TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload

Lynetta J. Jobe, Giselle C. Meléndez, Scott P. Levick, Yan Du, Gregory L. Brower, Joseph S. Janicki

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-α are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-α with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-α inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-α antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-α has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure.

Original languageEnglish (US)
Pages (from-to)H1462-H1468
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number4
DOIs
StatePublished - Oct 1 2009

Fingerprint

Tumor Necrosis Factor-alpha
Fistula
Heart Failure
Dilatation
Collagen
Etanercept
Cardiac Myocytes
Hypertrophy
Compliance
Sprague Dawley Rats
Cytokines

Keywords

  • Diastolic function
  • Etanercept
  • Extracellular matrix
  • Intrinsic contractility
  • Myocyte dimensions
  • Ventricular pressure-volume relationship

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload. / Jobe, Lynetta J.; Meléndez, Giselle C.; Levick, Scott P.; Du, Yan; Brower, Gregory L.; Janicki, Joseph S.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 297, No. 4, 01.10.2009, p. H1462-H1468.

Research output: Contribution to journalArticle

Jobe, Lynetta J. ; Meléndez, Giselle C. ; Levick, Scott P. ; Du, Yan ; Brower, Gregory L. ; Janicki, Joseph S. / TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload. In: American Journal of Physiology - Heart and Circulatory Physiology. 2009 ; Vol. 297, No. 4. pp. H1462-H1468.
@article{63b72917dfef46bb952f7e8e6c7b44b6,
title = "TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload",
abstract = "Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-α are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-α with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-α inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-α antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-α has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure.",
keywords = "Diastolic function, Etanercept, Extracellular matrix, Intrinsic contractility, Myocyte dimensions, Ventricular pressure-volume relationship",
author = "Jobe, {Lynetta J.} and Mel{\'e}ndez, {Giselle C.} and Levick, {Scott P.} and Yan Du and Brower, {Gregory L.} and Janicki, {Joseph S.}",
year = "2009",
month = "10",
day = "1",
doi = "10.1152/ajpheart.00442.2009",
language = "English (US)",
volume = "297",
pages = "H1462--H1468",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload

AU - Jobe, Lynetta J.

AU - Meléndez, Giselle C.

AU - Levick, Scott P.

AU - Du, Yan

AU - Brower, Gregory L.

AU - Janicki, Joseph S.

PY - 2009/10/1

Y1 - 2009/10/1

N2 - Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-α are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-α with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-α inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-α antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-α has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure.

AB - Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-α are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-α with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-α inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-α antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-α has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure.

KW - Diastolic function

KW - Etanercept

KW - Extracellular matrix

KW - Intrinsic contractility

KW - Myocyte dimensions

KW - Ventricular pressure-volume relationship

UR - http://www.scopus.com/inward/record.url?scp=70349611560&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349611560&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00442.2009

DO - 10.1152/ajpheart.00442.2009

M3 - Article

C2 - 19666842

AN - SCOPUS:70349611560

VL - 297

SP - H1462-H1468

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 4

ER -