Extracellular ATP Induces Immediate-Early Gene Expression but Not Cellular Hypertrophy in Neonatal Cardiac Myocytes

• Published in: Circulation research Vol. 74; no. 6; pp. 1034 - 1041
• Main Authors: Zheng, Jing-Sheng, Boluyt, Marvin O, OʼNeill, Lydia, Crow, Michael T, Lakatta, Edward G
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.06.1994; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Adenosine Triphosphate - pharmacology; Animals; Animals, Newborn; Calcium - metabolism; Cardiomegaly - chemically induced; Cells, Cultured; Gene Expression Regulation - drug effects; Genes, fos - drug effects; Genes, Immediate-Early - drug effects; Genes, jun - drug effects; Phenylalanine - metabolism; Proto-Oncogene Proteins c-fos - analysis; Rats; Rats, Wistar; RNA, Messenger - analysis
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.74.6.1034

It is well-documented that norepinephrine (NE) induces the expression of immediate-early genes (IEGs), such as c-fos, c-jun, and jun-B, in cultured neonatal heart cells and leads to cell growth without cell division (ie, hypertrophy). Although purinergic receptors activated by ATP are present on cardiac myocytes and ATP is coreleased with NE from sympathetic nerve endings within the heart, the potential role of the purinergic system in the cascade of events that leads to cardiac hypertrophy is unknown. We report in the present study that stimulation of purinergic receptors by micromolar concentrations of extracellular ATP increased the levels of c-fos and jun-B mRNA as well as FOS and JUN-B proteins in neonatal cardiac myocytes. The magnitude of response to micromolar ATP was comparable to that elicited by NE. The increase in IEG expression induced by ATP was preceded by a rapid transient increase in cytosolic Ca. Pretreatment of myocytes with the intracellular Ca chelator BAPTA-AM prevented the ATP-stimulated increase in cytosolic Ca and attenuated the ATP-stimulated increase in c-fos expression. In contrast, NE did not increase cytosolic Ca in quiescent myocytes, and pretreatment with BAPTA-AM did not inhibit the NE-stimulated increase in c-fos gene expression. Furthermore, although NE markedly increased [C]phenylalanine incorporation into protein and myocyte hypertrophy measured by cell size, ATP did not. These results demonstrate that stimulation of purinergic receptors by ATP activates IEGs via a Ca-dependent pathway in cardiac myocytes that differs from the NE-stimulated activation of these genes. Since ATP activated IEG expression but did not increase the rate of protein synthesis nor augment cell size, we conclude that the activation of c-fos and jun-B expression is not sufficient to induce cellular hypertrophy in neonatal cardiac myocytes.