Posttranscriptional Control of BNP Gene Expression in Angiotensin II–Induced Hypertension

Abstract

Abstract-B-type natriuretic peptide (BNP) plasma concentrations are raised in patients with heart failure. In several experimental models of cardiac overload, however, BNP mRNA and plasma BNP peptide levels are normal, despite the persistent increase in blood pressure and ventricular hypertrophy. In this study, the role of transcriptional mechanisms in the regulation of BNP gene expression were studied in angiotensin (Ang) II-induced hypertension by injecting DNA constructs containing the BNP promoter (Ϫ2200 to 75 bp of the transcriptional start site) linked to luciferase reporter into rat myocardium. Ang II was administered to conscious rats via intravenous infusion for 2 hours or by subcutaneous minipumps for 6 hours, 12 hours, 3 days, 1 week, and 2 weeks. Ang II increased blood pressure and cardiac mass and induced changes in diastolic function. The left ventricular BNP mRNA levels increased 2.2-fold (PϽ0.001) at 2 hours and peaked at 12 hours (5.2-fold, PϽ0.001). Thereafter, BNP mRNA levels decreased (1.8-fold induction at 3 days, PϽ0.05) and returned to control levels at 1 week, despite persistent hypertension and myocardial hypertrophy. Left ventricular BNP peptide concentrations followed the changes in BNP mRNA levels. The BNP promoter was activated 2.7-fold (PϽ0.05) at 2 hours and remained upregulated up to 2 weeks (2. The plasma concentration of BNP is raised in patients with cardiac disease, particularly those with heart failure. 3,4 BNP level is useful in the diagnosis of congestive heart failure 5 and may effectively guide treatment of patients in heart failure. 6,7 In experimental animal models, cardiac BNP gene expression increases rapidly in response to hemodynamic overload. 8 -10 However, controversy persists regarding to BNP gene expression in ventricular myocardium under normal conditions and in chronic cardiac overload. Indeed, conflicting studies both in the human and in animals describe either increased 9,11-14 or unchanged left ventricular BNP mRNA levels [15][16][17][18][19][20] in heart failure and hypertension. The reason for the normal BNP mRNA levels despite constant cardiac overload is not known but could result from transcriptional and/or translational mechanisms. To date, there are no reports on the molecular mechanisms responsible for regulating the BNP gene expression during cardiac overload in vivo.The aim of this study was to examine the effect of pressure overload on BNP gene expression and transcription in vivo.Hemodynamics, cardiac hypertrophy, systolic and diastolic function, left ventricular BNP mRNA and immunoreactive (ir)-BNP levels, and plasma ir-BNP concentrations were measured in rats infused with angiotensin (Ang) II for 2 hours, 6 hours, 12 hours, 3 days, 1 week, and 2 weeks. To measure the level of BNP gene transcription, DNA constructs containing the rat BNP promoter 2200 bp upstream of the transcription initiation site linked to a reporter gene 21 were injected into the left ventricular myocardium of rats. Finally, to explore further the possible mechanisms regu...

Mitogen-activated Protein Kinases p38 and ERK 1/2 Mediate the Wall Stress-induced Activation of GATA-4 Binding in Adult Heart

“…Previously, we have reported that a 4-h period of stretch in the cultured neonatal cardiomyocytes produced a 1.6-fold increase in the BNP gene expression, and infusion of angiotensin II in conscious animals resulted in a 2.2-fold increase in BNP mRNA levels at 2 h (8,25). In agreement with these studies, the increased ventricular wall stress for 2 h resulted in a 1.6-fold increase in BNP gene expression (Fig.…”

Genetic expression profiles during physiological and pathological cardiac hypertrophy and heart failure in rats

“…This finding contrasts with the plasma BNP levels in patients that present with heart failure. However, our finding regarding BNP is supported by the fact that tissue mRNA BNP levels may not correlate well with plasma BNP levels, and that posttranslational control may play a major role in the regulation of BNP gene expression in heart (52). This might explain the effectiveness of Nesiritide during decompensated heart failure, despite high circulating plasma BNP levels.…”

Correlation between brain natriuretic peptide levels and the prognosis of patients with left ventricular diastolic dysfunction

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