title: Rapamycin treatment of healthy pigs subjected to acute myocardial ischemia-reperfusion injury attenuates cardiac functions and increases myocardial necrosis.
abstract: BACKGROUND
  The mammalian target of rapamycin (mTOR) pathway is a major regulator of cell immunity and metabolism. mTOR is a well-known suppressor of tissue rejection in organ transplantation. However, it has other nonimmune functions: in the cardiovascular system, it is a regulator of heart hypertrophy and locally, in coated vascular stents, it inhibits vascular wall cell growth and hence neointimal formation/restenosis. Because the mTOR pathway plays major roles in normal cell growth, metabolism, and survival, we hypothesized that inhibiting it with rapamycin before an acute myocardial ischemia-reperfusion injury (IRI) would confer cardioprotection by virtue of slowing down cardiac function and metabolism.
  
  
  METHODS
  Yorkshire pigs received either placebo or 4 mg/d rapamycin orally for 7 days before the IRI. All animals underwent median sternotomy, and the mid-left anterior descending coronary artery was occluded for 60 minutes followed by 120 minutes of reperfusion. Left ventricular pressure-volume data were collected throughout the operation. The ischemic and infarcted areas were determined by monastral blue and triphenyltetrazolium chloride staining, respectively, and plasma cardiac troponin I concentration. mTOR kinase activities were monitored in remote cardiac tissue by Western blotting with specific antibodies against mTOR substrates phosphorylating sites.
  
  
  RESULTS
  Rapamycin before treatment impaired endothelial-dependent vasorelaxation, attenuated cardiac function during IRI, and increased myocardial necrosis. Western blotting confirmed effective inhibition of myocardial mTOR kinase activities.
  
  
  CONCLUSIONS
  Acute myocardial IRI, in healthy pigs treated with rapamycin, is associated with decreased cardiac function and higher myocardial necrosis.
authors.affiliation: Rhode Island Hospital Division of Cardiothoracic Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Antonio D
authors.initials: AD
authors.lastname: Lassaletta
authors.affiliation: Rhode Island Hospital Division of Cardiothoracic Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Nassrene Y
authors.initials: NY
authors.lastname: Elmadhun
authors.affiliation: Rhode Island Hospital Division of Cardiothoracic Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo, Sao Paulo, Brazil.
authors.forename: Arthus V D
authors.initials: AV
authors.lastname: Zanetti
authors.affiliation: Rhode Island Hospital Division of Cardiothoracic Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Rhode Island Hospital Division of Cardiothoracic Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Javier
authors.initials: J
authors.lastname: Anduaga
authors.affiliation: Organ Transplantation, and Cardiovascular Research Center, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Reginald Y
authors.initials: RY
authors.lastname: Gohh
authors.affiliation: Rhode Island Hospital Division of Cardiothoracic Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
authors.affiliation: Rhode Island Hospital Division of Cardiothoracic Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island. Electronic address: cbianchi1@lifespan.org.
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
mesh_terms: D000208:Acute Disease; D000818:Animals; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology*; D009336:Necrosis / Q000139:chemically induced; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D013552:Swine
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus