Apoptosis Induced by gp120 in the Neocortex of Rat Involves Enhanced Expression of Cyclooxygenase Type 2 and Is Prevented by NMDA Receptor Antagonists and by the 21-Aminosteroid U-74389G

Corasaniti, Maria Tiziana; Strongoli, M.C.; Piccirilli, Silvia; Nisticò, Robert; Costa, Alfredo; Bilotta, Anna; Turano, P.; Finazzi‐Agrò, Alessandro; Bagetta, Giacinto

doi:10.1006/bbrc.2000.3160

Cited by 44 publications

(35 citation statements)

References 26 publications

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“…A pathogenic role for gp120 in HIV cardiomyopathy is very similar to the role already proposed for gp120 in HIV dementia (5,10). HIV gp120 has been reported to have CD4-independent effects on rat neurons that may be mediated through the N-methyl-D-aspartate (NMDA) receptor (10,41).…”

Section: Discussionsupporting

confidence: 56%

“…HIV gp120 has been reported to have CD4-independent effects on rat neurons that may be mediated through the N-methyl-D-aspartate (NMDA) receptor (10,41). Drugs that either deplete (caffeine, thapsigargin) or block release from (dantrolene) intracellular Ca 2ϩ stores were effective in blocking the rise in intracellular Ca 2ϩ and cell death in rat neural tissue caused by gp120 (34).…”

Section: Discussionmentioning

confidence: 99%

“…This could conserve energy and diminish oxidative stress. However, the more prolonged activation of neurons by HIV gp120 has been shown to result in apoptosis (10,24). Similarly, prolonged and repeated activation of p38 MAP kinase in cardiac myocytes by gp120 could result in HIV cardiomyopathy in vulnerable individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Our data and those of Chen et al (7) indicate the presence of a high-affinity (nM) HIV binding site on cardiac myocytes. The previously identified binding sites for HIV gp120 include the CD4, CXCR4, CCR5, and NMDA receptors (10,30,37). Our data suggest the presence of structures homologous to CD4, CXCR4, CCR5, or NMDA receptors on ARVM.…”

Section: Discussionmentioning

confidence: 99%

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p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

Kan

Xie²,

Finkel³

2004

American Journal of Physiology-Cell Physiology

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Kan, Hong, Zirong Xie, and Mitchell S. Finkel. p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes. Am J Physiol Cell Physiol 286: C1-C7, 2004; 10.1152/ ajpcell.00059.2003.-Myocardial dysfunction leading to dilated cardiomyopathy has been documented with surprisingly high frequency in human immunodeficiency virus (HIV)-infected individuals. p38 MAP kinase has been implicated as a mediator of myocardial dysfunction. We previously reported p38 MAP kinase activation by the HIV coat protein gp120 in neonatal rat cardiac myocytes. We now report the direct inotropic effects of HIV gp120 on adult rat ventricular myocytes (ARVM). ARVM were continuously superfused with gp120, and percent fractional shortening (FS) was determined by automated border detection and simultaneous intracellular ionized free Ca 2ϩ concentration ([Ca 2ϩ ]i) measured by fura 2-AM fluorescence: gp120 alone increased FS and increased [Ca 2ϩ ]i within 5 min and then depressed FS without a decrease in [Ca 2ϩ ]i by 20-60 min, which persisted for at least 2 h. Exposure of ARVM to gp120 also resulted in the phosphorylation of the upstream regulator of p38 MAP kinase MKK3/6, p38 MAP kinase itself, and its downstream effector, ATF-2, over a similar time course. ERK (p44/42) and JNK stress signaling pathways were not similarly activated. The effects of the p38 MAP kinase inhibitor were concentration dependent. SB-203580 (10 M) blocked both p38 MAP kinase phosphorylation and the delayed negative inotropic effect of gp120. SB-203580 (5 M) selectively blocked phosphorylation of ATF-2 without blocking the phosphorylation of MKK3/6 or p38 MAP kinase itself. SB-203580 (5 M) administered before, with, or after gp120 blocked the negative inotropic effect of gp120 in ARVM. p38 MAP kinase activation may be a common stress-response mechanism contributing to myocardial dysfunction in HIV and other nonischemic as well as ischemic cardiomyopathies.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

