Proteasome Inhibition Attenuates Infarct Size and Preserves Cardiac Function in a Murine Model of Myocardial Ischemia-Reperfusion Injury

William E. Stansfield, Nancy C. Moss, Monte Willis, Ruhang Tang, Craig H. Selzman

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Background: Despite improvements in protection, myocardial ischemia-reperfusion remains an important cause of cardiac dysfunction. Multiple strategies exist experimentally; few are clinically accessible. Nuclear factor kappa-B (NF-κB) is a transcription factor central to the inflammatory response and is implicated in reperfusion injury. Its activation relies on the degradation of its inhibitory molecule, IκB, by the 20S proteasome. We hypothesized that proteasome inhibition would decrease the extent of infarction after temporary coronary occlusion. Methods: C57Bl6 mice received a specific proteasome inhibitor (PS-519) and were subjected to 30 minutes of transient occlusion of the left anterior descending artery. After 24 hours of reperfusion, echocardiography was performed to evaluate ventricular function and hearts were excised and analyzed for infarct size, areas at risk, and molecular markers of injury and NF-κB activation. Results: Compared with controls, PS-519 delivered before left anterior descending (coronary artery) ligation reduced the area of infarct without a change in the area at risk. Similar results were seen with PS-519 delivered at reperfusion. Echocardiography demonstrated a relative reduction in fractional shortening in the vehicle group of 9.8% versus only 2.7% in the PS-519 group. Markers of myocardial stress and injury were accordingly suppressed with PS-519. These physiologic findings were associated with PS-519 decreasing p65 and TNF expression while preserving IκBα expression. Conclusions: In this murine infarct model PS-519 significantly preserved regional myocardial function, reduced the size of infarction, and attenuated expression of myocardial inflammatory response genes. These data demonstrate that a currently available and well-tolerated inhibitor of NF-κB can decrease the risk of myocardial injury associated with ischemia-reperfusion.

Original languageEnglish (US)
Pages (from-to)120-125
Number of pages6
JournalAnnals of Thoracic Surgery
Volume84
Issue number1
DOIs
StatePublished - Jul 1 2007
Externally publishedYes

Fingerprint

Myocardial Reperfusion Injury
Proteasome Endopeptidase Complex
Reperfusion Injury
Myocardial Ischemia
NF-kappa B
Reperfusion
Infarction
Echocardiography
Wounds and Injuries
Myocardial Reperfusion
Proteasome Inhibitors
Ventricular Function
Coronary Occlusion
PS519
Ligation
Coronary Vessels
Transcription Factors
Ischemia
Arteries

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Proteasome Inhibition Attenuates Infarct Size and Preserves Cardiac Function in a Murine Model of Myocardial Ischemia-Reperfusion Injury. / Stansfield, William E.; Moss, Nancy C.; Willis, Monte; Tang, Ruhang; Selzman, Craig H.

In: Annals of Thoracic Surgery, Vol. 84, No. 1, 01.07.2007, p. 120-125.

Research output: Contribution to journalArticle

Stansfield, William E. ; Moss, Nancy C. ; Willis, Monte ; Tang, Ruhang ; Selzman, Craig H. / Proteasome Inhibition Attenuates Infarct Size and Preserves Cardiac Function in a Murine Model of Myocardial Ischemia-Reperfusion Injury. In: Annals of Thoracic Surgery. 2007 ; Vol. 84, No. 1. pp. 120-125.
@article{2f70de547df947d59b8f3309e2bd7482,
title = "Proteasome Inhibition Attenuates Infarct Size and Preserves Cardiac Function in a Murine Model of Myocardial Ischemia-Reperfusion Injury",
abstract = "Background: Despite improvements in protection, myocardial ischemia-reperfusion remains an important cause of cardiac dysfunction. Multiple strategies exist experimentally; few are clinically accessible. Nuclear factor kappa-B (NF-κB) is a transcription factor central to the inflammatory response and is implicated in reperfusion injury. Its activation relies on the degradation of its inhibitory molecule, IκB, by the 20S proteasome. We hypothesized that proteasome inhibition would decrease the extent of infarction after temporary coronary occlusion. Methods: C57Bl6 mice received a specific proteasome inhibitor (PS-519) and were subjected to 30 minutes of transient occlusion of the left anterior descending artery. After 24 hours of reperfusion, echocardiography was performed to evaluate ventricular function and hearts were excised and analyzed for infarct size, areas at risk, and molecular markers of injury and NF-κB activation. Results: Compared with controls, PS-519 delivered before left anterior descending (coronary artery) ligation reduced the area of infarct without a change in the area at risk. Similar results were seen with PS-519 delivered at reperfusion. Echocardiography demonstrated a relative reduction in fractional shortening in the vehicle group of 9.8{\%} versus only 2.7{\%} in the PS-519 group. Markers of myocardial stress and injury were accordingly suppressed with PS-519. These physiologic findings were associated with PS-519 decreasing p65 and TNF expression while preserving IκBα expression. Conclusions: In this murine infarct model PS-519 significantly preserved regional myocardial function, reduced the size of infarction, and attenuated expression of myocardial inflammatory response genes. These data demonstrate that a currently available and well-tolerated inhibitor of NF-κB can decrease the risk of myocardial injury associated with ischemia-reperfusion.",
author = "Stansfield, {William E.} and Moss, {Nancy C.} and Monte Willis and Ruhang Tang and Selzman, {Craig H.}",
year = "2007",
month = "7",
day = "1",
doi = "10.1016/j.athoracsur.2007.02.049",
language = "English (US)",
volume = "84",
pages = "120--125",
journal = "Annals of Thoracic Surgery",
issn = "0003-4975",
publisher = "Elsevier USA",
number = "1",

