Cardiac Dysfunction Occurs in the HIV-1 Transgenic Mouse Treated with Zidovudine

Abstract

SUMMARY:Cardiomyopathy in AIDS is an increasingly important clinical problem. Mechanisms of AIDS cardiomyopathy were explored using AIDS transgenic mice that express replication-incompetent HIV-1 (NL4 -3⌬ gag/pol). Transgenic and FVB/n mice (n ϭ 3 to 6 per cohort) received water ad libitum with and without zidovudine (3Ј-azido-2Ј,3Ј-deoxythymidine; AZT; 0.7 mg/ml) for 21 or 35 days. After 21 days, echocardiographic studies were performed and abundance of mRNA for cardiac sarcoplasmic reticulum calcium ATPase (SERCA2), sodium calcium exchanger (NCX1), and atrial natriuretic factor were determined individually using Northern analysis of extracts of left ventricles. After 35 days, contractile function and relaxation were analyzed in isolated work-performing hearts. Histopathological and ultrastructural (transmission electron microscopy) changes were identified. After 21 days, molecular indicators of cardiac dysfunction were found. Depressed SERCA2 and increased atrial natriuretic factor mRNA abundance occurred in left ventricles from AZT-treated transgenic mice. NCX1 abundance was unchanged. Eccentric left ventricle hypertrophy was determined echocardiographically. After 35 days, cardiac dysfunction was worst in AZT-treated and AZT-untreated transgenic mice. Decreases in the first derivative of the maximal change in left ventricle systolic pressure with respect to time (ϩdP/dt) occurred in transgenic mice with and without AZT. Increased half-time of relaxation and ventricular relaxation (ϪdP/dt) occurred in AZT-treated and -untreated transgenic mice. Increased time to peak pressure was found only in AZT-treated transgenic mice. In AZT-treated FVB/n mice, ϪdP/dt was decreased. Ultrastructurally, mitochondrial destruction was most pronounced in AZT-treated transgenic mice, but also was found in AZT-treated FVB/n mice. Transgenic mice that express HIV-1 demonstrate cardiac dysfunction. AZT treatment of FVB/n mice causes mitochondrial ultrastructural alterations that are similar to those in other species. In transgenic mice, AZT treatment worsens molecular and ultrastructural features of cardiomyopathy. HIV-1 constructs and AZT each contribute to cardiac dysfunction in this murine model of AIDS cardiomyopathy.

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

“…9,[41][42][43][44][45][46] It is reasonable to conclude that DNC plays a mechanistic role in mitochondrial defects from thymidine analog-based HAART. Intramitochondrial abundance of phosphorylated and unphosphorylated native nucleo- sides and NRTIs affects inhibition mtDNA replication at the level of the nucleotide substrate.…”

“…9 Photomicrographs were enlarged to 8 Â 10 inch prints. Each electron photomicrograph was reviewed independently by two investigators for the presence of structurally abnormal mitochondria, for the presence of intramitochondrial lamellar bodies, and for intramitochondrial paracrystals as reported in human AZT-induced skeletal muscle mitochondrial myopathy.…”

Cardiovascular complications in the acquired immunodeficiency syndrome

“…Studies of transgenic mice suggest that zidovudine is associated with diffuse destruction of the cardiac mi tochondrial ultrastructure and inhibition of mito chondrial DNA replication 31 .This mito chondrial dysfunction may result in lactic acidosis, which could also contribute to myocardial cell dys function. However, in a study of infants born to HIV-infected mothers followed from birth to age 5, perinatal exposure to zidovudine was not found to be associated with acute or chronic abnormalities in left ventricular structure or function 32 .Other nucleoside reverse transcriptase inhibitors, such as didanosine, zalcitabine or lamivudine, do not seem to promote or prevent dilated cardiomyopathy.…”

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ

“…In those studies, TGs were treated with NRTIs that compete with native nucleotides for intramitochondrial phosphorylation and transport. 31,32,39,46,47 Data indicated transport of nucleotides into mitochondria may be disrupted by NRTIs.…”