Overexpression of sarcolemmal calcium pump attenuates induction of cardiacgene expression in response to ET-1

The function of the plasma membrane calmodulin-dependent calcium ATPase (PM CA) in myocardium is unknown. PMCA is localized in caveolae, 50- to 100-nm membrane invaginations, which also contain receptors for endothelin-1 (ET-1 ) and various other ligands. PMCA has been suggested to play a role in regu lation of caveolar signal transduction. We studied the effects of the hyper trophic agonist ET-1 and increased coronary perfusion pressure on cardiac s ynthesis of B-type natriuretic peptide (BNP) in transgenic rats overexpress ing the human PMCA 4CI in isolated perfused heart preparation. ET-1 infusio n for 2 h increased BNP mRNA levels twofold in left ventricles (LV) of nont ransgenic rats, whereas no increase was noted in PMCA rat hearts. Similar r esponses were seen in adrenomedullin and c-fos mRNA levels, and in immunore active BNP secretion. Increased mechanical load produced by elevated perfus ion pressure induced similar 1.5- to 1.6-fold increases in LV BNP mRNA in b oth nontransgenic and PMCA rat hearts. These results show that cardiac over expression of PMCA attenuates ET-1-stimulated early induction of cardiac ge ne expression, suggesting that PMCA may modulate myocardial growth response s.