Kan

Xie²,

Finkel³

2004

American Journal of Physiology-Cell Physiology

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“…Interestingly, gp120, another HIV-1 protein involved in HAD, has been found to induce COX-2 in neuroblastoma cells (43) and aggravate excitotoxic conditions by impairing astrocyte uptake of glutamate via COX-derived products resulting in calcium overload and neuronal dysfunction or death (20,54,55). Besides, intracerebroventricular gp120 injection enhanced the expression of COX-2 and apoptotic death in the brain neocortex of rats was prevented by COX-2 inhibitors (29,56).…”

Section: Discussionmentioning

confidence: 99%

Extracellular HIV-Tat Induces Cyclooxygenase-2 in Glial Cells through Activation of Nuclear Factor of Activated T Cells

Blanco

Álvarez

Fresno

et al. 2008

The Journal of Immunology

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Both the HIV-1 protein Tat and cyclooxygenase-2 (COX-2) have been involved in the neuropathogenesis associated with HIV-1 infection. However, the relationship among them has not been addressed. Here, we found that extracellular Tat was able to induce COX-2 mRNA and protein expression and PGE2 synthesis in astrocytoma cell lines and primary human astrocytes. Moreover, Tat induced COX-2 promoter transcription. Deletion of NF-κB sites of the promoter did not diminish Tat-dependent transcription. Interestingly, Tat did not induce NF-κB activity, suggesting that NF-κB was not necessary to control COX-2 transcription induced by Tat. In contrast, deletion or mutation of the NFAT and/or AP-1 site abrogated COX-2 induction by Tat. Moreover, Tat induced transcription of NFAT- and AP-1-dependent reporter genes. Transfection of a dominant negative c-Jun mutant protein, TAM-67, or of a dominant negative version of NFAT, efficiently blocked the induction of COX-2 promoter by Tat, confirming the requirement of both transcription factors. Moreover, Tat induced NFAT translocation to the nucleus and binding to the distal site of the COX-2 promoter. The importance of NFAT and AP-1 in COX-2 induction and PGE2 synthesis by Tat was corroborated by using pharmacological inhibitors of the NFΑΤ, ERK, and JNK pathways. In summary, our results indicate that HIV-1 Tat was able to induce COX-2 and PGE2 synthesis in astrocytic cells through an NFAT/AP-1-dependent mechanism.

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Inflammatory mediators and reversible myocardial dysfunction

Kan

Finkel

2003

Journal Cellular Physiology

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A variety of seemingly unrelated clinical conditions manifest the same effects on the heart. These effects include: (1) reversible myocardial dysfunction, (2) b-adrenergic desensitization, and (3) activation of inflammatory mediators. We provide evidence supporting a role for cytokines, mitogen activated protein kinases (MAP kinases), and nitric oxide (NO) as common mediators of reversible myocardial dysfunction and b-adrenergic desensitization. Data from animal models and human studies support a pathogenic role for these inflammatory mediators in ischemic as well as non-ischemic myocardial dysfunction. It is suggested that compensatory cellular programs are activated to provide short-term protection from brief periods of ischemia and infection. Continuous activation of these compensatory pathways leads to cardiomyopathy and chronic (congestive) heart failure. Elucidating the signaling pathways involved has the potential to provide the opportunity to exploit the cardioprotective advantages of these agents without bearing the burden of excessive stimulation.

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Apoptosis Induced by gp120 in the Neocortex of Rat Involves Enhanced Expression of Cyclooxygenase Type 2 and Is Prevented by NMDA Receptor Antagonists and by the 21-Aminosteroid U-74389G

Cited by 44 publications

References 26 publications

p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

Extracellular HIV-Tat Induces Cyclooxygenase-2 in Glial Cells through Activation of Nuclear Factor of Activated T Cells

Inflammatory mediators and reversible myocardial dysfunction

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