Stimulation of cardiac apoptosis in ovariectomized hypertensive rats: potential role of the renin-angiotensin system.
OBJECTIVE
The mechanisms underlying the increased cardiovascular risk after menopause are poorly understood. Estrogens modulate the cardiac renin-angiotensin system (RAS) and influence cardiac adaptation to afterload. To investigate whether the loss of the natural inhibition of the RAS by estrogen may be linked to an increase of cardiac apoptosis, we studied 17β-estradiol (E2) and/or angiotensin-converting enzyme (ACE) inhibitor treatment effects on cardiomyocyte survival in ovariectomized spontaneously hypertensive rats (SHRs).


METHODS
Five groups of female SHRs were evaluated for 8 weeks. One group served as nonovariectomized control; the other four groups underwent bilateral ovariectomy and were randomized to receive 60-day-release pellets containing placebo or 0.5 mg of E2, the ACE inhibitor ramipril at the dosage of 2.5 mg/kg per day, or the combination of the two treatments.


RESULTS
Ovariectomy increased cardiomyocyte apoptosis and induced proapoptotic changes of Bcl-2 and Bax genes and proteins. These modifications were associated with an upregulation of ACE and angiotensin II type 1 (AT1) receptor genes. Ramipril was as effective as E2 in preventing cardiac apoptosis and in restoring cardiac brain natriuretic peptide in association with reduced cardiac ACE and AT1 receptor gene expression. In contrast to the ramipril treatment, the favorable effect of E2 on cardiac apoptosis occurred independently from changes in SBP. No synergistic effect was observed when the two treatments were combined.


CONCLUSIONS
These data show that ovariectomy stimulates myocardium apoptosis by a mechanism involving Bax and Bcl-2 genes. The antiapoptotic effect of E2 and ACE inhibitor treatment was linked to a downregulation of cardiac RAS.
Dipartimento Universitario Clinico di Scienze Mediche Tecnologiche e Traslazionali, University of Trieste, Trieste, Italy. b.fabris@fmc.units.it
Bruno
B
Fabris
Riccardo
R
Candido
Monica
M
Bortoletto
Barbara
B
Toffoli
Stella
S
Bernardi
Marco
M
Stebel
Moreno
M
Bardelli
Lorena
L
Zentilin
Mauro
M
Giacca
Renzo
R
Carretta
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D019254:Genes, bcl-2; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology*; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D010052:Ovariectomy; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D017257:Ramipril / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; C494828:Bax protein, rat; D017931:DNA Primers; D044140:Receptor, Angiotensin, Type 1; D051028:bcl-2-Associated X Protein; C495963:natriuretic peptide precursor type B, rat; D020097:Natriuretic Peptide, Brain; D004958:Estradiol; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril