PARACRINE AND TRANSCRIPTION FACTORS MEDIATING THE NATRIURETIC PEPTIDE GENE EXPRESSION DURING HEMODYNAMIC STRESS

MINNAMARTTILA

Department of Pharmacology andToxicology

OULU 1999

OULUN YLIOPISTO, OULU 1999

PARACRINE AND TRANSCRIPTION FACTORS MEDIATING THE NATRIURETIC PEPTIDE GENE EXPRESSION DURING HEMODYNAMIC STRESS

MINNA MARTTILA

Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditoium of the Department of Pharmacology and Toxicology, on December 3rd, 1999, at 12 noon.

Copyright © 1999Oulu University Library, 1999

OULU UNIVERSITY LIBRARYOULU 1999

ALSO AVAILABLE IN PRINTED FORMAT

Manuscript received 12 November 1999Accepted 17 November 1999

Communicated by Docent Mika Kähönen Docent Ullamari Pesonen

ISBN 951-42-5449-X

ISBN 951-42-5448-1ISSN 0355-3221 (URL: http://herkules.oulu.fi/issn03553221/)

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Cardiac pathologies, including ventricular hypertrophy, are the primary cause of death inindustrialized countries. Cardiac hypertrophy is often the consequence of work overload on the heartand characterizes several cardiovascular diseases, including atherosclerosis and hypertension.Cardiac hypertrophy is accompanied by genetic reprogramming characterized by the reexpression ofseveral embryonic and growth response genes. Two of these genes encode A- and B-type natriureticpeptides (ANP and BNP), two cardiac-specific hormones secreted by myocytes, which play animportant role in blood pressure regulation. The aim of the present study was to study the effect ofacute pressure overload on BNP gene expression in the hearts of normal and hypertensive rats andthen to examine the role of a passerine factor, angiotensin II (Ang II), on volume and pressureoverload -induced ANP and BNP secretion and synthesis. Further, the aim was to characterizeelements on the BNP promoter mediating hemodynamic stress�LQ�YLYR�

BNP gene expression was studied in conscious spontaneously hypertensive (SHR) rats andtogether with ANP in two hypertensive, ream Transgenic rat models. The increased workload of theheart was produced by the infusion of vasopressin (AVP), phenylephrine (PHE) or bolus salineinfusion. The increased workload caused rapid increases in cardiac BNP mRNA levels. Daring bothAVP and PHE infusions, substantial increases in ventricular BNP mRNA levels were already evidentafter I h, and peak levels of BNP mRNA were reached at 4 h. Transgenic rats carrying one extramouse renin gene showed impaired secretion and synthesis of ANP and BNP, while double transgenicrats carrying both human angiotensinogen and human renin genes showed augmentation of left atrial,but not ventricular BNP gene expression in response ta acute pressure overload. To characterize theelements mediating hemodynamic stress, bi-lateral nephrectomy was performed. GATA motiftransduced the hemodynamic stress stimulus 26-28 hrs postnephrectomy in BNP gene expression.Inconclusion, these results show that pressure overload abruptly stimulates the cardiac expression of anoncontractile protein gene BNP, suggesting that it may be used as a myocyte-specific marker ofmechanical loading. BNP gene expression was augmented in atria hut nut in ventricles in response topressure overload in an experimental model of hypertension, suggesting that high local levels of AngII may differentially regulate cardiac gene expression in atrial and ventricular myocytes in doubletransgenic rats. At the transcriptional level, acute hemodynamic stress produced by nephrectomyincreases BNP reporter expression through a GATA-dependent pathway.

.H\ZRUGV��angiotensin II, hemodynamic stress, natriuretic peptides, transcription factors

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