title: Bone morphogenetic protein-2--a potential autocrine/paracrine factor in mediating the stretch activated B-type and atrial natriuretic peptide expression in cardiac myocytes.
abstract: Hemodynamic overload exposes the heart to variety of neural, humoral and mechanical stresses. Even without the neurohumoral control of the entire organism cardiac myocytes have the ability to sense mechanical stretch and convert it into adaptive intracellular signals. This process is controlled by several growth factors. Here we show that mechanical stretch in vitro and hemodynamic overload in vivo activated the expression of bone morphogenetic protein-2 (BMP-2), while expression of BMP-4 was temporarily attenuated by stretch. BMP-2 and BMP-4 alone stimulated B-type and atrial natriuretic peptide (BNP and ANP) expression and protein synthesis, and activated transcription factor GATA-4 resembling the effects of mechanical stretch of cultured cardiac myocytes. Further, BMP antagonist Noggin was able to inhibit stretch and hypertrophic agonist induced BNP and ANP expression. Together these data provide evidence for BMP-2 as a new autocrine/paracrine factor that regulates cardiomyocyte mechanotransduction and adaptation to increased mechanical stretch.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland; Department of Pathology, Institute of Diagnostics, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland; Department of Pathology, Oulu University Hospital, P.O. BOX 50, Oulu FI-90029 OYS, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Tokola
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio FIN-70211, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Rysä
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland; Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, P.O. BOX 340, Helsinki FI-00029 HUS, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Pikkarainen
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland; Department of Ophthalmology, Oulu University Hospital, P.O. BOX 21, Oulu FI-90029 OYS, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Hautala
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Leskinen
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Ilves
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland.
authors.forename: Jani
authors.initials: J
authors.lastname: Aro
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Vuolteenaho
authors.affiliation: Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, Oulu FI-90014, Finland; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. BOX 56, Viikinkaari 5E, Helsinki FI-00014, Finland. Electronic address: heikki.ruskoaho@helsinki.fi.
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis*; D019898:Autocrine Communication / Q000502:physiology*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis*; D019899:Paracrine Communication / Q000502:physiology*; D014176:Protein Biosynthesis / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099176:Noggin Protein
chemical_list: D009320:Atrial Natriuretic Factor; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D050991:GATA4 Transcription Factor; D020097:Natriuretic Peptide, Brain; D000099176:Noggin Protein; C525720:Bmp2 protein, rat; C525811:Bmp4 protein, rat; C084365:Gata4 protein, rat
keywords: BMP-2; BNP; Cardiac myocyte; Hemodynamic stress; Mechanical stretch; Noggin