title: BMP-7 attenuates left ventricular remodelling under pressure overload and facilitates reverse remodelling and functional recovery.
abstract: TGF-β regulates tissue fibrosis: TGF-β promotes fibrosis, whereas bone morphogenetic protein (BMP)-7 is antifibrotic. To demonstrate that (i) left ventricular (LV) remodelling after pressure overload is associated with disequilibrium in the signalling mediated by these cytokines, and (ii) BMP-7 exerts beneficial effects on LV remodelling and reverse remodelling.
  
  
  
  We studied patients with aortic stenosis (AS) and mice subjected to transverse aortic constriction (TAC) and TAC release (de-TAC). LV morphology and function were assessed by echocardiography. LV biopsies were analysed by qPCR, immunoblotting, and histology. Pressure overload reduced BMP-7 and pSmad1/5/8 and increased TGF-β and pSmad2/3 in AS patients and TAC mice. BMP-7 correlated inversely with collagen, fibronectin, and β-MHC expressions, and with hypertrophy and diastolic dysfunction, and directly with the systolic function. Multiple linear regression disclosed BMP-7 and TGF-β as hypertrophy predictors, negative and positive, respectively. BMP-7 prevented TGF-β-elicited hypertrophic program in cardiomyocytes, and Col1A1 promoter activity in NIH-3T3 fibroblasts. The treatment of TAC mice with rBMP-7 attenuated the development of structural damage and dysfunction, and halted ongoing remodelling. The reverse remodelling after pressure overload release was facilitated by rBMP-7, and hampered by disrupting BMP-7 function using a neutralizing antibody or genetic deletion.
  
  
  
  The disequilibrium between BMP-7 and TGF-β signals plays a relevant role in the LV remodelling response to haemodynamic stress in TAC mice and AS patients. Our observations may provide new important insights aimed at developing novel therapies designed to prevent, halt, or reverse LV pathological remodelling in pressure overload cardiomyopathy.
authors.affiliation: Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Avda. Herrera Oria s/n, Santander E-39011, Spain Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Merino
authors.affiliation: Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Avda. Herrera Oria s/n, Santander E-39011, Spain Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain.
authors.forename: Ana V
authors.initials: AV
authors.lastname: Villar
authors.affiliation: Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Avda. Herrera Oria s/n, Santander E-39011, Spain Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: García
authors.affiliation: Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Avda. Herrera Oria s/n, Santander E-39011, Spain Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Tramullas
authors.affiliation: Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain Servicio de Cardiología, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Ruiz
authors.affiliation: Departamento de Biología Molecular y Centro de Biologia Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Catalina
authors.initials: C
authors.lastname: Ribas
authors.affiliation: Departamento de Biología Molecular y Centro de Biologia Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Sofía
authors.initials: S
authors.lastname: Cabezudo
authors.affiliation: Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain Servicio de Cirugía Cardiovascular, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Avda. de Valdecilla s/n, Santander E-39008, Spain jfnistal@gmail.com hurlem@unican.es.
authors.forename: Juan Francisco
authors.initials: JF
authors.lastname: Nistal
authors.affiliation: Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Avda. Herrera Oria s/n, Santander E-39011, Spain Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain jfnistal@gmail.com hurlem@unican.es.
authors.forename: María A
authors.initials: MA
authors.lastname: Hurlé
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications; D055419:Bone Morphogenetic Protein 7 / Q000008:administration & dosage / Q000032:analysis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D041681:NIH 3T3 Cells; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D005353:Fibronectins; D011994:Recombinant Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C525820:bmp7 protein, mouse; D003094:Collagen; D018995:Myosin Heavy Chains
keywords: Aortic stenosis; BMP-7; Myocardial remodelling; Pressure overload; Reverse remodelling; TGF-β