title: Highly active antiretroviral therapy attenuates re-endothelialization and alters neointima formation in the rat carotid artery after balloon injury.
abstract: Highly active antiretroviral therapy (HAART) has led to a sustained decline of HIV-associated morbidity and mortality. HAART exhibits significant side effects, however, such as hyperlipidemia and hyperglycemia, which possibly contribute to accelerated atherosclerosis in HAART-treated patients. In addition, direct effects of HAART on vascular cells have been described, which may promote atherosclerotic lesion formation. The effects of HAART on balloon-induced neointima formation have not been studied previously. The rat carotid artery balloon model was used to evaluate the effects of HAART (lopinavir, ritonavir, lamivudine, and zidovudine) on neointima formation and endothelial recovery. Furthermore, the effects of concomitant administration of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor rosuvastatin were investigated. HAART-treated animals displayed an increase in lesion size (neointima/media ratio: 1.14 +/- 0.32 vs. 1.31 +/- 0.20 in control vs. HAART; P < 0.05) and an impaired regenerative capacity of the endothelium, as indicated by reduction in endothelial regrowth from an adjacent undilated vessel segment 14 days after injury (re-endothelialization area: 8.29 +/- 1.45 mm vs. 5.09 +/- 0.53 mm in control vs. HAART; P < 0.05). When rosuvastatin was given in addition to HAART, these effects were not observed. In conclusion, HAART inhibited endothelial cell-mediated healing and promoted neointima formation after angioplasty in rats. These deleterious effects were attenuated by cotreatment with rosuvastatin, however. Our studies suggest that currently used drug regimens against HIV infection may lead to an increased risk for restenosis after percutaneous vascular interventions. Moreover, the findings indicate that the additional treatment with statins might counteract these adverse effects by HAART.
authors.affiliation: Karolinska Cancer Center, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
authors.forename: Olli
authors.initials: O
authors.lastname: Leppänen
authors.forename: Janna
authors.initials: J
authors.lastname: Paulsson
authors.forename: Masao
authors.initials: M
authors.lastname: Furuhashi
authors.forename: Mari-Anne
authors.initials: MA
authors.lastname: Carlsson
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Gerd
authors.initials: G
authors.lastname: Fätkenheuer
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
mesh_terms: D000818:Animals; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D002339:Carotid Arteries / Q000473:pathology*; D002404:Catheterization / Q000009:adverse effects*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
chemical_list: D005464:Fluorobenzenes; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium