Perindopril regulates beta-agonist-induced cardiac apoptosis.
Administration of the beta-adrenergic agonist isoproterenol results in cardiac apoptosis. The effect of short-term beta-adrenergic stimulation by isoproterenol on the activity of plasma, lung, and left ventricular (LV) angiotensin I-converting enzyme (ACE) activity and its association with the development of cardiac apoptosis was investigated. beta-Adrenergic stimulation for 24 hours produced an early increase only in the proapoptotic proteins bax and bcl-XS without changes in the levels of the antiapoptotic protein bcl-XL. The ratio between these bcl family proteins was indicative of apoptosis and correlated with an early and significant increase (300%) in DNA laddering. However, after 5 days of the beta-adrenergic stimulation, the ratio changed in favor of antiapoptotic proteins and correlated with the absence of DNA fragmentation. In addition, LV and plasma ACE activities increased markedly with isoproterenol over the study period up to 5 days. ACE activity also regulated expression of the antiapoptotic gene bcl-XL. The administration of perindopril (an ACE inhibitor) prevented the observed increase in bax and bcl-XS levels and attenuated (50% decrease, P<0.05) the effect of isoproterenol on DNA fragmentation. Thus, early and transient cardiac apoptosis triggered by the beta-adrenergic agonist isoproterenol is reversed in the presence of perindopril.
Gálvez
Anita S
AS
Departamento de Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, and Departamento de Enfermedades Cardiovasculares, Hospital Clínico, P. Universidad Católica de Chile, Santiago, Chile.
Fiedler
Jenny L
JL
Ocaranza
María Paz
MP
Jalil
Jorge E
JE
Lavandero
Sergio
S
Díaz-Araya
Guillermo
G
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053938:DNA Fragmentation; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D020913:Perindopril / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000096:biosynthesis / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000806:Angiotensin-Converting Enzyme Inhibitors; C494813:Bcl2l1 protein, rat; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D007703:Peptidyl-Dipeptidase A; D007545:Isoproterenol; D020913:Perindopril