Combined antiretroviral therapy causes cardiomyopathy and elevates plasma lactate in transgenic AIDS mice.
Highly active antiretroviral therapy (HAART) is implicated in cardiomyopathy (CM) and in elevated plasma lactate (LA) in AIDS through mechanisms of mitochondrial dysfunction. To determine mitochondrial events from HAART in vivo, 8-week-old hemizygous transgenic AIDS mice (NL4-3Delta gag/pol; TG) and wild-type FVB/n littermates were treated with the HAART combination of zidovudine, lamivudine, and indinavir or vehicle control for 10 days or 35 days. At termination of the experiments, mice underwent echocardiography, quantitation of abundance of molecular markers of CM (ventricular mRNA encoding atrial natriuretic factor [ANF] and sarcoplasmic calcium ATPase [SERCA2]), and determination of plasma LA. Myocardial histologic features were analyzed semiquantitatively and results were confirmed by transmission electron microscopy. After 35 days in the TG + HAART cohort, left ventricular mass increased 160% by echocardiography. Molecularly, ANF mRNA increased 250% and SERCA2 mRNA decreased 57%. Biochemically, LA was elevated (8.5 +/- 2.0 mM). Pathologically, granular cytoplasmic changes were found in cardiac myocytes, indicating enlarged, damaged mitochondria. Findings were confirmed ultrastructurally. No changes were found in other cohorts. After 10 days, only ANF was elevated, and only in the TG + HAART cohort. Results show that cumulative HAART caused mitochondrial CM with elevated LA in AIDS transgenic mice.
Lewis
W
W
Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. wlewis@emory.edu
Haase
C P
CP
Raidel
S M
SM
Russ
R B
RB
Sutliff
R L
RL
Hoit
B D
BD
Samarel
A M
AM
D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D009320:Atrial Natriuretic Factor / Q000235:genetics; D000252:Calcium-Transporting ATPases / Q000235:genetics; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology / Q000821:virology; D004359:Drug Therapy, Combination; D004452:Echocardiography; D015870:Gene Expression; D017320:HIV Protease Inhibitors / Q000009:adverse effects; D019469:Indinavir / Q000009:adverse effects; D019344:Lactic Acid / Q000097:blood*; D019259:Lamivudine / Q000009:adverse effects; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000032:analysis; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015215:Zidovudine / Q000009:adverse effects
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D012333:RNA, Messenger; D019259:Lamivudine; D019344:Lactic Acid; D015215:Zidovudine; D019469:Indinavir; D009320:Atrial Natriuretic Factor; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D000252:Calcium-Transporting ATPases