P647Bone morphogenetic protein-2 is induced in the heart after ischemic injury

Abstract

Purpose: Bone morphogenetic protein-2 (BMP2) is known for its wide role in embryonic heart development, encompassing the differentiation of cardiomyocytes, vascularization, valvulogenesis and connective tissue formation. However, BMP2 function in the adult heart is unknown. Recent work indicates that other BMP family members may be involved in myocardial remodeling. We hypothesized that BMP2 is expressed during ischemic cardiac injury and in heart failure. Furthermore we wanted to study which cells in the heart express BMP2 and what stimuli may induce this expression. Methods: Left ventricular biopsies were sampled from explanted hearts of patients with end-stage dilated cardiomyopathy and ischemic heart disease, from hearts of patients undergoing coronary artery bypass grafting and from donor hearts. Mice were subjected to infarction by permanent coronary artery ligation or sham operated, and hearts were sampled serially thereafter. Other hearts were dissected into ventricles and atria, as well as used for cell isolation and culture. Human umbilical vein endothelial cells (HUVEC) were subjected to mechanical stretch, hypoxia/reoxygenation and oxidative stress by means of hydrogen peroxide. Expression of BMP2 and some of its downstream targets was assessed using qPCR and Western blot. Results: BMP2 mRNA was upregulated in biopsies of coronary artery bypass grafting patients and in infarcted mouse hearts, but not in end-stage heart failure. Examination of its cellular source in untreated heart revealed that BMP2 protein expression was confined to cardiac myocytes, rather than to cardiac fibroblasts or endothelial cells, with the left ventricle displaying higher BMP2 expression than the atria. HUVEC had similar levels of BMP2 expression as cardiomyocytes. To investigate the potential mechanism of BMP2 activation, we subjected HUVEC to different modalities of cellular stress. Mechanical stress, but not hypoxia/reoxygenation or hydrogen peroxide induced BMP2 expression, as well expression of its downstream target genes sprouty-1 and beta-catenin. Conversely, oxidative stress strongly inhibited expression of sprouty-1 and BMP signaling co-factor thrombospondin-1. Conclusion: BMP2 is induced in biopsies from CABG patients and in postinfarction mouse hearts. Activation of BMP2 and its targets was also observed in HUVECs subjected to mechanical stress, but not in hypoxia/reoxygenation or oxidative stress. The significance of BMP2 activation in these situations is not clarified.