Modulation of ceramide content and lack of apoptosis in the chronically hypoxic neonatal rat heart.

To assess the effect of chronic hypoxia on cardiomyocyte apoptosis, we used an animal model that mimics cyanotic heart disease. Rats were placed in a hypoxic environment at birth, and oxygen levels were maintained at 10% in an air-tight Plexiglas chamber. Controls remained in room air. Animals were killed, and the hearts were harvested at 1 and 4 wk. Significant polycythemia developed in the hypoxic rats at 1 and 4 wk. Right ventricular mass in the hypoxic rats was 192% and 278% that of controls, and hypoxic left ventricular mass was 140% and 178% that of the controls at 1 and 4 wk, respectively. The increase in cardiac mass was paralleled by only mild hypertrophy (10 to 20%). Contrary to previous reports showing increased apoptosis in response to hypoxia in cultured cardiomyocytes, there was no difference in the number of apoptotic cardiomyocytes between the chronically hypoxic rats and controls, as assayed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and Hoechst staining. We then examined the role of the sphingolipid ceramide because of its reported role in the stress response, growth suppression, and apoptosis. We found that the right ventricular ceramide content was significantly decreased in the hypoxic rats to 73% of control levels at the age of 4 wk. We suggest that the decrease in the ceramide content in the hypoxic right ventricular rat heart may be an adaptive response to chronic hypoxia and pulmonary hypertension. Lower ceramide levels may help suppress apoptosis and allow compensatory right ventricular cardiomyocyte proliferation.