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 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 for 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.
Ding
B
B
Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Mass., USA.
Price
R L
RL
Borg
T K
TK
Weinberg
E O
EO
Halloran
P F
PF
Lorell
B H
BH
D000818:Animals; D001011:Aorta / Q000601:surgery; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D006973:Hypertension / Q000150:complications*; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D008026:Ligation; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000473:pathology; D011897:Random Allocation
D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D019703:Calcineurin