OVEREXPRESSION OF BAX PROTEIN AND ENHANCED APOPTOSIS IN THE LEFT-VENTRICLE OF SPONTANEOUSLY HYPERTENSIVE RATS - EFFECTS OF AT(1) BLOCKADE WITH LOSARTAN

An association of increased apoptosis with overactivity of the local a ngiotensin-converting enzyme has been reported in cells from the left ventricle of adult rats with spontaneous hypertension (SHR). To gain i nsight into the regulation of cardiac apoptosis in arterial hypertensi on, we investigated the expression of the proteins Bcl-2 tan inhibitor of apoptosis) and Bar tan inducer of apoptosis) in the left ventricle of 30-week-old normotensive Wistar-Kyoto rats (WKY), SHR, and SHR tre ated with the angiotensin II type 1 receptor (AT(1)) antagonist losart an (20 mg.kg(-1).d(-1)) during 14 weeks before death. The density of a poptotic cells was assessed by direct immunoperoxidase detection of bi otin-labeled deoxyuridin nucleotides. The expression of Bcl-2 and Bar was assessed by Western blot analysis. Compared with WKY, untreated SH R exhibited increased (P<0.05) apoptosis, increased (P<0.01) Bar, and similar Bcl-2. The Bcl-2/Bax ratio tan inverse index of cell susceptib ility to apoptosis) was lower (P<0.05) in untreated SHR than in WKY. T he chronic administration of losartan was associated with the normaliz ation of apoptosis, Bar expression, and the Bcl-2/Bax ratio in treated SHR. No changes in the expression of Bcl-2 were observed in these rat s after treatment. No significant changes in the apoptotic density wer e observed between treated SHR with normal blood pressure and treated SHR with abnormally high blood pressure at the end of the treatment pe riod. These results suggest that an association exists between increas ed apoptosis and overexpression of Bar oncoprotein in cells from the l eft ventricle of adult SHR. Chronic blockade of AT(1) receptors preven ts Bar overexpression and normalizes apoptosis in the left ventricle o f SHR independently of its hemodynamic effect. On the basis of our fin dings, it can be proposed that the interaction of angiotensin II with its AT(1) receptors may participate in the stimulation of Bar protein, which in turn renders cells from the left ventricle of SHR more susce ptible to apoptosis.