Targeted myocardial transgenic expression of HIV Tat causes cardiomyopathy and mitochondrial damage.
Cardiac effects of human immunodeficiency virus (HIV) transactivator (Tat) are unclear, but Tat decreases liver glutathione (an important mitochondrial antioxidant) when ubiquitously expressed in transgenic mice (TG). With an alpha-myosin heavy chain promoter, Tat was selectively targeted to murine cardiac myocytes. One high-expression hemizygous ((+/-)Tat(high); 12 copies) and two low-expression ((+/-)Tat(lowA,B); 2-5 copies) TG lines were created. Cardiomyopathy was documented with increased left ventricle (LV) mass, ventricular expression of atrial natriuretic factor (ANF) mRNA, mitochondrial ultrastructural defects, and myocardial depletion of glutathione. In (+/-)Tat(high) TGs, normalized LV mass (determined echocardiographically) increased 46% (90 days), 134% (240 days), and 96% (365 days) compared with wild-type littermates (WT). LV fractional shortening was decreased to 28% (90 days), 27% (240 days), and 19% (365 days). (+/-)Tat(low) LV mass was unchanged (<or=365 days). ANF in (+/-)Tat(high) ventricles (180 days) was twofold WT values. Glutathione was selectively decreased in (+/-)Tat(high) hearts (120 days). (+/-)Tat(high) hearts contained damaged mitochondria (>or=210 days); however, profound mitochondrial destruction occurred in homozygous (+/+)Tat(high) hearts (10 days) and the pups died (14 days). Tat caused cardiac dysfunction in this TG and may impact on cardiomyopathy in acquired immunodeficiency syndrome.
Raidel
Scott M
SM
Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Haase
Chad
C
Jansen
Natalie R
NR
Russ
Rodney B
RB
Sutliff
Roy L
RL
Velsor
Leonard W
LW
Day
Brian J
BJ
Hoit
Brian D
BD
Samarel
Allen M
AM
Lewis
William
W
D000818:Animals; D000975:Antioxidants / Q000032:analysis; D001205:Ascorbic Acid / Q000032:analysis; D009320:Atrial Natriuretic Factor / Q000235:genetics; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000209:etiology* / Q000503:physiopathology; D004452:Echocardiography; D004562:Electrocardiography; D015870:Gene Expression; D015696:Gene Products, tat / Q000235:genetics* / Q000502:physiology; D018390:Gene Targeting; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000473:pathology*; D018482:Muscle, Skeletal / Q000737:chemistry; D009200:Myocardial Contraction; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D009928:Organ Specificity; D012333:RNA, Messenger / Q000032:analysis
D000975:Antioxidants; D015696:Gene Products, tat; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D005978:Glutathione; D001205:Ascorbic Acid