nuclear antigen (PCNA) protein expression in VSMCs, demonstrated by western blot analysis. Moreover, overexpression of AAT1 or AAT2 markedly reduced incorporation of BrdU in serum-treated VSMCs. By contrast, either AAT1 or AAT2 knockdown significantly exacerbated serum-stimulated VSMC proliferation. Thus, both exogenous- and endogenous-derived SO2 suppressed serum-induced VSMC proliferation. However, annexin V-propidium iodide (PI) staining and cell cycle analysis demonstrated that SO2 did not influence VSMC apoptosis in the serum-induced proliferation model. In a platelet-derived growth factor (PDGF)-BB-stimulated VSMC proliferation model, SO2 dephosphorylated the active sites of Erk1/2, MAPK kinase 1/2 and RAF proto-oncogene serine/threonine-protein kinase (c-Raf) induced by PDGF-BB. However, the inactivation of the three kinases of the Erk/MAPK pathway was not due to the separate interferences on them by SO2 simultaneously, but a consequence of the influence on the upstream activity of the c-Raf molecule. Hence, we examined the cAMP/PKA pathway, which could inhibit Erk/MAPK transduction in VSMCs. The results showed that SO2 could stimulate the cAMP/PKA pathway to block c-Raf activation, whereas the Ser259 site on c-Raf had an important role in SO2-induced suppression of Erk/MAPK pathway. The present study firstly demonstrated that SO2 exerted a negative regulation of VSMC proliferation via suppressing the Erk/MAPK pathway mediated by cAMP/PKA signaling.

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