Effect of cyclosporin A on cardiac hypertrophy induced by catecholamine in rat

目的观察环孢素A（CsA）对儿茶酚胺诱导的大鼠心肌肥大的作用。方法雄性Wistar大鼠21只，实验分三组，每组7只：(1）单纯肥大组：给大鼠皮下注射异丙肾上腺素（5 mg*kg-1*d-1），连续10 d；(2）CsA治疗组：除注射异丙肾上腺素外，同时腹腔注射CsA（20 mg*kg-1*d-1），连续10 d；(3）对照组：不作特殊处理。观察三组大鼠心脏大小、组织形态、心系数以及心肌组织抑制钙调神经磷酸酶(CaN)、丝裂素活化蛋白激酶(MAPK)及蛋白激酶C(PKC)活性的变化。在培养的大鼠心肌细胞上，观察CsA对去甲肾上腺素（NE）刺激的3H-亮氨酸掺入的影响。结果单纯注射异丙肾上腺素组的大鼠心脏明显增大，心肌细胞肥大、排列紊乱，并出现广泛间质纤维化。CsA治疗组大鼠心脏未见明显增大，但仍可见部分心肌纤维化，大鼠心重及心系数明显低于单纯肥大组(P<0.05)。肥大组大鼠心肌组织CaN活性明显高于对照组(P<0.05)，CsA治疗组大鼠心肌组织CaN活性低于肥大组(P<0.05)；三组大鼠心肌组织MAPK活性差异无显著性，但肥大组大鼠心肌组织PKC活性较对照组增高4倍(P<0.001)，CsA治疗组的大鼠心肌组织PKC活性较肥大组下降50%(P<0.001)。CsA可明显抑制NE刺激的大鼠心肌细胞3H-亮氨酸掺入。结论 CaN信号通路可能在儿茶酚胺诱导的心肌肥大中起一定作用，CsA可阻滞儿茶酚胺诱导的心肌肥大，这种作用可能主要通过抑制 CaN及PKC活性，阻断CaN和PKC介导的信号传导通路所致。Objectives To determine the effect of cyclosporin A on catecholamine-induced cardiac hypertrophy in rats. Methods The rats were divided into 3 groups: 1) Isoporoterenol-treated group: The rats were injected with isoporoterenol (5 mg*kg-1*d-1); 2) CsA-treated group: Except injection of isoporoterenol, the rats were treated by CsA (20 mg*kg-1*d-1) ; 3) Control group: without any treatment. The heart size, heart/body weight ratio, CaN, MAPK and PKC activity in heart tissues were measured. The effect of CsA to 3H-Leucine incorporation of cultured neonatal rat cardiac myocytes stimulated by norepinephrine was investegated. Results In the isoporoterenol-treated group, the heart size of each rat was increased, the myofibrillar disarray and myofibrilize was evident. The heart size of the rat treated with CsA was not inceased, and CsA treatment prevented the increase in heart/body weight ratio characteristic of the isoporoterenol-treated group. The calcineurin activity in hearts from isoporoterenol-treated group was increased (P<0.05) compared with that of the control group. CsA treatment can reduce the CaN activity in hearts. There was no significant differences in MAPK activity between the three groups, but the PKC activity in hearts from the isoporoterenol-treated group was dramaticly increased (P<0.001), which is reduced by 50% in CsA-treated rat's hearts. CsA can markedly prevent the increase in 3H-Leucine incorporation of cultrued neonatal rat cardiac myocytes promoted by norepinephrine. Conclusion Calcineurin dependent signal pathway may play a role in catecholamine-induced cardiac hypertrophy. CsA can prevent the cardiac hypertrophy by blocking calcineurin- and PKC-mediated signal transduction.国家自然科学基金中文核心期刊要目总览(PKU)中国科学引文数据库(CSCD)0141-442