}

TY - JOUR

T1 - Proteasome Inhibition Attenuates Infarct Size and Preserves Cardiac Function in a Murine Model of Myocardial Ischemia-Reperfusion Injury

AU - Stansfield, William E.

AU - Moss, Nancy C.

AU - Willis, Monte

AU - Tang, Ruhang

AU - Selzman, Craig H.

PY - 2007/7/1

Y1 - 2007/7/1

N2 - Background: Despite improvements in protection, myocardial ischemia-reperfusion remains an important cause of cardiac dysfunction. Multiple strategies exist experimentally; few are clinically accessible. Nuclear factor kappa-B (NF-κB) is a transcription factor central to the inflammatory response and is implicated in reperfusion injury. Its activation relies on the degradation of its inhibitory molecule, IκB, by the 20S proteasome. We hypothesized that proteasome inhibition would decrease the extent of infarction after temporary coronary occlusion. Methods: C57Bl6 mice received a specific proteasome inhibitor (PS-519) and were subjected to 30 minutes of transient occlusion of the left anterior descending artery. After 24 hours of reperfusion, echocardiography was performed to evaluate ventricular function and hearts were excised and analyzed for infarct size, areas at risk, and molecular markers of injury and NF-κB activation. Results: Compared with controls, PS-519 delivered before left anterior descending (coronary artery) ligation reduced the area of infarct without a change in the area at risk. Similar results were seen with PS-519 delivered at reperfusion. Echocardiography demonstrated a relative reduction in fractional shortening in the vehicle group of 9.8% versus only 2.7% in the PS-519 group. Markers of myocardial stress and injury were accordingly suppressed with PS-519. These physiologic findings were associated with PS-519 decreasing p65 and TNF expression while preserving IκBα expression. Conclusions: In this murine infarct model PS-519 significantly preserved regional myocardial function, reduced the size of infarction, and attenuated expression of myocardial inflammatory response genes. These data demonstrate that a currently available and well-tolerated inhibitor of NF-κB can decrease the risk of myocardial injury associated with ischemia-reperfusion.

AB - Background: Despite improvements in protection, myocardial ischemia-reperfusion remains an important cause of cardiac dysfunction. Multiple strategies exist experimentally; few are clinically accessible. Nuclear factor kappa-B (NF-κB) is a transcription factor central to the inflammatory response and is implicated in reperfusion injury. Its activation relies on the degradation of its inhibitory molecule, IκB, by the 20S proteasome. We hypothesized that proteasome inhibition would decrease the extent of infarction after temporary coronary occlusion. Methods: C57Bl6 mice received a specific proteasome inhibitor (PS-519) and were subjected to 30 minutes of transient occlusion of the left anterior descending artery. After 24 hours of reperfusion, echocardiography was performed to evaluate ventricular function and hearts were excised and analyzed for infarct size, areas at risk, and molecular markers of injury and NF-κB activation. Results: Compared with controls, PS-519 delivered before left anterior descending (coronary artery) ligation reduced the area of infarct without a change in the area at risk. Similar results were seen with PS-519 delivered at reperfusion. Echocardiography demonstrated a relative reduction in fractional shortening in the vehicle group of 9.8% versus only 2.7% in the PS-519 group. Markers of myocardial stress and injury were accordingly suppressed with PS-519. These physiologic findings were associated with PS-519 decreasing p65 and TNF expression while preserving IκBα expression. Conclusions: In this murine infarct model PS-519 significantly preserved regional myocardial function, reduced the size of infarction, and attenuated expression of myocardial inflammatory response genes. These data demonstrate that a currently available and well-tolerated inhibitor of NF-κB can decrease the risk of myocardial injury associated with ischemia-reperfusion.

UR - http://www.scopus.com/inward/record.url?scp=34250368734&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34250368734&partnerID=8YFLogxK

U2 - 10.1016/j.athoracsur.2007.02.049

DO - 10.1016/j.athoracsur.2007.02.049

M3 - Article

VL - 84

SP - 120

EP - 125

JO - Annals of Thoracic Surgery

JF - Annals of Thoracic Surgery

SN - 0003-4975

IS - 1

ER -