Neuregulin-1 antagonizes myocardial fibrosis and diastolic dysfunction in angiotensin-II treated mice

Introduction: The neuregulin-1 (NRG-1)/ErbB system emerges as an endothelium-controlled cardioprotective system, indispensable for cardiac development and function. Treatment with NRG-1 of animal models with heart failure has been shown to impede LV remodeling and to reduce mortality. Phase III clinical trials in patients are currently performed. The underlying mechanisms of NRG-1 in heart failure are however incompletely understood. Here, we tested whether NRG-1 interferes with the cardiac actions of angiotensin II. Methods and results: Male C57Bl/6 mice (n=50) treated with angiotensin II (Ang II, osmotic mini-pumps, 1000 ng kg-1 day-1) or saline were daily treated with rhNRG-1 (20 μg.kg-1.day-1, i.p. injection) or placebo during 4 weeks. Mice were then analyzed by transthoracic echocardiography and invasive hemodynamic recordings, and sacrificed for (immuno-) histochemical and molecular myocardial analyses (collagen fraction, cross-sectional myocyte area, BNP mRNA, procollagen type III mRNA). In absence of NRG-1, Ang II induced arterial hypertension, concentric LV hypertrophy, interstitial myocardial fibrosis, and LV diastolic failure (increased slope of the end-diastolic pressure-volume relation, increased LV end diastolic pressure, concomitant with a reduced LV stroke volume and increased lung volumes). LV ejection fraction and hemodynamic parameters of LV systolic function remained normal. In presence of NRG-1, Ang II-induced arterial hypertension remained unaffected, whereas all echocardiographic, hemodynamic, histochemical and molecular parameters of LV hypertrophy, myocardial fibrosis and LV diastolic failure significantly decreased towards control levels. Subsequent experiments with cultured rat cardiac fibroblasts and myocytes (both expressing NRG-1 responsive-ErbB2/4 receptors) confirmed that NRG-1 (20 ng.ml-1, 15 min pre-treatment) directly attenuated Ang II-induced myocyte hypertrophy and fibroblast collagen synthesis. Also, NRG-1 significantly attenuated Ang II-induced phosphorylation of p38, extracellular signal-regulated kinases 1/2 (ERK1/2), and protein kinase C, pathways of Ang II mediated fibrosis. Conclusion: NRG-1 prevents Ang II-induced LV concentric remodeling and diastolic dysfunction, independently of effects on arterial blood pressure. These effects are explained by direct actions of NRG-1 on Ang II signaling in cardiomyocytes and fibroblasts. These effects help explaining the beneficial actions of NRG-1 in heart failure, and suggest that NRG-1 may provide a new treatment strategy in hypertensive heart disease.