Mitochondrial division/mitophagy inhibitor (Mdivi) ameliorates pressure overload induced heart failure

PLoS One. 2012;7(3):e32388. doi: 10.1371/journal.pone.0032388. Epub 2012 Mar 27.


Background: We have previously reported the role of anti-angiogenic factors in inducing the transition from compensatory cardiac hypertrophy to heart failure and the significance of MMP-9 and TIMP-3 in promoting this process during pressure overload hemodynamic stress. Several studies reported the evidence of cardiac autophagy, involving removal of cellular organelles like mitochondria (mitophagy), peroxisomes etc., in the pathogenesis of heart failure. However, little is known regarding the therapeutic role of mitochondrial division inhibitor (Mdivi) in the pressure overload induced heart failure. We hypothesize that treatment with mitochondrial division inhibitor (Mdivi) inhibits abnormal mitophagy in a pressure overload heart and thus ameliorates heart failure condition.

Materials and methods: To verify this, ascending aortic banding was done in wild type mice to create pressure overload induced heart failure and then treated with Mdivi and compared with vehicle treated controls.

Results: Expression of MMP-2, vascular endothelial growth factor, CD31, was increased, while expression of anti angiogenic factors like endostatin and angiostatin along with MMP-9, TIMP-3 was reduced in Mdivi treated AB 8 weeks mice compared to vehicle treated controls. Expression of mitophagy markers like LC3 and p62 was decreased in Mdivi treated mice compared to controls. Cardiac functional status assessed by echocardiography showed improvement and there is also a decrease in the deposition of fibrosis in Mdivi treated mice compared to controls.

Conclusion: Above results suggest that Mdivi inhibits the abnormal cardiac mitophagy response during sustained pressure overload stress and propose the novel therapeutic role of Mdivi in ameliorating heart failure.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiostatins / genetics
  • Angiostatins / metabolism
  • Animals
  • Aorta / pathology
  • Apoptosis / drug effects
  • Constriction, Pathologic / complications
  • Echocardiography
  • Electron Transport Complex IV / metabolism
  • Endostatins / genetics
  • Endostatins / metabolism
  • Gene Expression / drug effects
  • Heart / drug effects*
  • Heart / physiopathology
  • Heart Failure / diagnostic imaging
  • Heart Failure / etiology
  • Heart Failure / prevention & control*
  • Hypertrophy, Left Ventricular / diagnostic imaging
  • Hypertrophy, Left Ventricular / physiopathology
  • Hypertrophy, Left Ventricular / prevention & control
  • Immunohistochemistry
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Pressure
  • Quinazolinones / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Inhibitor of Metalloproteinase-3 / genetics
  • Tissue Inhibitor of Metalloproteinase-3 / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Endostatins
  • Quinazolinones
  • Tissue Inhibitor of Metalloproteinase-3
  • Vascular Endothelial Growth Factor A
  • Angiostatins
  • cytochrome C oxidase subunit II
  • Electron Transport Complex IV
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9