压力负荷增加大鼠模型血浆内皮素水平的改变(2)
ET的释放受许多因素的调节,如缺氧、机械性应力、神经内分泌激素(如NE、AngⅡ)、细胞因子(包括转化生长因子-β和白介素-1β)等均可诱导ET-1的表达。HF时,血中ET-1水平明显升高,升高的程度与HF的严重程度呈正相关关系。随着年龄的增长,血浆ET-1活性水平随之上升,而有氧锻炼可降低血浆ET-1的活性[9]。最近研究发现,特异性ET-1基因敲除大鼠心肌细胞的凋亡增加,而ET-1可通过FasL/TNF信号通路削弱TNF介导的凋亡[10]。Khan等[11]的实验认为big-ET是进展期HF患者的独立预后因素;还有一些学者提出了不同意见,但大多数研究者已达成共识,认为ET-1是HF强烈的独立预后因素[12]。本研究通过腹主动脉缩窄法制作的大鼠模型,造模8周后LVMI模型组较假手术组有显著升高(P<0.01);模型组左室心肌经HE染色光镜下见心肌纤维排列紊乱,细胞横径稍大,循环ET水平升高。
由于ET在心血管系统中举足轻重的作用,近年来对ET的认识也逐渐深刻。研究发现ET-1即ETA和ETB对心脏的作用主要通过内皮素受体(endothelin receptor,ETR)介导,其中以ETA为主。人类ETA受体mRNA主要表达于血管平滑肌细胞,ETB受体mRNA大量表达于血管内皮细胞,也表达于主动脉、肺动脉和冠状动脉的血管平滑肌细胞。ETA受体选择性与ET-1结合,而ETB受体与ET的各种异构体均具有相同的亲和力,也称为非特异性受体[13]。由于ETR的分布具有组织特异性,所以它们发挥的功能也不尽相同,ETA受体主要介导心血管收缩作用,ETB受体通过释放舒张因子,如前列环素(PGI2)、一氧化氮(NO)而介导心血管舒张作用,ETB受体还有清除循环ET-1作用。最近研究发现,ET-1和ETR结合后通过一系列过程可激活促分裂原活化蛋白激酶(MAPK),使细胞生长、肥大,参与心肌重塑。而ET拮抗剂在慢性心力衰竭中的研究观察到波生坦可减轻HF病人的临床症状[14]。由于ET和ETB受体结合后可起到扩血管、增加NO和PGI2浓度、增强肺清除ETA等作用,所以选择性ETA受体拮抗剂可能比同时抑制ETA和ETB受体的拮抗剂更为有利[15]。
, 百拇医药
本实验运用光镜观察左室心肌HE染色结果,同时检测LVMI、血浆ET水平的改变,证实腹主动脉缩窄8周后大鼠心肌肥厚模型建立成功,符合针对CHF的病理生理改变的要求,为临床及基础研究提供新的思路。
[参考文献]
[1] VON-LUEDER T G, KJEKSHUS H, EDVARDSEN T, et al. Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary synthesis and secretion of endothelin-1[J]. Cardiovasc Res,2004,63(1):41-50.
[2] YAMAMOTO S, MATSUMOTO N, KANAZAWA M, et al. Different contributions of endothelin-A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine overflow in rat hearts [J]. Circulation,2005,111(3):302-309.
, 百拇医药
[3] DOERING C W, JALIL J E, JANICKI J S, et al. Collagen network remodeling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy[J]. Cardiovasc Res,1998,22:686-694.
[4] HIGASHIYAMA H, SUGAI M, INOUE H, et al. Histopathological study of time course changes in inter-renal aortic banding-induced left ventricular hypertrophy of mice[J]. Int J Exp Path, 2007,88(1):31-38.
[5] BREDIN F, FRANCO-CERECEDA A. Reversed remodeling in dilated cardiomyopathy by passive containment surgery is associated with decreased circulating levels of endothelin-1[J]. Eur J Cardiothoracic Surg,2006,29(3):299-303.
, http://www.100md.com
[6] CLOZEL M, SALLOUKH H. Role of endothelin in fibrosis and antifibrotic potential of bosentan[J]. Ann Med,2005,37:2-12.
[7] 肖继明,陈锐华,徐军,等.急性心肌梗死患者血浆内皮素的动态变化及意义[J].医学研究生学报,2007,20(3):331-332.
[8] SHAH R. Endothelins in health and disease [J]. Eur J Inter Med,2007,18:272-282.
[9] van GUILDER G P, WESTBY C M, GREINER J J, et al. Endothelin-1 vasoconstrictor tone increases with age in healthy men but can be reduced by regular aerobic exercise[J]. Hypertension,2007,50:403-409.
