HIV viral protein R causes atrial cardiomyocyte mitosis, mesenchymal tumor, dysrhythmia, and heart failure.
HIV viral protein R (Vpr) affects the immunocyte cell cycle and circulates as free polypeptide in plasma of AIDS patients. Effects of Vpr on cardiomyocytes were explored using transgenic mice (TG) with Vpr targeted to cardiomyocytes by the alpha-myosin heavy-chain promoter. TG and WT littermate hearts were evaluated histopathologically, ultrastructurally, molecularly via RNA microarray analysis and quantitative RT-PCR, and functionally by cardiac magnetic resonance imaging (MRI) and electrocardiograms (ECG). Six hemizygous lines were created (Vpr(a,b,c,d,e,h)). Vpr RNA was expressed exclusively in myocardium and Vpr mRNA expression correlated with phenotypic changes. Vpr(b) exhibited the highest expression and mortality. TGs developed congestive heart failure ( approximately 8 weeks), abnormal cardiomyocyte nuclei and mitoses ( approximately 12 weeks), and became moribund ( approximately 20 weeks) with atrial mesenchymal tumors. MRI revealed four-chamber dilation, defective contraction, and atrial masses. Pathologically, cardiomegaly and atrial mesenchymal tumors occurred ( approximately 16-20 weeks). ECGs showed prolonged R-R, Q-T, and P-R intervals ( approximately 12 weeks). RNA encoding collagen and bone morphogenic protein 4, 6, and 7 were increased. Vpr targeted to cardiomyocytes caused defective contractility and atrial tumors. Since some Vpr cardiomyocytic effects resemble those found in terminally differentiated immunocytes, some pathogenetic mechanisms may be shared at the subcellular level.
Lewis
William
W
Department of Pathology, Emory University, Atlanta, GA, USA. w.lewis@emory.edu
Miller
Yoon K
YK
Haase
Chad P
CP
Ludaway
Tomika
T
McNaught
Jamie
J
Russ
Rodney
R
Steltzer
Jeffrey
J
Folpe
Andrew
A
Long
Robert
R
Oshinski
John
J
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D015415:Biomarkers; D006332:Cardiomegaly / Q000235:genetics; D004562:Electrocardiography; D015967:Gene Expression Regulation, Viral; D016336:Gene Products, vpr / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics; D006325:Heart Atria / Q000473:pathology; D006333:Heart Failure / Q000235:genetics*; D006338:Heart Neoplasms / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D054325:vpr Gene Products, Human Immunodeficiency Virus
D015415:Biomarkers; D016336:Gene Products, vpr; D012333:RNA, Messenger; D054325:vpr Gene Products, Human Immunodeficiency Virus; D018995:Myosin Heavy Chains