Endothelin-1 and angiotensin II contribute to BNP but not c-fos gene expression response to elevated load in isolated mice hearts

The early events in the cardiac hypertrophic process induced by hemodynamic load include activation of B-type natriuretic peptide (BNP) and c-fos gene expression. However, it is unknown whether stretch acts directly or through local paracrine factors to trigger changes in cardiac gene expression. Herein we studied the involvement of endothelin-1 (ET-1) and angiotensin II (Ang II) in load-induced activation of left ventricular BNP and c-fos gene expression using an in vitro stretch model in isolated perfused adult mice hearts. Two-hour stretch induced by increasing coronary flow rate from 2 to 5 ml/min increased the expression of BNP and c-fos genes by 1.9- and 1.5-fold, respectively (P < 0.001 and P < 0.05). A mixed ETA/B receptor antagonist bosentan attenuated the BNP gene expression response to load by 58% (P < 0.005). A similar 53% inhibition was observed with the selective ETA receptor blocker BQ-123 (P < 0.05). Type 1 Ang II receptor antagonist CV-11974 decreased the activation of BNP gene expression by 50% (P < 0.05). In contrast, the activation of c-fos gene expression was not inhibited by antagonists of ETA/B and AT1 receptors. Our results show that ET-1 and Ang II play a key role in the induction of BNP, but not c-fos gene expression in response to load in intact adult murine hearts.