title: Mitochondrial division/mitophagy inhibitor (Mdivi) ameliorates pressure overload induced heart failure.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Givvimani
authors.forename: Charu
authors.initials: C
authors.lastname: Munjal
authors.forename: Neetu
authors.initials: N
authors.lastname: Tyagi
authors.forename: Utpal
authors.initials: U
authors.lastname: Sen
authors.forename: Naira
authors.initials: N
authors.lastname: Metreveli
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D043168:Angiostatins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D003251:Constriction, Pathologic / Q000150:complications; D004452:Echocardiography; D003576:Electron Transport Complex IV / Q000378:metabolism; D043169:Endostatins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000517:prevention & control; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011312:Pressure; D052999:Quinazolinones / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D043169:Endostatins; D052999:Quinazolinones; D019717:Tissue Inhibitor of Metalloproteinase-3; D042461:Vascular Endothelial Growth Factor A; D043168:Angiostatins; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9