Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy

Enkhsaikhan Purevjav, David P. Nelson, Jacquelin J. Varela, Shinawe Jimenez, Debra L. Kearney, Ximena V. Sanchez, Gilberto DeFreitas, Blasé Carabello, Michael D. Taylor, Matteo Vatta, William T. Shearer, Jeffrey Towbin, Neil E. Bowles

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: Dilated cardiomyopathy (DCM) and myocarditis occur in many HIV-infected individuals, resulting in symptomatic heart failure in up to 5% of patients. Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality of acquired immunodeficiency syndrome (AIDS), but has resulted in an increase in cardiac and skeletal myopathies. Methods and Results: In order to investigate whether the HAART component zidovudine (3′-azido-2′,3′-deoxythymidine; AZT) triggers the Fas-dependent cell-death pathway and cause cytoskeletal disruption in a murine model of DCM, 8-week-old transgenic (expressing Fas ligand in the myocardium: FasL Tg) and non-transgenic (NTg) mice received water ad libitum containing different concentrations of AZT (0, 0.07, 0.2, and 0.7 mg/ml). After 6 weeks, cardiac function was assessed by echocardiography and morphology was assessed by histopathologic and immunohistochemical methods. NTg and untreated FasL Tg mice showed little or no change in cardiac structure or function. In contrast, AZT-treated FasL Tg mice developed cardiac dilation and depressed cardiac function in a dose-dependent manner, with concomitant inflammatory infiltration of both ventricles. These changes were associated with an increased sarcolemmal expression of Fas and FasL, as well as increased activation of caspase 3, translocation of calpain 1 to the sarcolemma and sarcomere, and increased numbers of cells undergoing apoptosis. These were associated with changes in dystrophin and cardiac troponin I localization, as well as loss of sarcolemmal integrity. Conclusions: The expression of Fas ligand in the myocardium, as identified in HIV-positive patients, might increase the susceptibility to HAART-induced cardiomyopathy due to activation of apoptotic pathways, resulting in cardiac dilation and dysfunction.

Original languageEnglish (US)
Pages (from-to)255-263
Number of pages9
JournalCardiovascular Toxicology
Volume7
Issue number4
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

Fingerprint

Fas Ligand Protein
Highly Active Antiretroviral Therapy
Cardiomyopathies
Zidovudine
Dilated Cardiomyopathy
Dilatation
Myocardium
Chemical activation
HIV
Echocardiography
Sarcolemma
Dystrophin
Sarcomeres
Troponin I
Calpain
Myocarditis
Muscular Diseases
Cell death
Infiltration
Caspase 3

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Toxicology
  • Cardiology and Cardiovascular Medicine

Cite this

Purevjav, E., Nelson, D. P., Varela, J. J., Jimenez, S., Kearney, D. L., Sanchez, X. V., ... Bowles, N. E. (2007). Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy. Cardiovascular Toxicology, 7(4), 255-263. https://doi.org/10.1007/s12012-007-9004-9

Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy. / Purevjav, Enkhsaikhan; Nelson, David P.; Varela, Jacquelin J.; Jimenez, Shinawe; Kearney, Debra L.; Sanchez, Ximena V.; DeFreitas, Gilberto; Carabello, Blasé; Taylor, Michael D.; Vatta, Matteo; Shearer, William T.; Towbin, Jeffrey; Bowles, Neil E.

In: Cardiovascular Toxicology, Vol. 7, No. 4, 01.12.2007, p. 255-263.

Research output: Contribution to journalArticle

Purevjav, E, Nelson, DP, Varela, JJ, Jimenez, S, Kearney, DL, Sanchez, XV, DeFreitas, G, Carabello, B, Taylor, MD, Vatta, M, Shearer, WT, Towbin, J & Bowles, NE 2007, 'Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy', Cardiovascular Toxicology, vol. 7, no. 4, pp. 255-263. https://doi.org/10.1007/s12012-007-9004-9
Purevjav, Enkhsaikhan ; Nelson, David P. ; Varela, Jacquelin J. ; Jimenez, Shinawe ; Kearney, Debra L. ; Sanchez, Ximena V. ; DeFreitas, Gilberto ; Carabello, Blasé ; Taylor, Michael D. ; Vatta, Matteo ; Shearer, William T. ; Towbin, Jeffrey ; Bowles, Neil E. / Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy. In: Cardiovascular Toxicology. 2007 ; Vol. 7, No. 4. pp. 255-263.
@article{d816c418232146b4bf82410c89cc01bb,
title = "Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy",
abstract = "Background: Dilated cardiomyopathy (DCM) and myocarditis occur in many HIV-infected individuals, resulting in symptomatic heart failure in up to 5{\%} of patients. Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality of acquired immunodeficiency syndrome (AIDS), but has resulted in an increase in cardiac and skeletal myopathies. Methods and Results: In order to investigate whether the HAART component zidovudine (3′-azido-2′,3′-deoxythymidine; AZT) triggers the Fas-dependent cell-death pathway and cause cytoskeletal disruption in a murine model of DCM, 8-week-old transgenic (expressing Fas ligand in the myocardium: FasL Tg) and non-transgenic (NTg) mice received water ad libitum containing different concentrations of AZT (0, 0.07, 0.2, and 0.7 mg/ml). After 6 weeks, cardiac function was assessed by echocardiography and morphology was assessed by histopathologic and immunohistochemical methods. NTg and untreated FasL Tg mice showed little or no change in cardiac structure or function. In contrast, AZT-treated FasL Tg mice developed cardiac dilation and depressed cardiac function in a dose-dependent manner, with concomitant inflammatory infiltration of both ventricles. These changes were associated with an increased sarcolemmal expression of Fas and FasL, as well as increased activation of caspase 3, translocation of calpain 1 to the sarcolemma and sarcomere, and increased numbers of cells undergoing apoptosis. These were associated with changes in dystrophin and cardiac troponin I localization, as well as loss of sarcolemmal integrity. Conclusions: The expression of Fas ligand in the myocardium, as identified in HIV-positive patients, might increase the susceptibility to HAART-induced cardiomyopathy due to activation of apoptotic pathways, resulting in cardiac dilation and dysfunction.",
author = "Enkhsaikhan Purevjav and Nelson, {David P.} and Varela, {Jacquelin J.} and Shinawe Jimenez and Kearney, {Debra L.} and Sanchez, {Ximena V.} and Gilberto DeFreitas and Blas{\'e} Carabello and Taylor, {Michael D.} and Matteo Vatta and Shearer, {William T.} and Jeffrey Towbin and Bowles, {Neil E.}",
year = "2007",
month = "12",
day = "1",
doi = "10.1007/s12012-007-9004-9",
language = "English (US)",
volume = "7",
pages = "255--263",
journal = "Cardiovascular Toxicology",
issn = "1530-7905",
publisher = "Humana Press",
number = "4",

