Regulation of Plasma PAI-1 Concentrations in HAART-Associated Lipodystrophy During Rosiglitazone Therapy

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 23; no. 4; pp. 688 - 694
• Main Authors: Yki-Järvinen, Hannele, Sutinen, Jussi, Silveira, Angela, Korsheninnikova, Elena, Fisher, Rachel M., Kannisto, Katja, Ehrenborg, Ewa, Eriksson, Per, Hamsten, Anders
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.04.2003; Hagerstown, MD Lippincott
• Subjects: Adipose Tissue - metabolism; Adult; Antiretroviral Therapy, Highly Active - adverse effects; Biological and medical sciences; Cross-Sectional Studies; Drug toxicity and drugs side effects treatment; Female; HIV Infections - blood; HIV Infections - drug therapy; Humans; Hyperinsulinism - chemically induced; Hyperinsulinism - drug therapy; Hypertriglyceridemia - chemically induced; Hypertriglyceridemia - drug therapy; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Leptin - biosynthesis; Leptin - genetics; Lipodystrophy - blood; Lipodystrophy - chemically induced; Lipodystrophy - drug therapy; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Middle Aged; Miscellaneous (drug allergy, mutagens, teratogens...); Organ Specificity; Pharmacology. Drug treatments; Plasminogen Activator Inhibitor 1 - biosynthesis; Plasminogen Activator Inhibitor 1 - blood; Plasminogen Activator Inhibitor 1 - genetics; Receptors, Cytoplasmic and Nuclear - agonists; RNA, Messenger - biosynthesis; Subcutaneous Tissue - metabolism; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use; Transcription Factors - agonists; Human; Immunopathology; Skin disease; Serine endopeptidases; tissue plasminogen activator; Enzyme; Toxicity; AIDS; triglycerides; Triglyceride; Immune deficiency; Fibrinolysis; Insulin; t-Plasminogen activator; Infection; Peptidases; Chemotherapy; Treatment; Viral disease; Hydrolases; Antiviral; Lipodystrophy; Adipose tissue disorders; steatosis
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/01.ATV.0000062885.61917.A5

OBJECTIVE—Patients with highly active antiretroviral therapy–associated lipodystrophy (HAART+LD+) have high plasminogen activator inhibitor-1 (PAI-1) concentrations for unknown reasons. We determined whether (1) plasma PAI-1 antigen concentrations are related to liver fat content (LFAT) independently of the size of other fat depots and (2) rosiglitazone decreases PAI-1 and LFAT in these patients. METHODS AND RESULTS—In the cross-sectional study, 3 groups were investigated30 HIV-positive patients with HAART+LD+, 13 HIV-positive patients without lipodystrophy (HAART+LD−), and 15 HIV-negative subjects (HIV−). In the treatment study, the HAART+LD+ group received either rosiglitazone (8 mg, n=15) or placebo (n=15) for 24 weeks. Plasma PAI-1 was increased in HAART+LD+ (28±2 ng/mL) compared with the HAART+LD− (18±3, P <0.02) and HIV− (10±3, P <0.001) groups. LFAT was higher in HAART+LD+ (7.6±1.7%) than in the HAART+LD− (2.1±1.1%, P <0.001) and HIV− (3.6±1.2%, P <0.05) groups. Within the HAART+LD+ group, plasma PAI-1 was correlated with LFAT (r =0.49, P <0.01) but not with subcutaneous or intra-abdominal fat or serum insulin or triglycerides. In subcutaneous adipose tissue, PAI-1 mRNA was 2- to 3-fold higher in the HAART+LD+ group than in either the HAART+LD− or HIV− group. Rosiglitazone decreased LFAT, serum insulin, and plasma PAI-1 and increased serum triglycerides but had no effect on intra-abdominal or subcutaneous fat mass or PAI-1 mRNA. CONCLUSIONS—Plasma PAI-1 concentrations are increased in direct proportion to LFAT in HAART+LD+ patients. Rosiglitazone decreases LFAT, serum insulin, and plasma PAI-1 without changing the size of other fat depots or PAI-1 mRNA in subcutaneous fat. These data suggest that liver fat contributes to plasma PAI-1 concentrations in these patients.