Involvement of the mitochondrial permeability transition pore in angiotensin II-mediated apoptosis.
BACKGROUND
Angiotensin II plays a central role in the development of congestive heart failure. Among its many actions linked to heart failure is the promotion of ventricular remodelling. Although the growth component of ventricular remodelling may initially be compensatory, the apoptotic component is associated with a decline in contractile function. Therefore, the uncoupling of angiotensin II-induced apoptosis from its other actions may prove to be clinically beneficial. However, the development of proper therapy awaits information on the mechanism underlying angiotensin II-induced apoptosis.


OBJECTIVE
To establish the signalling pathway responsible for angiotensin II-induced apoptosis.


METHODS
Isolated neonatal cardiomyocytes were incubated for several hours with medium containing 1 nM angiotensin II. The extent of angiotensin II-mediated mitochondrial DNA damage was assessed by Southern blot analysis, and the expression of electron transport proteins was evaluated by Western blot analysis. The effect of cyclosporin A on terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine-5'-triphosphate-biotin nick end labelling and cytosolic cytochrome c content were used to monitor mitochondrial permeability transition pore involvement in angiotensin II-induced apoptosis.


RESULTS
Angiotensin II caused significant DNA damage, an effect associated with the downregulation of NADH dehydrogenase subunit 5, a component of complex 1 of the electron transport chain. Angiotensin II-mediated apoptosis, as assessed by cytochrome c release and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine-5'-triphosphate-biotin nick end labelling, was largely blocked by the mitochondrial permeability transition pore antagonist, cyclosporin A.


CONCLUSIONS
Angiotensin II-induced apoptosis proceeds through a signalling pathway involving DNA damage, reduced rates of electron transport and the opening of the mitochondrial permeability transition pore. Thus, an inhibitor of the mitochondrial permeability transition pore would largely block angiotensin II-induced apoptosis without affecting the other actions of angiotensin II.
Ricci
Craig
C
University of South Alabama, College of Medicine, Department of Pharmacology, Mobile, Alabama, USA.
Pastukh
Viktor
V
Schaffer
Stephen W
SW