, 百拇医药
[10] ZHAO X S, PAN W T, BEKEREDJIAN R, et al. Endogenous endothelin-1 is required for cardiomyocyte survival in vivo[J]. Circulation,2006,114:830-837.
[11] KHAN S Q, DHILLON O, STRUCK J, et al. C-terminal pro-endothelin-1 offers additional prognostic information in patients after acute myocardial infarction: leicester acute myocardial infarction peptide(LAMP) study[J].Am Heart J,2007,154:736-742.
, 百拇医药
由于ET在心血管系统中举足轻重的作用,近年来对ET的认识也逐渐深刻。研究发现ET-1即ETA和ETB对心脏的作用主要通过内皮素受体(endothelin receptor,ETR)介导,其中以ETA为主。人类ETA受体mRNA主要表达于血管平滑肌细胞,ETB受体mRNA大量表达于血管内皮细胞,也表达于主动脉、肺动脉和冠状动脉的血管平滑肌细胞。ETA受体选择性与ET-1结合,而ETB受体与ET的各种异构体均具有相同的亲和力,也称为非特异性受体[13]。由于ETR的分布具有组织特异性,所以它们发挥的功能也不尽相同,ETA受体主要介导心血管收缩作用,ETB受体通过释放舒张因子,如前列环素(PGI2)、一氧化氮(NO)而介导心血管舒张作用,ETB受体还有清除循环ET-1作用。最近研究发现,ET-1和ETR结合后通过一系列过程可激活促分裂原活化蛋白激酶(MAPK),使细胞生长、肥大,参与心肌重塑。而ET拮抗剂在慢性心力衰竭中的研究观察到波生坦可减轻HF病人的临床症状[14]。由于ET和ETB受体结合后可起到扩血管、增加NO和PGI2浓度、增强肺清除ETA等作用,所以选择性ETA受体拮抗剂可能比同时抑制ETA和ETB受体的拮抗剂更为有利[15]。
, 百拇医药
本实验运用光镜观察左室心肌HE染色结果,同时检测LVMI、血浆ET水平的改变,证实腹主动脉缩窄8周后大鼠心肌肥厚模型建立成功,符合针对CHF的病理生理改变的要求,为临床及基础研究提供新的思路。
[参考文献]
[1] VON-LUEDER T G, KJEKSHUS H, EDVARDSEN T, et al. Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary synthesis and secretion of endothelin-1[J]. Cardiovasc Res,2004,63(1):41-50.
[2] YAMAMOTO S, MATSUMOTO N, KANAZAWA M, et al. Different contributions of endothelin-A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine overflow in rat hearts [J]. Circulation,2005,111(3):302-309.
, 百拇医药
[3] DOERING C W, JALIL J E, JANICKI J S, et al. Collagen network remodeling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy[J]. Cardiovasc Res,1998,22:686-694.
[4] HIGASHIYAMA H, SUGAI M, INOUE H, et al. Histopathological study of time course changes in inter-renal aortic banding-induced left ventricular hypertrophy of mice[J]. Int J Exp Path, 2007,88(1):31-38.
[5] BREDIN F, FRANCO-CERECEDA A. Reversed remodeling in dilated cardiomyopathy by passive containment surgery is associated with decreased circulating levels of endothelin-1[J]. Eur J Cardiothoracic Surg,2006,29(3):299-303.
, http://www.100md.com
[6] CLOZEL M, SALLOUKH H. Role of endothelin in fibrosis and antifibrotic potential of bosentan[J]. Ann Med,2005,37:2-12.
[7] 肖继明,陈锐华,徐军,等.急性心肌梗死患者血浆内皮素的动态变化及意义[J].医学研究生学报,2007,20(3):331-332.
[8] SHAH R. Endothelins in health and disease [J]. Eur J Inter Med,2007,18:272-282.
[9] van GUILDER G P, WESTBY C M, GREINER J J, et al. Endothelin-1 vasoconstrictor tone increases with age in healthy men but can be reduced by regular aerobic exercise[J]. Hypertension,2007,50:403-409.
, 百拇医药
[10] ZHAO X S, PAN W T, BEKEREDJIAN R, et al. Endogenous endothelin-1 is required for cardiomyocyte survival in vivo[J]. Circulation,2006,114:830-837.
[11] KHAN S Q, DHILLON O, STRUCK J, et al. C-terminal pro-endothelin-1 offers additional prognostic information in patients after acute myocardial infarction: leicester acute myocardial infarction peptide(LAMP) study[J].Am Heart J,2007,154:736-742.
, 百拇医药