AIDS-related vasculopathy: evidence for oxidative and inflammatory pathways in murine and human AIDS

Abstract

Increased life expectancy of human immunodeficiency virus (HIV)-positive patients has led to evidence of complications apparently not directly related to immunodeficiency or opportunistic infection, including increased cardiovascular risk. We tested the hypothesis that vascular dysfunction occurs in the murine acquired immune deficiency syndrome (AIDS) model and evaluated potential mechanisms in murine AIDS tissues and relevant human HIV/AIDS vascular tissues. We also investigated endothelial activation and/or endothelial protein nitration and their association with time-dependent vascular dysfunction. At 1 and 5 wk of murine AIDS, statistically significant decreases in KCl contractility and time-dependent contractile deficits in response to phenylephrine were observed. The maximal response (E(max)) was reduced by approximately 40% at 10 wk, and EC(50) values were significantly changed: 102 +/- 7.3 ng for control vs. 190 +/- 37 and 130 +/- 22 ng at 5 and 10 wk, respectively (P < 0.05). Endothelium-dependent relaxation to ACh was decreased (EC(50) = 120 +/- 27 and 343 +/- 94 nM for control and at 10 wk, respectively), whereas the response to an exogenous nitric oxide donor, sodium nitroprusside, remained unchanged, suggesting a specific endothelial dysfunction. Histochemical investigations of the same vascular tissues as well as corresponding coronary endothelium showed an increase in protein 3-nitrotyrosine, intercellular adhesion molecule, and nitric oxide synthase isoforms 2 and 3. These findings were corroborated in concurrent experiments in a cohort of well-cataloged human cardiac microvascular tissues. We have demonstrated, for the first time, a specific functional vasculopathy with endothelial involvement in a murine model of AIDS that was also associated with and correlated to increased oxidative stress and specific endothelial activation. This finding was echoed in a relevant population of human HIV/AIDS patients. Research into sources and intracellular targets of oxidants in this disease could provide important mechanistic insights and may reveal new therapeutic opportunities for this increasingly important cardiovascular disease state.

HIV-1 Tat Activates Dual Nox Pathways Leading to Independent Activation of ERK and JNK MAP Kinases

“…Notably, Tat activates an NADPH oxidase upstream of JNK in endothelial cells, suggesting activation of a pathway common to mitogens and cytokines (15,16). This oxidant-related pathway is consistent with evidence of oxidant production in vivo by the vasculature in both murine and human AIDS (17).…”

Human Immunodeficiency Virus (HIV) Infects Human Arterial Smooth Muscle Cells in Vivo and in Vitro

“…44 In all of the tissue sections from different HIV-infected individuals with atherosclerosis, a population of HIV-infected SMCs was detected by p24 staining, suggesting active HIV replication. A striking difference between the sections obtained from atherosclerotic vessels from uninfected people compared to those from HIV-infected individuals was the symmetry of the SMC accumulation in the intima of tissues from HIVinfected people.…”

Inibição da expressão de ciclooxigenase 2 em feridas cutâneas de camundongos NOD submetidos à terapia a laser de baixa intensidade

“…Estudo envolvendo tratamento com LLLT na isquemia cerebral induzida experimentalmente sugere que este tipo de terapia pode inibir a produção do NO e regular a expressão da citocina TGF-β2 que apresenta potencial anti--inflamatório além de induzir a proliferação fibroblástica, controlando o processo cicatricial 27 . Diversos pesquisadores também têm estudado o papel imunomodulador pró-inflamatório do NO através da elevação dos níveis de COX2 [14][15][16][17] . A COX2 pertence à família de enzimas que convertem o ácido araquidônico em prostaglandina (PG).…”

“…O camundongo diabético não obeso (NOD) é amplamente utilizado em trabalhos experimentais por apresentar um genoma bem definido que induz o desenvolvimento espontâneo de um quadro fenotípico de DM1 [10][11][12][13] . Diversos pesquisadores têm estudado o papel imunomodulador pró-inflamatório da interação de mediadores inflamatórios, como por exemplo, os efeitos do óxido nítri-co (NO) através da elevação dos níveis de ciclooxigenase 2 (COX2) no sítio inflamatório induzindo a vasodilatação e a migração de células para o local da lesão tecidual [14][15][16][17] . No presente estudo, avaliou-se o efeito da LLLT sobre a síntese de COX2 durante a resposta cicatricial em feridas cutâneas em camundongos diabéticos.…”