Pressure overload induces severe hypertrophy in mice treated with cyclosporine, an inhibitor of calcineurin
Pressure overload induces severe hypertrophy in mice treated with cyclosporine, an inhibitor of calcineurin
复制标题
DOI：
10.1161/01.res.84.6.729
复制
发表时间：
1999-04-02
影响因子：
20.1
通讯作者：
Lorell, BH
中科院分区：
文献类型：
--
作者：
Ding, B;Price, RL;Lorell, BH
心脏肥厚是成人心脏对机械负荷的基本适应。最近的研究表明，环孢素抑制钙调磷酸酶活性可抑制钙调磷酸酶转基因小鼠和肽生长因子刺激的新生大鼠心肌体外系统的肥厚发展。为了验证钙调磷酸酶信号通路对体内负荷诱导的肥厚至关重要的假设，我们观察了环孢素对小鼠实验性升主动脉狭窄引起的左心室肥厚的影响。在主动脉瓣狭窄小鼠中，左心室收缩压升高到与未使用环孢素治疗的相似水平。主动脉瓣狭窄治疗组和未治疗组的左心室质量和心肌细胞大小相似，且明显大于对照组，表明环孢素治疗不能抑制肥厚性生长。治疗和未治疗的小鼠左心室负荷敏感基因心房利钠因子表达增加，对照组小鼠和主动脉瓣狭窄小鼠的左心室和脾脏钙调磷酸酶活性被测量给环孢素治疗与未给药。主动脉瓣狭窄小鼠脾脏中钙调磷酸酶活性水平与对照组相似，但与对照组相比，主动脉瓣狭窄小鼠左心室组织钙调磷酸酶活性严重降低，环孢素治疗后钙调磷酸酶活性进一步降低。因此，体内压力过载引起的病理性肥大和心脏限制性基因表达不受环孢素治疗的抑制，也不依赖于左心室钙调磷酸酶活性的升高。
Cardiac hypertrophy is the fundamental adaptation of the adult heart to mechanical load. Recent work has shown that inhibition of calcineurin activity with cyclosporine suppresses the development of hypertrophy in calcineurin transgenic mice and in in vitro systems of neonatal rat cardiocytes stimulated with peptide growth factors, To test the hypothesis that the calcineurin signaling pathway is critical fur load-induced hypertrophy in vivo, we examined the effects of cyclosporine treatment on left ventricular hypertrophy induced by experimental ascending aortic stenosis for 4 weeks in mice. Left ventricular systolic pressure was elevated to a similar level in aortic stenosis mice that were treated with cyclosporine versus no drug. Left ventricular mass and myocyte size were similar in treated and untreated aortic stenosis animals and significantly greater than control animals, showing that cyclosporine treatment does not suppress hypertrophic growth. Both treated and untreated animals showed increased left ventricular expression of the load-sensitive gene atrial natriuretic factor, Calcineurin activity was measured in the left ventricle and the spleen from control mice and aortic stenosis mice treated with cyclosporine versus no drug. Levels of calcineurin activity were similar in the spleens of control and untreated aortic stenosis mice, However, calcineurin activity was severely depressed in left ventricular tissue of untreated aortic stenosis mice compared with control mice and was further reduced by cyclosporine treatment. Thus, pathological hypertrophy and cardiac-restricted gene expression induced by pressure overload in vivo are not suppressed by treatment with cyclosporine and do not appear to depend on the elevation of left ventricular calcineurin activity.