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(Circulation Research. 1997;81:694-702.)
© 1997 American Heart Association, Inc.

Articles

Involvement of Transcriptional and Posttranscriptional Mechanisms in Cardiac Overload–Induced Increase of B-Type Natriuretic Peptide Gene Expression

Jarkko Magga, Olli Vuolteenaho, Heikki Tokola, Minna Marttila, , Heikki Ruskoaho

From the Department of Pharmacology and Toxicology (J.M., H.T., M.M., H.R.) and Physiology (O.V.), Biocenter Oulu, University of Oulu (Finland).

Correspondence to Heikki Ruskoaho, MD, Department of Pharmacology and Toxicology, University of Oulu, Kajaanintie 52 D, FIN-90220 Oulu, Finland. E-mail heikki.ruskoaho{at}oulu.fi

Abstract The induction of atrial and ventricular B-type natriuretic peptide (BNP) gene expression is one of the earliest events occurring during hemodynamic overload. To examine the molecular mechanisms for increased BNP gene expression during cardiac overload, we studied the induction of the BNP gene expression compared with that of atrial natriuretic peptide (ANP) in a modified perfused rat heart preparation. An increase in right atrial pressure of 5 mm Hg resulted in a 1.4-fold (P<.05) and 2.2-fold (P<.01) increase in BNP mRNA levels after 1 and 2 hours, respectively, whereas ANP mRNA levels remained unchanged. Stretching for up to 2 hours also significantly increased right atrial immunoreactive BNP (ir-BNP) levels (from 15.8±2.2 to 20.1±1.2 ng/mg, P<.05). Actinomycin D (10 µg/mL), a transcriptional inhibitor, completely inhibited the stretch-induced increase in atrial BNP mRNA levels at 1 hour (P<.05) and 2 hours (P<.001), whereas a protein synthesis inhibitor, cycloheximide (90 µg/mL), had no effect on basal or direct mechanical stretch-induced increase in right atrial BNP mRNA levels. Furthermore, we examined the role of tyrosine kinase and protein kinase C activities in acute mechanical stretch–induced increase in BNP synthesis. Tyrosine kinase inhibitors lavendustin A (1 µmol/L) and tyrphostin A25 (3 µmol/L) and protein kinase C inhibitors staurosporine (30 nmol/L) and chelerythrine (1 µmol/L) prevented the stretch-induced increase in right atrial ir-BNP concentrations at 2 hours. In addition, chelerythrine inhibited the increase of right atrial BNP mRNA levels stimulated by cardiac overload. These results demonstrate that the early increase of BNP mRNA levels by mechanical stretch results from increased transcriptional activation and is independent of protein synthesis. Our results also suggest that protein kinase C and tyrosine kinases activities may be involved in coupling cardiac overload to alterations in atrial BNP synthesis.

Key Words: cardiac gene expression • mechanical load • natriuretic peptide • transcription

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