}

TY - JOUR

T1 - Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy

AU - Purevjav, Enkhsaikhan

AU - Nelson, David P.

AU - Varela, Jacquelin J.

AU - Jimenez, Shinawe

AU - Kearney, Debra L.

AU - Sanchez, Ximena V.

AU - DeFreitas, Gilberto

AU - Carabello, Blasé

AU - Taylor, Michael D.

AU - Vatta, Matteo

AU - Shearer, William T.

AU - Towbin, Jeffrey

AU - Bowles, Neil E.

PY - 2007/12/1

Y1 - 2007/12/1

N2 - Background: Dilated cardiomyopathy (DCM) and myocarditis occur in many HIV-infected individuals, resulting in symptomatic heart failure in up to 5% of patients. Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality of acquired immunodeficiency syndrome (AIDS), but has resulted in an increase in cardiac and skeletal myopathies. Methods and Results: In order to investigate whether the HAART component zidovudine (3′-azido-2′,3′-deoxythymidine; AZT) triggers the Fas-dependent cell-death pathway and cause cytoskeletal disruption in a murine model of DCM, 8-week-old transgenic (expressing Fas ligand in the myocardium: FasL Tg) and non-transgenic (NTg) mice received water ad libitum containing different concentrations of AZT (0, 0.07, 0.2, and 0.7 mg/ml). After 6 weeks, cardiac function was assessed by echocardiography and morphology was assessed by histopathologic and immunohistochemical methods. NTg and untreated FasL Tg mice showed little or no change in cardiac structure or function. In contrast, AZT-treated FasL Tg mice developed cardiac dilation and depressed cardiac function in a dose-dependent manner, with concomitant inflammatory infiltration of both ventricles. These changes were associated with an increased sarcolemmal expression of Fas and FasL, as well as increased activation of caspase 3, translocation of calpain 1 to the sarcolemma and sarcomere, and increased numbers of cells undergoing apoptosis. These were associated with changes in dystrophin and cardiac troponin I localization, as well as loss of sarcolemmal integrity. Conclusions: The expression of Fas ligand in the myocardium, as identified in HIV-positive patients, might increase the susceptibility to HAART-induced cardiomyopathy due to activation of apoptotic pathways, resulting in cardiac dilation and dysfunction.

AB - Background: Dilated cardiomyopathy (DCM) and myocarditis occur in many HIV-infected individuals, resulting in symptomatic heart failure in up to 5% of patients. Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality of acquired immunodeficiency syndrome (AIDS), but has resulted in an increase in cardiac and skeletal myopathies. Methods and Results: In order to investigate whether the HAART component zidovudine (3′-azido-2′,3′-deoxythymidine; AZT) triggers the Fas-dependent cell-death pathway and cause cytoskeletal disruption in a murine model of DCM, 8-week-old transgenic (expressing Fas ligand in the myocardium: FasL Tg) and non-transgenic (NTg) mice received water ad libitum containing different concentrations of AZT (0, 0.07, 0.2, and 0.7 mg/ml). After 6 weeks, cardiac function was assessed by echocardiography and morphology was assessed by histopathologic and immunohistochemical methods. NTg and untreated FasL Tg mice showed little or no change in cardiac structure or function. In contrast, AZT-treated FasL Tg mice developed cardiac dilation and depressed cardiac function in a dose-dependent manner, with concomitant inflammatory infiltration of both ventricles. These changes were associated with an increased sarcolemmal expression of Fas and FasL, as well as increased activation of caspase 3, translocation of calpain 1 to the sarcolemma and sarcomere, and increased numbers of cells undergoing apoptosis. These were associated with changes in dystrophin and cardiac troponin I localization, as well as loss of sarcolemmal integrity. Conclusions: The expression of Fas ligand in the myocardium, as identified in HIV-positive patients, might increase the susceptibility to HAART-induced cardiomyopathy due to activation of apoptotic pathways, resulting in cardiac dilation and dysfunction.

UR - http://www.scopus.com/inward/record.url?scp=36949021070&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36949021070&partnerID=8YFLogxK

U2 - 10.1007/s12012-007-9004-9

DO - 10.1007/s12012-007-9004-9

M3 - Article

C2 - 17943461

AN - SCOPUS:36949021070

VL - 7

SP - 255

EP - 263

JO - Cardiovascular Toxicology

JF - Cardiovascular Toxicology

SN - 1530-7905

IS - 4

ER -