INDUCTION AND NUCLEAR ACCUMULATION OF FOS AND JUN PROTOONCOGENES IN HYPOXIC CARDIAC MYOCYTES

Hypoxic and ischemic stresses cause a series of well documented change s in myocardial cells and tissues, including increased anaerobic glyco lysis, loss of contractility, changes in lipid and fatty acid metaboli sm, and eventual irreversible membrane damage and cell death. In this article we describe changes in the expression and regulation of the pr oto-oncogenes fos and jun in cardiac myocytes exposed to severe hypoxi a. The mRNAs encoding c-Fos, c-Jun, Jun-D, and Jun-B were induced with in 1 h of exposure to hypoxia, increased 5-10-fold between 1 and 4 h a nd then declined. These inductions coincided with loss in myocyte cont ractility but occurred before there was irreversible cell damage or si gnificant ATP loss. Immunostaining with anti-Fos and anti-Jun antibodi es revealed the accumulation of these proteins in hypoxic cell nuclei. Pre-treatment of cells with protein kinase inhibitors significantly r epressed the response at the mRNA level. We propose that hypoxic stres s in these cells activates signal transduction pathways, possibly invo lving protein kinases, that result in the inductions of fos and jun ge ne families. Therefore AP1 may regulate myocardial adaptive responses to hypoxia in advance of energy depletion, cell damage, or reoxygenati on.