BMP-7 Attenuates Inflammation-Induced Pyroptosis and Improves Cardiac Repair in Diabetic Cardiomyopathy

Cells. 2021 Oct 2;10(10):2640. doi: 10.3390/cells10102640.

Abstract

In the present study, we investigated a novel signaling target in diabetic cardiomyopathy where inflammation induces caspase-1-dependent cell death, pyroptosis, involving Nek7-GBP5 activators to activate the NLRP3 inflammasome, destabilizes cardiac structure and neovascularization. Furthermore, we explored the therapeutic ability of bone morphogenetic protein-7 (BMP-7) to attenuate these adverse effects. C57BL/6J mice (n = 16 mice/group) were divided into: control (200 mg/kg, 0.9% saline intraperitoneal injection, i.p.); Streptozotocin (STZ) and STZ-BMP-7 groups (STZ, 200 mg/kg, i.p. injection). After 6 weeks, heart function was examined with echocardiography, and mice were sacrificed. Immunostaining, Western blotting, H&E, and Masson's trichrome staining was performed on heart tissues. STZ-induced diabetic cardiomyopathy significantly increased inflammasome formation (TLR4, NLRP3, Nek7, and GBP5), pyroptosis markers (caspase-1, IL-1β, and IL-18), inflammatory cytokines (IL-6 and TNF-α), MMP9, and infiltration of monocytes (CD14), macrophage (iNOS), and dendritic cells (CD11b and CD11c) (p < 0.05). Moreover, a significant endothelial progenitor cells (EPCs) dysfunction (c-Kit/FLk-1, CD31), adverse cardiac remodeling, and reduction in left ventricular (LV) heart function were observed in STZ versus control (p < 0.05). Treatment with BMP-7 significantly reduced inflammasome formation, pyroptosis, and inflammatory cytokines and infiltrated inflammatory cells. In addition, BMP-7 treatment enhanced EPC markers and neovascularization and subsequently improved cardiac remodeling in a diabetic heart. Moreover, a significant improvement in LV heart function was achieved after BMP-7 administration relative to diabetic mice (p < 0.05). In conclusion, BMP-7 attenuated inflammation-induced pyroptosis, adverse cardiac remodeling, and improved heart function via the TLR4-NLRP3 inflammasome complex activated by novel signaling Nek7/GBP5. Our BMP-7 pre-clinical studies of mice could have significant potential as a future therapy for diabetic patients.

Keywords: BMP-7; cytokines; diabetic cardiomyopathy; heart function; pyroptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Bone Morphogenetic Protein 7 / pharmacology*
  • Bone Morphogenetic Protein 7 / therapeutic use
  • Cardiomegaly / complications
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Caspase 1 / metabolism
  • Cytokines / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Diabetic Cardiomyopathies / complications
  • Diabetic Cardiomyopathies / metabolism
  • Diabetic Cardiomyopathies / pathology*
  • Diabetic Cardiomyopathies / physiopathology
  • Endothelial Cells / metabolism
  • Fibrosis
  • Inflammasomes / metabolism
  • Inflammation / pathology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Myocardium / pathology*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Neovascularization, Physiologic
  • Organ Size / drug effects
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Pyroptosis* / drug effects
  • Toll-Like Receptor 4 / metabolism
  • Ventricular Function, Left

Substances

  • Biomarkers
  • Bone Morphogenetic Protein 7
  • Cytokines
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Toll-Like Receptor 4
  • Caspase 1
  • Matrix Metalloproteinase 9