Xueping Wu1, Julia Sagave1, Arkady Rutkovskiy2, Fred Haugen3, Anton Baysa3, Ståle Nygård4, Gabor Czibik3, Christen Peder Dahl5, Lars Gullestad5, Jarle Vaage6, Guro Valen3. 1. Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway. 2. Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway; Department of Emergency and Intensive Care at the Institute of Clinical Medicine, Oslo University Hospital, Ullevål, Norway. Electronic address: arkady.rutkovskiy@medisin.uio.no. 3. Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway. 4. Center for Heart Failure Research, University of Oslo, Norway; Bioinformatics Core Facility at the Institute for Medical Informatics, Oslo University Hospital, Ullevål, Norway. 5. Center for Heart Failure Research, University of Oslo, Norway; Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway. 6. Department of Emergency and Intensive Care at the Institute of Clinical Medicine, Oslo University Hospital, Ullevål, Norway.
Abstract
AIMS: Heart failure is associated with activation of fetal gene programs. Bone morphogenetic proteins (BMPs) regulate embryonic development through interaction with BMP receptors (BMPRs) on the cell surface. We investigated if the expression of BMP4 and its receptors BMPR1a and BMPR2 were activated in post-infarction remodeling and heart failure. MAIN METHODS: Left ventricular biopsies were taken from explanted hearts of patients with end-stage heart failure due to dilated cardiomyopathy (CMP; n=15) or ischemic heart disease (CAD; n=9), and compared with homograft control preparations from organ donors deceased due to non-cardiac causes (n=7). Other samples were taken from patients undergoing coronary artery bypass grafting (CABG; n=11). Mice were subjected to induced infarction by permanent coronary artery ligation or sham operation, and hearts were sampled serially thereafter (n=7 at each time point). KEY FINDINGS: Human and mouse hearts expressed BMP4 and both receptor subtypes. CABG and CMP patients had increased expression of mRNA encoding for BMP4, but unchanged protein. Mouse hearts had increased BMP4 precursor protein 24h after infarction. BMPR1a protein decreased in CAD patients and initially in postinfarcted mouse hearts, but increased again in the latter after two weeks. Human recombinant BMP4 promoted survival after H2O2 injury in HL-1 cells, and also protected adult mouse cardiomyocytes against hypoxia-reoxygenation injury. SIGNIFICANCE: Adult hearts express BMP4, the mRNA increasingly so in patients with coronary artery disease with good cardiac function. BMPRs are downregulated in cardiac remodeling and failure. Recombinant BMP4 has protective effects on cultured cardiomyocytes.
AIMS: Heart failure is associated with activation of fetal gene programs. Bone morphogenetic proteins (BMPs) regulate embryonic development through interaction with BMP receptors (BMPRs) on the cell surface. We investigated if the expression of BMP4 and its receptors BMPR1a and BMPR2 were activated in post-infarction remodeling and heart failure. MAIN METHODS: Left ventricular biopsies were taken from explanted hearts of patients with end-stage heart failure due to dilated cardiomyopathy (CMP; n=15) or ischemic heart disease (CAD; n=9), and compared with homograft control preparations from organ donors deceased due to non-cardiac causes (n=7). Other samples were taken from patients undergoing coronary artery bypass grafting (CABG; n=11). Mice were subjected to induced infarction by permanent coronary artery ligation or sham operation, and hearts were sampled serially thereafter (n=7 at each time point). KEY FINDINGS:Human and mouse hearts expressed BMP4 and both receptor subtypes. CABG and CMP patients had increased expression of mRNA encoding for BMP4, but unchanged protein. Mouse hearts had increased BMP4 precursor protein 24h after infarction. BMPR1a protein decreased in CAD patients and initially in postinfarcted mouse hearts, but increased again in the latter after two weeks. Human recombinant BMP4 promoted survival after H2O2 injury in HL-1 cells, and also protected adult mouse cardiomyocytes against hypoxia-reoxygenation injury. SIGNIFICANCE: Adult hearts express BMP4, the mRNA increasingly so in patients with coronary artery disease with good cardiac function. BMPRs are downregulated in cardiac remodeling and failure. Recombinant BMP4 has protective effects on cultured cardiomyocytes.
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