半边莲生物碱和山梗菜碱对内皮素-1诱导的人脐动脉平滑肌细胞增殖作用的机制研究
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摘要
血管平滑肌细胞(vascular smooth muscle cells，VSMCs)增殖是动脉硬化(atherosclerosis，AS)、原发性高血压(primary hypertension，EH)、经皮冠状动脉腔内血管成形术后再狭窄的病理基础，因此探讨抑制VSMCs增殖的药物成为人们研究的热点。近来的研究表明，血管内皮细胞(vascular endothelial cells，VEC)释放的内皮素(endothelin，ET)具有强烈的缩血管作用。除了收缩血管作用外，ET还能够激活有丝分裂原活化的蛋白激酶，刺激c-fos和c-myc的表达而使VSMCs肥大和增殖。
ET是一族生物活性多肽，目前发现生物体内有4种形式的异型体，分别称为ET-1、ET-2和ET-3及血管活性肠收缩物质(Vasoactive intestinal
contractor peptide，VIC)，其中生物活性以ET-1最强。ET与自然界存在的某些生物毒素有一定亲缘关系，包括蛇毒、蝎毒和蜂毒等。Sarafotoxins(SRTX)是从蛇毒中提取的一种毒素，与ET具有共同的祖基因和相似的生物学活性，一级结构具有明显的同源性，至少有60％～80％氨基酸同源，而且有相同的C-末端。研究证实，ET的C-末端特别是Trp21，两个二硫键，氨基和羧基端，以及Asp8和Glu10的羧酸组对它的生物学活性起了重要的作用，构成了SRTX和ET表面的“共同和基本”的生物活性位点。SRTX和ET构成一组同源性异构肽家族，竞争性结合相同的G蛋白偶联受体，通过IP_3、Ca~(2+)、钙调蛋白激酶途径，引发各类生物学效应，因此可能从抗蛇毒中药中寻找防治动脉硬化、高血压等ET相关性疾病的药物。
民间早就流传抗蛇毒药徐长卿治疗高血压的偏方，1993年，张继峰等对抗蛇毒药物：徐长卿、半边莲和七叶一支花等做了初步的研究。通过离体血管条和整体动物实验发现半边莲和七叶一支花水提物可部分拮抗ET-1致小鼠的死亡作用，并可以抑制ET-1的缩血管和升压效应。王峰等对抗蛇
Vascular smooth muscle cells (VSMCs) proliferation and migration induced by various growth factors can develop a variety of pathological processes including atherosclerosis, hypertension and restenosis after balloon angioplasty. Consequently, inhibition of VSMCs proliferation represents a potentially important therapeutic strategy for the treatment of diseases such as atherosclerosis, hypertension and restenosis. It is well known that endothelin (ET), secreted by vascular endothelial cells (VEC), induces a prolonged vasoconstriction and enhances proliferation of VSMCs by activating c-fos and c-myc.
ETs have strong affinities to biologic toxins such as snake venoms, scorpion venoms and Bee Venoms. Sarafotoxins (SRTXs), initially isolated from the venom of Atractaspis engaddensis, constitute a family of vasoactive peptides, which are structurally and functionally related to ETs. SRTXs and ETs display about 60% of amino acid sequence identity and identical C-terminus. Different studies performed on ETs have confirmed the crucial role played by the C-terminus, the two disulphide bridges, the amino and carboxy terminal groups, together with the carboxylic groups of Asp8 and Glu10, for their vasoconstrictor activity. These observations and results strongly suggest that these residues might form the 'common and basic' vasoconstrictor site onto the surface of SRTXs and ETs. SRTXs form with ETs a homogeneous family of potently vasoconstrictive isopeptides that act on the vascular system via identical G protein receptors and activate the IP_3, Ca~(2+), CaM pathway to modulate various biologic effects. These interesting relationships between ETs and SRTXs led us to investigate the effect of Chinese anti-snake venom herbal
ET是一族生物活性多肽，目前发现生物体内有4种形式的异型体，分别称为ET-1、ET-2和ET-3及血管活性肠收缩物质(Vasoactive intestinal
contractor peptide，VIC)，其中生物活性以ET-1最强。ET与自然界存在的某些生物毒素有一定亲缘关系，包括蛇毒、蝎毒和蜂毒等。Sarafotoxins(SRTX)是从蛇毒中提取的一种毒素，与ET具有共同的祖基因和相似的生物学活性，一级结构具有明显的同源性，至少有60％～80％氨基酸同源，而且有相同的C-末端。研究证实，ET的C-末端特别是Trp21，两个二硫键，氨基和羧基端，以及Asp8和Glu10的羧酸组对它的生物学活性起了重要的作用，构成了SRTX和ET表面的“共同和基本”的生物活性位点。SRTX和ET构成一组同源性异构肽家族，竞争性结合相同的G蛋白偶联受体，通过IP_3、Ca~(2+)、钙调蛋白激酶途径，引发各类生物学效应，因此可能从抗蛇毒中药中寻找防治动脉硬化、高血压等ET相关性疾病的药物。
民间早就流传抗蛇毒药徐长卿治疗高血压的偏方，1993年，张继峰等对抗蛇毒药物：徐长卿、半边莲和七叶一支花等做了初步的研究。通过离体血管条和整体动物实验发现半边莲和七叶一支花水提物可部分拮抗ET-1致小鼠的死亡作用，并可以抑制ET-1的缩血管和升压效应。王峰等对抗蛇
Vascular smooth muscle cells (VSMCs) proliferation and migration induced by various growth factors can develop a variety of pathological processes including atherosclerosis, hypertension and restenosis after balloon angioplasty. Consequently, inhibition of VSMCs proliferation represents a potentially important therapeutic strategy for the treatment of diseases such as atherosclerosis, hypertension and restenosis. It is well known that endothelin (ET), secreted by vascular endothelial cells (VEC), induces a prolonged vasoconstriction and enhances proliferation of VSMCs by activating c-fos and c-myc.
ETs have strong affinities to biologic toxins such as snake venoms, scorpion venoms and Bee Venoms. Sarafotoxins (SRTXs), initially isolated from the venom of Atractaspis engaddensis, constitute a family of vasoactive peptides, which are structurally and functionally related to ETs. SRTXs and ETs display about 60% of amino acid sequence identity and identical C-terminus. Different studies performed on ETs have confirmed the crucial role played by the C-terminus, the two disulphide bridges, the amino and carboxy terminal groups, together with the carboxylic groups of Asp8 and Glu10, for their vasoconstrictor activity. These observations and results strongly suggest that these residues might form the 'common and basic' vasoconstrictor site onto the surface of SRTXs and ETs. SRTXs form with ETs a homogeneous family of potently vasoconstrictive isopeptides that act on the vascular system via identical G protein receptors and activate the IP_3, Ca~(2+), CaM pathway to modulate various biologic effects. These interesting relationships between ETs and SRTXs led us to investigate the effect of Chinese anti-snake venom herbal
引文
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