title: Opposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy.
abstract: BACKGROUND
  Previously, we demonstrated that inhibition of poly(ADP-ribose) polymerase (PARP) exerts protective effects against high-fat (HF) diet-induced atherogenesis in part by increasing tissue inhibitor of metalloproteinase (TIMP)-2 expression. Given that characteristics of dilated cardiomyopathy closely associate with atherosclerosis and are mediated by an imbalance between matrix metalloproteinases (MMPs) and TIMPs, we hypothesized that PARP-1 gene deletion may protect against HF-induced cardiac hypertrophy and dilatations by altering TIMP-2/MMPs balance in favor of a maintenance of tissue homeostasis.
  
  
  RESULTS
  Hemodynamic parameters determined by echocardiography were similar in ApoE(-/-) mice and PARP-1-deficient ApoE(-/-) mice (DKO) fed a regular diet (RD). However, histological analysis revealed that cardiomyocytes of ApoE(-/-) mice on RD were hypertrophied, displaying an enlarged cell body and nucleus, traits that were absent in DKO animals. HF diet-fed ApoE(-/-) mice exhibited increased interventricular septum, left ventricular (LV) internal dimension, LV volume, and LV mass in addition to a separation of myocardial fibers suggestive of dilated cardiomyopathy. PARP-1 gene deletion protected against these degenerative changes. MMP activity was dramatically increased in hearts of ApoE(-/-) mice on HF diet and was accompanied by increased collagen degradation, mast cell degranulation, and increased myocyte cell death. PARP-1 gene knockout was associated with increased TIMP-2 expression antagonizing, as a result, the damaging effects of active MMPs.
  
  
  CONCLUSIONS
  The present study demonstrates that PARP-1 gene deletion exerts protective effects against HF diet-induced dilated cardiomyopathy by maintaining increased expression of TIMP-2. With additional protective effects against cell death and inflammation, PARP-1 deficiency preserves cardiac tissue homeostasis.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA, USA. chetan.hans@nationwidechildrens.org
authors.forename: Chetan P
authors.initials: CP
authors.lastname: Hans
authors.forename: Yumei
authors.initials: Y
authors.lastname: Feng
authors.forename: Amarjit S
authors.initials: AS
authors.lastname: Naura
authors.forename: Dana
authors.initials: D
authors.lastname: Troxclair
authors.forename: Mourad
authors.initials: M
authors.lastname: Zerfaoui
authors.forename: Danish
authors.initials: D
authors.lastname: Siddiqui
authors.forename: Ju
authors.initials: J
authors.lastname: Jihang
authors.forename: Hogyoung
authors.initials: H
authors.lastname: Kim
authors.forename: Alan D
authors.initials: AD
authors.lastname: Kaye
authors.forename: Khalid
authors.initials: K
authors.lastname: Matrougui
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
authors.forename: A Hamid
authors.initials: AH
authors.lastname: Boulares
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000473:pathology; D015550:Cell Degranulation / Q000502:physiology; D004036:Diet, Atherogenic; D050171:Dyslipidemias / Q000201:enzymology / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008407:Mast Cells / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis*; D014162:Transfection
chemical_list: D019716:Tissue Inhibitor of Metalloproteinase-2; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse