title: Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium.
abstract: OBJECTIVE
  Impaired angiogenesis is a known consequence of metabolic syndrome (MetS); however, the mechanism is not fully understood. Recent studies have shown that the notch signaling pathway is an integral component of cardiac angiogenesis. We tested, in a clinically relevant swine model, the effects of MetS on notch and apoptosis signaling in chronically ischemic myocardium.
  
  
  METHODS
  Ossabaw swine were fed either a regular diet (control [CTL], n = 8) or a high-cholesterol diet (MetS, n = 8) to induce MetS. An ameroid constrictor was placed to induce chronic myocardial ischemia. Eleven weeks later, the wine underwent cardiac harvest of the ischemic myocardium.
  
  
  RESULTS
  Downregulation of pro-angiogenesis proteins notch2, notch4, jagged2, angiopoietin 1, and endothelial nitric oxide synthase were found in the MetS group compared with the CTL group. Also, upregulation of pro-apoptosis protein caspase 8 and downregulation of anti-angiogenesis protein phosphorylated forkhead box transcription factor 03 and pro-survival proteins phosphorylated P38 and heat shock protein 90 were present in the MetS group. Cell death was increased in the MetS group compared with the CTL group. Both CTL and MetS groups had a similar arteriolar count and capillary density, and notch3 and jagged1 were both similarly concentrated in the smooth muscle wall.
  
  
  CONCLUSIONS
  MetS in chronic myocardial ischemia significantly impairs notch signaling by downregulating notch receptors, ligands, and pro-angiogenesis proteins. MetS also increases apoptosis signaling, decreases survival signaling, and increases cell death in chronically ischemic myocardium. Although short-term angiogenesis appears unaffected in this model of early MetS, the molecular signals for angiogenesis are impaired, suggesting that inhibition of notch signaling might underlie the decreased angiogenesis in later stages of MetS.
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Brown University Warren Alpert School of Medicine, Providence, RI.
authors.forename: Nassrene Y
authors.initials: NY
authors.lastname: Elmadhun
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Brown University Warren Alpert School of Medicine, Providence, RI.
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Sabe
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Brown University Warren Alpert School of Medicine, Providence, RI.
authors.forename: Antonio D
authors.initials: AD
authors.lastname: Lassaletta
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Brown University Warren Alpert School of Medicine, Providence, RI.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Chu
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Brown University Warren Alpert School of Medicine, Providence, RI.
authors.forename: Katelyn
authors.initials: K
authors.lastname: Kondra
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Ind.
authors.forename: Michael
authors.initials: M
authors.lastname: Sturek
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Brown University Warren Alpert School of Medicine, Providence, RI. Electronic address: fsellke@lifespan.org.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors
chemical_list: D042501:Angiogenic Proteins; D051017:Apoptosis Regulatory Proteins; D051880:Receptors, Notch