Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload.

TLDR

Hypertrophy is a fundamental adaptive response in postmitotic cardiac and skeletal muscle cells, during which cardiac myosins switch to fetal isoforms. The authors used gene‑specific cDNA probes to detect re‑expression of fetal alpha‑actin and sarcomeric tropomyosin mRNAs within two days of pressure overload. Pressure overload triggers an early up‑regulation of proto‑oncogenes (c‑fos, c‑myc) and heat‑shock protein hsp70 within one hour, followed by later re‑expression of fetal contractile protein isoforms and atrial natriuretic factor in adult ventricles, whereas thyroid‑hormone‑induced hypertrophy does not elicit these gene changes.

Abstract

Hypertrophy, an increase in cell size without cell division, is a fundamental adaptive process employed by postmitotic cardiac and skeletal muscle cells. Cardiac myosins undergo an adult-to-fetal isoform transition in various models of hypertrophy. Using gene-specific cDNA probes, we show here that in the adult myocardium the mRNAs encoding the fetal (skeletal muscle type) isoforms of alpha-actin and sarcomeric tropomyosin are re-expressed within 2 days in response to pressure overload. In addition, atrial natriuretic factor mRNA, so far believed to be expressed primarily in the atria, was readily detectable in the ventricles of neonates and was induced to markedly high levels in pressure-overloaded adult ventricles. In contrast, cardiac hypertrophy produced by thyroid hormone excess was not associated with induction of the atrial natriuretic factor gene or fetal contractile protein isogenes. Furthermore, the c-fos and c-myc protooncogenes and a major heat shock protein gene (hsp70) are induced in the ventricular myocardium within 1 hr after imposition of pressure overload. These results suggest that induction of cellular protooncogenes and heat shock (stress) protein genes is an early response to pressure overload, whereas reinduction of the genes normally expressed only in perinatal life, such as fetal isoforms of contractile proteins and atrial natriuretic factor, is a later event. These two types of responses might represent the general pattern of growth induction to work overload by terminally differentiated cells that have lost the ability to undergo DNA replication.