The role and mechanisms of angiotensin II in regulating the natriuretic peptide gene expression in response to cardiac overload
University of Oulu, Faculty of Medicine, Department of Pharmacology and Toxicology
University of Oulu, Biocenter Oulu
Kokoteksti (PDF, 1.1 MB)
Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium of the Department of Pharmacology and Toxicology, on May 17th, 2002, at 12 noon.
|Tarkastaja(t):|| Docent Risto Huupponen
Docent Ken A. Lindstedt
Heart responds to pathological hemodynamic stress by increasing cardiac myocyte size, reprogramming gene expression and enhancing contractile protein synthesis. Neurohumoral factors mediate hypertrophic adaptation either directly via specific receptors or indirectly by increasing blood pressure and cardiac load. The aim of this study was to evaluate the role of angiotensin II (Ang II) in the atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression during cardiac overload. Furthermore, the mechanisms of action of Ang II in regulating cardiac gene expression were studied.
Hemodynamic stress was produced by Ang II or nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) administration in conscious rats. Despite hypertension and increased left ventricular ANP and BNP mRNA levels, L-NAME administration for 8 weeks did not induce left ventricular hypertrophy. Ang II type 1 receptor (AT1) antagonism decreased significantly L-NAME-induced hypertension and ventricular ANP gene expression. Ang II-induced cardiac overload produced significant increase in ventricular ANP and BNP mRNA levels at 12 and 72 h, respectively. To study whether the factors synthesized by adrenals modulate the response of Ang II, the effects of adrenalectomy were studied. In Ang II-treated rats, adrenalectomy either abolished or blunted the early activation of ANP and BNP gene expression, respectively.
Ang II infusion for 2 weeks increased cardiac mass and blood pressure measured by telemetry, and produced changes in diastolic function detected by echocardiography. By using direct plasmid DNA injections into the rat myocardium, BNP promoter activity was observed to increase at 2 h and remain up-regulated up to 2 weeks of Ang II infusion, except at 12 h. BNP mRNA levels increased at 2 h but decreased to basal levels after 72 h. Mutation of GATA elements of the BNP promoter and DNA binding assays revealed that GATA4 mediates the Ang II-responsiveness of the BNP gene.
These results indicate that Ang II plays an important role in regulating natriuretic peptide gene expression during cardiac overload. ANP and BNP gene expression in the rat heart is modulated by the adrenal factors during Ang II-stimulated hemodynamic stress and the AT1 receptor antagonism in NO-deficient hypertension. Moreover, ventricular BNP gene expression in Ang II-induced hypertension in vivo is controlled by posttranscriptional mechanisms and GATA elements.
Acta Universitatis Ouluensis. Series D, Medica
|ISBN Print:|| 951-42-6698-6
|Tekijänoikeustiedot:||Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.|