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BMP-7 attenuates left ventricular remodelling under pressure overload and facilitates reverse remodelling and functional recovery.
Cardiovasc Res 2016; 110(3):331-45CR

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.

Authors+Show Affiliations

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.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.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.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.Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain Servicio de Cardiología, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27068510

Citation

Merino, David, et al. "BMP-7 Attenuates Left Ventricular Remodelling Under Pressure Overload and Facilitates Reverse Remodelling and Functional Recovery." Cardiovascular Research, vol. 110, no. 3, 2016, pp. 331-45.
Merino D, Villar AV, García R, et al. BMP-7 attenuates left ventricular remodelling under pressure overload and facilitates reverse remodelling and functional recovery. Cardiovasc Res. 2016;110(3):331-45.
Merino, D., Villar, A. V., García, R., Tramullas, M., Ruiz, L., Ribas, C., ... Hurlé, M. A. (2016). BMP-7 attenuates left ventricular remodelling under pressure overload and facilitates reverse remodelling and functional recovery. Cardiovascular Research, 110(3), pp. 331-45. doi:10.1093/cvr/cvw076.
Merino D, et al. BMP-7 Attenuates Left Ventricular Remodelling Under Pressure Overload and Facilitates Reverse Remodelling and Functional Recovery. Cardiovasc Res. 2016 06 1;110(3):331-45. PubMed PMID: 27068510.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BMP-7 attenuates left ventricular remodelling under pressure overload and facilitates reverse remodelling and functional recovery. AU - Merino,David, AU - Villar,Ana V, AU - García,Raquel, AU - Tramullas,Mónica, AU - Ruiz,Luis, AU - Ribas,Catalina, AU - Cabezudo,Sofía, AU - Nistal,Juan Francisco, AU - Hurlé,María A, Y1 - 2016/04/11/ PY - 2015/09/23/received PY - 2016/03/18/accepted PY - 2016/4/13/entrez PY - 2016/4/14/pubmed PY - 2017/2/7/medline KW - Aortic stenosis KW - BMP-7 KW - Myocardial remodelling KW - Pressure overload KW - Reverse remodelling KW - TGF-β SP - 331 EP - 45 JF - Cardiovascular research JO - Cardiovasc. Res. VL - 110 IS - 3 N2 - 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. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/27068510/BMP_7_attenuates_left_ventricular_remodelling_under_pressure_overload_and_facilitates_reverse_remodelling_and_functional_recovery_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvw076 DB - PRIME DP - Unbound Medicine ER -