DOSE AND TIME-DEPENDENT APOPTOTIC EFFECTS BY ANGIOTENSIN II INFUSION ON LEFT VENTRICULAR CARDIOMYOCYTES.

Objective To gain insight into the regulation of cardiac apoptosis we studied the dose–response and time-course effects of angiotensin II (Ang II) infusion on ventricular cardiomyocyte apoptosis and on the expression of Bax and Bcl-2 genes and proteins. Study design and methods In the dose–response study, Ang II was infused subcutaneously at doses of 100, 200, 400, 800 and 1200 ng/kg per min for 14 days. In the timecourse study, rats infused with Ang II at doses of 200 and 400 ng/kg per min were followed for 7 and 14 days. The cardiomyocyte apoptotic density was assessed by DNA end labelling (terminal deoxynucleotide nick-end labelling; TUNEL). Gene and protein expression of Bcl-2 and Bax were evaluated by reverse transcriptase-polymerase chain reaction and by Western blots. Results Systolic blood pressure and left ventricular mass were increased in a dose-dependent manner in Ang II-infused rats. A statistically significant increase in the rate of cardiac apoptosis and pro-apoptotic changes of Bcl-2 and Bax gene and protein expression was observed when high doses of Ang II (800–1200 ng/kg per min) were infused. A positive correlation of apoptotic density with Bax and a negative correlation with Bcl-2 and Bcl-2/Bax ratio were found. Cardiac apoptosis was greatly influenced by the timing of Ang II infusion. Losartan-treated Ang II-infused rats exhibited normalized systolic blood pressure, left ventricular weight, apoptosis, and Bax and Bcl-2 levels. Conclusions Our results are consistent with the pathophysiological role of Ang II in induction of cardiac apoptosis, and explain the cardioprotective effect of Ang II receptor antagonists.