title: PPAR agonist-mediated protection against HIV Tat-induced cerebrovascular toxicity is enhanced in MMP-9-deficient mice.
abstract: The strategies to protect against the disrupted blood-brain barrier (BBB) in HIV-1 infection are not well developed. Therefore, we investigated the potential of peroxisome proliferator-activated receptor (PPAR) agonists to prevent enhanced BBB permeability induced by HIV-1-specific protein Tat. Exposure to Tat via the internal carotid artery (ICA) disrupted permeability across the BBB; however, this effect was attenuated in mice treated with fenofibrate (PPARα agonist) or rosiglitazone (PPARγ agonist). In contrast, exposure to GW9662 (PPARγ antagonist) exacerbated Tat-induced disruption of the BBB integrity. Increased BBB permeability was associated with decreased tight junction (TJ) protein expression and activation of ERK1/2 and Akt in brain microvessels; these effects were attenuated by cotreatment with fenofibrate but not with rosiglitazone. Importantly, both PPAR agonists also protected against Tat-induced astrogliosis and neuronal loss. Because disruption of TJ integrity has been linked to matrix metalloproteinase (MMP) activity, we also evaluated Tat-induced effects in MMP-9-deficient mice. Tat-induced cerebrovascular toxicity, astrogliosis, and neuronal loss were less pronounced in MMP-9-deficient mice as compared with wild-type controls and were further attenuated by PPAR agonists. These results indicate that enhancing PPAR activity combined with targeting MMPs may provide effective therapeutic strategies in brain infection by HIV-1.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Minseon
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects*; D002452:Cell Count; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D062725:Tight Junction Proteins / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000633:toxicity*
chemical_list: D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D062725:Tight Junction Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D000077154:Rosiglitazone; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D011345:Fenofibrate