Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium

Nassrene Y. Elmadhun, Ashraf A. Sabe, Antonio D. Lassaletta, Louis M. Chu, Katelyn Kondra, Michael Sturek, Frank W. Sellke

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1048-1055
Number of pages8
JournalJournal of Thoracic and Cardiovascular Surgery
Volume148
Issue number3
DOIs
StatePublished - 2014

Fingerprint

Myocardium
Apoptosis
Down-Regulation
Notch2 Receptor
Myocardial Ischemia
Proteins
Cell Death
Swine
Angiopoietin-1
Notch Receptors
Diet
Forkhead Transcription Factors
HSP90 Heat-Shock Proteins
Control Groups
Caspase 8
Nitric Oxide Synthase Type III
Wine
Smooth Muscle
Up-Regulation
Cholesterol

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Pulmonary and Respiratory Medicine

Cite this

Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium. / Elmadhun, Nassrene Y.; Sabe, Ashraf A.; Lassaletta, Antonio D.; Chu, Louis M.; Kondra, Katelyn; Sturek, Michael; Sellke, Frank W.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 148, No. 3, 2014, p. 1048-1055.

Research output: Contribution to journalArticle

Elmadhun, Nassrene Y. ; Sabe, Ashraf A. ; Lassaletta, Antonio D. ; Chu, Louis M. ; Kondra, Katelyn ; Sturek, Michael ; Sellke, Frank W. / Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium. In: Journal of Thoracic and Cardiovascular Surgery. 2014 ; Vol. 148, No. 3. pp. 1048-1055.
@article{25d3f557e9504e1cb54e92574c2e4cd9,
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.",
author = "Elmadhun, {Nassrene Y.} and Sabe, {Ashraf A.} and Lassaletta, {Antonio D.} and Chu, {Louis M.} and Katelyn Kondra and Michael Sturek and Sellke, {Frank W.}",
year = "2014",
doi = "10.1016/j.jtcvs.2014.05.056",
language = "English",
volume = "148",
pages = "1048--1055",
journal = "Journal of Thoracic and Cardiovascular Surgery",
issn = "0022-5223",
publisher = "Mosby Inc.",
number = "3",

}

TY - JOUR

T1 - Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium

AU - Elmadhun, Nassrene Y.

AU - Sabe, Ashraf A.

AU - Lassaletta, Antonio D.

AU - Chu, Louis M.

AU - Kondra, Katelyn

AU - Sturek, Michael

AU - Sellke, Frank W.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84908499718&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908499718&partnerID=8YFLogxK

U2 - 10.1016/j.jtcvs.2014.05.056

DO - 10.1016/j.jtcvs.2014.05.056

M3 - Article

VL - 148

SP - 1048

EP - 1055

JO - Journal of Thoracic and Cardiovascular Surgery

JF - Journal of Thoracic and Cardiovascular Surgery

SN - 0022-5223

IS - 3

ER -