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Combined antiretroviral therapy causes cardiomyopathy and elevates plasma lactate in transgenic AIDS mice
W Lewis1, C P Haase, S M Raidel
1Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. wlewis@emory.edu
Insights
Highly active antiretroviral therapy (HAART) can cause mitochondrial cardiomyopathy and elevated plasma lactate in AIDS patients. This study demonstrated HAART-induced mitochondrial damage and cardiac dysfunction in AIDS transgenic mice.
Area of Science:
- Cardiology
- Virology
- Biochemistry
Background:
- Highly active antiretroviral therapy (HAART) is associated with cardiomyopathy (CM) and elevated plasma lactate (LA) in AIDS patients.
- Mitochondrial dysfunction is a proposed mechanism linking HAART, CM, and LA.
Purpose of the Study:
- To investigate the in vivo mitochondrial events induced by HAART in an AIDS mouse model.
- To determine the effects of HAART on cardiac function, molecular markers, and plasma lactate levels.
Main Methods:
- Hemizygous transgenic AIDS mice and wild-type littermates were treated with a HAART combination or vehicle for 10 or 35 days.
- Echocardiography, molecular marker quantitation (ANF, SERCA2 mRNA), plasma LA determination, and transmission electron microscopy were performed.
Main Results:
- After 35 days, HAART-treated AIDS mice showed a 160% increase in left ventricular mass, 250% increase in ANF mRNA, 57% decrease in SERCA2 mRNA, and elevated plasma LA (8.5 mM).
- Cardiac myocytes exhibited cytoplasmic changes indicative of enlarged, damaged mitochondria, confirmed ultrastructurally.
- No significant changes were observed in control groups or after 10 days of treatment, except for elevated ANF in the HAART-treated AIDS mice.
Conclusions:
- Cumulative HAART exposure induces mitochondrial cardiomyopathy (CM) with elevated plasma lactate (LA) in AIDS transgenic mice.
- The findings highlight HAART-induced mitochondrial dysfunction as a key factor in cardiac complications in AIDS.
Abstract:
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.