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


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.
Purevjav
Enkhsaikhan
E
Department of Pediatrics, Section of Cardiology, Baylor College of Medicine, Houston, TX 77030, USA.
Nelson
David P
DP
Varela
Jacquelin J
JJ
Jimenez
Shinawe
S
Kearney
Debra L
DL
Sanchez
Ximena V
XV
DeFreitas
Gilberto
G
Carabello
Blasé
B
Taylor
Michael D
MD
Vatta
Matteo
M
Shearer
William T
WT
Towbin
Jeffrey A
JA
Bowles
Neil E
NE
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000503:physiopathology; D004452:Echocardiography; D053222:Fas Ligand Protein / Q000096:biosynthesis* / Q000235:genetics; D006679:HIV Seropositivity / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019210:Troponin I / Q000097:blood; D015215:Zidovudine / Q000633:toxicity*
D019380:Anti-HIV Agents; D053222:Fas Ligand Protein; D019210:Troponin I; D015215:Zidovudine