BMP-7 attenuates left ventricular remodelling under pressure overload and facilitates reverse remodelling and functional recovery

Cardiovasc Res. 2016 Jun 1;110(3):331-45. doi: 10.1093/cvr/cvw076. Epub 2016 Apr 11.

Abstract

Aims: 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.

Methods and results: 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.

Conclusion: 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.

Keywords: Aortic stenosis; BMP-7; Myocardial remodelling; Pressure overload; Reverse remodelling; TGF-β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Aortic Valve Stenosis / complications
  • Bone Morphogenetic Protein 7 / administration & dosage
  • Bone Morphogenetic Protein 7 / analysis*
  • Bone Morphogenetic Protein 7 / deficiency
  • Bone Morphogenetic Protein 7 / genetics
  • Bone Morphogenetic Protein 7 / metabolism*
  • Case-Control Studies
  • Collagen / metabolism
  • Disease Models, Animal
  • Female
  • Fibronectins / metabolism
  • Fibrosis
  • Humans
  • Hypertrophy, Left Ventricular / genetics
  • Hypertrophy, Left Ventricular / metabolism
  • Hypertrophy, Left Ventricular / physiopathology
  • Hypertrophy, Left Ventricular / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Myosin Heavy Chains / metabolism
  • NIH 3T3 Cells
  • Rats, Wistar
  • Recombinant Proteins / administration & dosage
  • Signal Transduction
  • Smad Proteins / metabolism
  • Time Factors
  • Transforming Growth Factor beta1 / metabolism
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / prevention & control*
  • Ventricular Function, Left* / drug effects
  • Ventricular Remodeling* / drug effects

Substances

  • BMP7 protein, human
  • Bone Morphogenetic Protein 7
  • Fibronectins
  • Recombinant Proteins
  • Smad Proteins
  • Transforming Growth Factor beta1
  • bmp7 protein, mouse
  • Collagen
  • Myosin Heavy Chains