title: Targeted myocardial transgenic expression of HIV Tat causes cardiomyopathy and mitochondrial damage.
abstract: 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.
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Raidel
authors.forename: Chad
authors.initials: C
authors.lastname: Haase
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Jansen
authors.forename: Rodney B
authors.initials: RB
authors.lastname: Russ
authors.forename: Roy L
authors.initials: RL
authors.lastname: Sutliff
authors.forename: Leonard W
authors.initials: LW
authors.lastname: Velsor
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hoit
authors.forename: Allen M
authors.initials: AM
authors.lastname: Samarel
authors.forename: William
authors.initials: W
authors.lastname: Lewis
mesh_terms: 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
chemical_list: D000975:Antioxidants; D015696:Gene Products, tat; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D005978:Glutathione; D001205:Ascorbic Acid