title: Mitigation of myocardial fibrosis by molecular cardiac surgery-mediated gene overexpression.
abstract: OBJECTIVE
  Heart failure is accompanied by up-regulation of transforming growth factor beta signaling, accumulation of collagen and dysregulation of sarcoplasmic reticulum calcium adenosine triphosphatase cardiac isoform 2a (SERCA2a). We examined the fibrotic response in small and large myocardial infarct, and the effect of overexpression of the SERCA2a gene.
  
  
  METHODS
  Ischemic cardiomyopathy was induced via creation of large or small infarct in 26 sheep. Animals were divided into 4 groups: small infarct; large infarct with heart failure; gene-treated (large infarct with heart failure followed by adeno-associated viral vector, serotype 1.SERCA2a gene construct transfer by molecular cardiac surgery with recirculating delivery); and control.
  
  
  RESULTS
  Heart failure was significantly less pronounced in the gene-treated and small-infarct groups than in the large-infarct group. Expression of transforming growth factor beta signaling components was significantly higher in the large-infarct group, compared with the small-infarct and gene-treated groups. Both the angiotensin II type 1 receptor and angiotensin II were significantly elevated in the small- and large-infarct groups, whereas gene treatment diminished this effect. Active fibrosis with de novo collagen synthesis was evident in the large-infarct group; the small-infarct and gene-treated groups showed less fibrosis, with a lower ratio of de novo to mature collagen.
  
  
  CONCLUSIONS
  The data presented provide evidence that progression of fibrosis is mediated through increased transforming growth factor beta and angiotensin II signaling, which is mitigated by increased SERCA2a gene expression.
authors.affiliation: Department of Cardiothoracic Surgery, Sanger Heart and Vascular Institute, Charlotte, NC; Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY. Electronic address: dr.michael.katz@gmail.com.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katz
authors.affiliation: Liver Pathobiology Laboratory, Carolinas Medical Center, Charlotte, NC.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Brandon-Warner
authors.affiliation: Department of Cardiothoracic Surgery, Sanger Heart and Vascular Institute, Charlotte, NC; Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fargnoli
authors.affiliation: Department of Cardiothoracic Surgery, Sanger Heart and Vascular Institute, Charlotte, NC.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Williams
authors.affiliation: Department of Cardiothoracic Surgery, Sanger Heart and Vascular Institute, Charlotte, NC.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Kendle
authors.affiliation: Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: Liver Pathobiology Laboratory, Carolinas Medical Center, Charlotte, NC.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Schrum
authors.affiliation: Department of Cardiothoracic Surgery, Sanger Heart and Vascular Institute, Charlotte, NC. Electronic address: crbridges99@gmail.com.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Bridges
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006439:Hemodynamics; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D058628:Myofibroblasts / Q000201:enzymology / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis* / Q000235:genetics; D012756:Sheep; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D005353:Fibronectins; D044140:Receptor, Angiotensin, Type 1; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D003094:Collagen; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: TGFbeta; fibrosis; gene therapy; myocardial infarction