Biomolecular changes in the aging myocardium: the effect of enalapril.
Chronic administration of enalapril in the aging mouse prevents myocardial fibrosis. To investigate the mechanisms involved, we studied 30 CF1 female mice that received enalapril (ENAL:20 mg/L) in their drinking water after weaning and 30 control (CONT) mice. Ten animals from each group were killed at 12, 18, and 24 months. Half of the samples were prepared for light microscopy (LM) and the other half for electron microscopy (EM). Cardiac histologic sections were studied by an image analyzer (Bioscan OPTIMAS 4.1). We performed the following measurements in cardiomyocytes: mitochondrial number, mitochondrial superoxide dismutase (SOD) using immunohistochemical methods with EM, the percentage of cell cyclin, and apoptosis. The results obtained for CONT and ENAL, respectively were as follows. For cyclin (percentage of positive) our results were: 12 months 17.1+/-0.1% and 18.2+/-0.8%, 18 months 2.4+/-1.6% (P < .001), and 11.4+/-0.1% (P < .001), 24 months 1.2+/-1.3% (P < .001), and 8.2+/-1.2% (P < .001) with significant differences at 18 and 24 months. For the Feulgen method (cell/mm2) we found: 12 months CONT 89.7+/-1.2, ENAL 84.6+/-1.2; 18 months CONT 62.8+/-1.2, ENAL 98.7+/-1.3, and 24 months CONT 81.2+/-1.3, ENAL 112.3+/-1.4. Apoptosis (percentage of positive) was found to be 12 months 3.7+/-0.4% and 1.9+/-0.1%, 18 months 7.1 +/-0.3% (P < .001), and 1.5+/-0.1% (P < .001), 24 months 10.9+/-0.5% (P < .001) and 2.1+/-1.8% (P < .001), for CONT and ENAL, respectively; there were significant differences at 18 and 24 months. The number of mitochondria per cardiomyocyte were: 12 months 85.9+/-1.8 and 87.3+/-1.5, 18 months 69.2+/-1.5t and 82.2+/-1.8 (P < .001), 24 months 54.6+/-1.1 (P < .001) and 81.4+/-1.6 (P < .001) for CONT and ENAL respectively, with significant differences at 18 and 24 months. Mitochondrial SOD was found to be: 12 months 13.6%+/-0.2% (P < .05) and 17.8%+/-1.3% (P < .05), 18 months 7.1%+/-1.0% (P < .001) and 16.7%+/-1.6% (P < .001), 24 months 4.1%+/-0.5% (P < .001), and 12.4%+/-0.9% (P .001) for CONT and ENAL respectively, with significant differences at 12 months and at 18 and 24 months (ANOVA and contrast Scheffe's test). We conclude that chronic administration of ENAL modifies mitochondrial SOD at 12 months, whereas at 18 and 24 months ENAL was associated with higher mitochondrial SOD and a higher mitochondrial number with a greater cyclin expression, and a lower percentage of apoptosis. Enalapril may prevent myocardial fibrosis, possibly by causing changes related to enzymatic-mitochondrial or cellular cycle modifications.
Ferder
L
L
Institute of Biomedical Research and Centro de Investigaciones Medicas Albert Einstein, Argentine Hebrew University, Bar Ilan Foundation, Buenos Aires.
Romano
L A
LA
Ercole
L B
LB
Stella
I
I
Inserra
F
F
D000375:Aging / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D016213:Cyclins / Q000032:analysis; D004247:DNA / Q000096:biosynthesis; D004656:Enalapril / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects*; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D013482:Superoxide Dismutase / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D016213:Cyclins; D004656:Enalapril; D004247:DNA; D013482:Superoxide Dismutase