title: Infiltrated cardiac lipids impair myofibroblast-induced healing of the myocardial scar post-myocardial infarction.
abstract: OBJECTIVE
  Lipids have been detected in the ischemic myocardium of patients' post-myocardial infarction (MI). However, their effect on the cardiac healing process remains unknown. We investigated whether intramyocardial lipids affect the signaling pathways involved in the fibrotic reparative response impairing cardiac healing post-MI.
  
  
  METHODS
  Pigs, fed either a high-cholesterol diet (HC) or a regular-chow (NC), were subjected to experimentally-induced acute MI (90 min mid-LAD balloon occlusion) and then, upon reperfusion (R), maintained for 21 days with the same diet regime (HC/R(+) and NC/R(+), respectively). A group of hypercholesterolemic animals were sacrificed after ischemia without reperfusion (HC/R(-)). Cardiac tissue was obtained for molecular/cellular/histological analysis. Infarct size and echocardiography were assessed.
  
  
  RESULTS
  At the time of acute MI, hypercholesterolemic animals showed a higher incidence of ventricular dysrhythmias. At sacrifice, intramyocardial lipids were absent in HC/R(-). HC/R(+) showed higher lipid content (ApoB, cholesteryl-ester and triglycerides) and lower expression/activity of the TGFβ/TβRII/Smad2/3 pathway (involved in scar reparative fibrosis) than NC/R(+) in the forming scar. Collagen synthesis was accordingly reduced in the scar of HC/R(+). Infarct size was 44% larger in HC/R(+) which had higher apoptosis and lower Akt/eNOS activity in the jeopardized myocardium. Systolic function was similarly deteriorated post-MI in all animals whereas no changes were detected in diastolic-related parameters. No changes were detected in systolic parameters 21 days post-MI in NC/R(+) animals. In contrast, both systolic- and diastolic-related parameters were further deteriorated in HC/R(+) animals.
  
  
  CONCLUSIONS
  Intramyocardial lipid accumulation impairs TGFβ/TβRII/Smad2/3 signaling altering the fibrotic reparative process of the scar resulting in larger infarcts and cardiac dysfunction.
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Vilahur
authors.forename: Laura
authors.initials: L
authors.lastname: Casani
authors.forename: Oriol
authors.initials: O
authors.lastname: Juan-Babot
authors.forename: Jose M
authors.initials: JM
authors.lastname: Guerra
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D017209:Apoptosis; D002788:Cholesterol Esters / Q000378:metabolism; D002921:Cicatrix / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism; D050356:Lipid Metabolism; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013552:Swine; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000209:etiology / Q000378:metabolism; D016277:Ventricular Function, Left; D014945:Wound Healing
chemical_list: D001055:Apolipoproteins B; D002788:Cholesterol Esters; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D014280:Triglycerides; D003094:Collagen; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077294:Receptor, Transforming Growth Factor-beta Type II