title: BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy.
abstract: Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis.
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; mshahid.mgh@gmail.com.
authors.forename: Mohd
authors.initials: M
authors.lastname: Shahid
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Ester
authors.initials: E
authors.lastname: Spagnolli
authors.affiliation: Cardiac Ultrasound Laboratory, Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Laura
authors.initials: L
authors.lastname: Ernande
authors.affiliation: Cardiac Ultrasound Laboratory, Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Robrecht
authors.initials: R
authors.lastname: Thoonen
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Starsha A
authors.initials: SA
authors.lastname: Kolodziej
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Patricio A
authors.initials: PA
authors.lastname: Leyton
authors.affiliation: Cardiac Ultrasound Laboratory, Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Juan
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Robert E T
authors.initials: RE
authors.lastname: Tainsh
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Claire
authors.initials: C
authors.lastname: Mayeur
authors.affiliation: Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: David K
authors.initials: DK
authors.lastname: Rhee
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Mei X
authors.initials: MX
authors.lastname: Wu
authors.affiliation: Cardiac Ultrasound Laboratory, Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Warren M
authors.initials: WM
authors.lastname: Zapol
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Rheumatology, Allergy and Immunology of the Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Bloch
mesh_terms: D030201:Activin Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000804:Angiotensin II; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; C497454:ID1 protein, rat; D051798:Inhibitor of Differentiation Protein 1; C554430:LDN 193189; D050778:NFATC Transcription Factors; D011720:Pyrazoles; D011743:Pyrimidines; D051785:Smad Proteins; D000804:Angiotensin II; D010656:Phenylephrine; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498943:Acvr1 protein, mouse; C000610415:Acvr1 protein, rat; C498931:Acvrl1 protein, mouse; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: ALK2; BMP signaling; BMP type I receptor; calcineurin; cardiac hypertrophy