ANP GENE-EXPRESSION IN RAT HEARTS DURING HYPOXIA

It is unclear whether the increase in plasma atrial natriuretic peptid e (ANP) concentration during hypoxia is due to direct, hypoxia-induced upregulation of ANP secretion in the heart, or to pressure overload o f the right ventricle (RV) following hypoxia-induced pulmonary hyperte nsion. To test the hypothesis that hypoxia leads to an early upregulat ion of the ANP gene, we examined the influence of acute and prolonged inspiratory hypoxia (6 h, 1 or 3 weeks) on the expression of ANP messe nger ribonucleic acid (mRNA) in rat heart and compared the results wit h the expression of the ANP gene after acute pressure overload induced by experimental coarctation of the main pulmonary artery. As a molecu lar marker for hypertrophy we determined the ratio of alpha- and beta- myosin gene expression. Hypoxia increased systolic RV pressure from 20 .0 +/- 1.6 mmHg to 27.8 +/- 1.6 mmHg (P < 0.01) and 41.6 +/- 2.1 mmHg (P < 0.05) after 1 and 3 weeks hypoxia respectively. The ANP plasma co ncentration did not change significantly after 6 h or 1 week: 232 +/- 21 pg/ml (control), 246 +/- 25 pg/ml (6 h), 268 +/- 25 pg/ml (1 week), but increased significant ly after 3 weeks hypoxia (446.8 +/- 99.56 p g/ml; P < 0.05). ANP mRNA levels in different regions of the heart did not change after 6 h or 1 week hypoxia. After 3 weeks hypoxia ANP mRN A had increased 2.7-fold in the RV (P < 0.05), 4.2-fold in the left ve ntricle (LV, P < 0.05), 3.5-fold in the septum (S, P < 0.05) and about 1.4-fold in the right (n.s.) and left atrium (n.s.). Relative ventric ular masses increased significantly only for the RV (190%, P < 0.05) d uring hypoxia. The beta/alpha-myosin mRNA ratio did not change after 6 h hypoxia but, contrary to ANP gene expression, increased after just 1 week (6.1-fold in RV, 7.8-fold in LV, 6-fold in S; P < 0.05) and was more pronounced in the RV after 3 weeks (9.4-fold in RV, 7.6-fold in LV, 9.1-fold in S; P < 0.05). The increase in the beta/alpha-myosin mR NA ratio in the LV contrasts with a lack of increase in relative ventr icular mass. Acute pressure overload in the RV after pulmonary arteria l banding significantly increased ANP-mRNA and the beta/alpha-myosin m RNA ratio after 1 day in the RV. In the LV ANP mRNA was unchanged. The delayed upregulation of the ANP gene suggests that hypoxia per se is not a significant stimulus for ANP gene expression in the heart and th at hypoxia-induced ANP-gene expression in the heart is regulated predo minantly by the increase in RV afterload due to hypoxia-induced increa sed pulmonary pressure. The upregulation of ANP and beta-myosin mRNA i n the LV during chronic hypoxia has yet to be elucidated.