Ghiselli Giancarlo, Chen Jia, Kaou Mohamad, Hallak Hazam, Rubin Raphael
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Arterioscler Thromb Vasc Biol. 2003 Oct 1;23(10):1808-13. doi: 10.1161/01.ATV.0000090140.20291.CE. Epub 2003 Aug 7.
Epidemiological studies have demonstrated that moderate alcohol consumption reduces mortality associated with coronary artery disease. The protective effect is correlated with the amount of ethanol consumed but is unrelated to the form of alcoholic beverage. Adoption of a favorable lipoprotein profile accounts for about half of the protective action of alcohol, but the remaining causative factors remain conjectural. Fibroblast growth factors (FGFs) play important roles in mediating smooth muscle cell (SMC) proliferation and migration, which are key factors in the atherosclerotic process. In the present study, we examined the effect of ethanol on FGF-mediated SMC growth and signaling.
Pharmacologically relevant concentrations of ethanol inhibited the proliferation of a rat aortic SMC line (SV40LT-SMCs) in response to FGF1 and FGF2. Human aortic SMC growth was similarly inhibited by ethanol. Transition into the G2/M phase was specifically affected. FGF-mediated phosphorylation of p42/p44 mitogen-activated protein kinase (MAPK) c-Raf, MAP kinase kinase kinase, MEK1/2 MAP kinase, kinase, stress-activated protein kinase/c-Jun-NH2-terminal kinase, and p38 MAPK were variably reduced by ethanol. The inhibition of intracellular signaling by ethanol was correlated with inhibition of FGF receptor autophosphorylation. By contrast, neither epidermal growth factor receptor autophosphorylation nor epidermal growth factor-mediated p42/p44 MAPK activation was affected by ethanol.
The findings identify the FGF receptor as an inhibitory target for ethanol, which could account in part for the inhibitory actions of ethanol on SMC proliferation observed in vivo.
流行病学研究表明，适度饮酒可降低与冠状动脉疾病相关的死亡率。这种保护作用与乙醇摄入量相关，但与酒精饮料的形式无关。脂蛋白谱的改善约占酒精保护作用的一半，但其余致病因素仍属推测。成纤维细胞生长因子（FGFs）在介导平滑肌细胞（SMC）增殖和迁移中起重要作用，而SMC增殖和迁移是动脉粥样硬化过程中的关键因素。在本研究中，我们检测了乙醇对FGF介导的SMC生长和信号传导的影响。
药理学相关浓度的乙醇抑制大鼠主动脉SMC系（SV40LT-SMCs）对FGF1和FGF2的增殖反应。乙醇同样抑制人主动脉SMC生长。乙醇特别影响细胞向G2/M期的转变。乙醇不同程度地降低了FGF介导的p42/p44丝裂原活化蛋白激酶（MAPK）、c-Raf、MAP激酶激酶激酶、MEK1/2 MAP激酶、激酶、应激激活蛋白激酶/c-Jun-NH2末端激酶和p38 MAPK的磷酸化。乙醇对细胞内信号传导的抑制与FGF受体自身磷酸化的抑制相关。相比之下，乙醇既不影响表皮生长因子受体自身磷酸化，也不影响表皮生长因子介导的p42/p44 MAPK激活。
这些发现确定FGF受体是乙醇的抑制靶点，这可能部分解释了乙醇在体内对SMC增殖的抑制作用。
