Pressure overload induces severe hypertrophy in mice treated with cyclosporine, an inhibitor of calcineurin

Cardiac hypertrophy is the fundamental adaptation of the adult heart to mec hanical 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 stimul ated with peptide growth factors, To test the hypothesis that the calcineur in signaling pathway is critical fur load-induced hypertrophy in vivo, we e xamined the effects of cyclosporine treatment on left ventricular hypertrop hy induced by experimental ascending aortic stenosis for 4 weeks in mice. L eft ventricular systolic pressure was elevated to a similar level in aortic stenosis mice that were treated with cyclosporine versus no drug. Left ven tricular mass and myocyte size were similar in treated and untreated aortic stenosis animals and significantly greater than control animals, showing t hat cyclosporine treatment does not suppress hypertrophic growth. Both trea ted and untreated animals showed increased left ventricular expression of t he 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 calcineur in activity were similar in the spleens of control and untreated aortic ste nosis mice, However, calcineurin activity was severely depressed in left ve ntricular tissue of untreated aortic stenosis mice compared with control mi ce and was further reduced by cyclosporine treatment. Thus, pathological hy pertrophy and cardiac-restricted gene expression induced by pressure overlo ad in vivo are not suppressed by treatment with cyclosporine and do not app ear to depend on the elevation of left ventricular calcineurin activity.