HIV Tat-Mediated Induction of Human Brain Microvascular Endothelial Cell Apoptosis Involves Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

Ma, Rong; Lü, Yang; Niu, Fang; Buch, Shilpa

doi:10.1007/s12035-014-8991-3

Cited by 47 publications

(54 citation statements)

References 44 publications

(46 reference statements)

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“…This study demonstrated that although SREBP2 activation and HMGCR levels were increased, HMGCR activity was reduced by 70% under ER stress, which led to decreased cholesterol synthesis. There are a number of reports of ER stress induced by cocaine or Tat contributing to neurotoxicity (Desai et al 2010; Fan and He 2016; Ma et al 2016; Periyasamy et al 2016). Therefore, it is possible that ER stress may be an upstream event mediating cholesterol dysregulation following cocaine and Tat exposure.…”

Section: Discussionmentioning

confidence: 99%

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cotto

Natarajaseenivasan

Ferrero

et al. 2018

Glia

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Cholesterol synthesis and clearance by astrocytes are tightly regulated to maintain constant levels within the brain. In this context, liver X receptors (LXRs) are the master regulators of cholesterol homeostasis in the central nervous system (CNS). Increasing levels of cholesterol in astrocytes trigger LXR activation leading to the transcription of target genes involved in cholesterol trafficking and efflux, including apolipoprotein E, cytochrome P450 enzymes, sterol regulatory binding protein, and several ATP-binding cassette transporter proteins. The disturbance of LXR signaling in the brain can lead to significant dysfunctions in cholesterol homeostasis, and disruptions in this pathway have been implicated in numerous neurological diseases including Alzheimer's disease and Huntington's disease. HIV infection of the CNS in combination with cocaine use is associated with astrocyte and neuronal energy deficit and damage. We propose that dysregulation in CNS cholesterol metabolism may be involved in the progression of HIV-associated neurocognitive disorders (HAND) and in cocaine-mediated neurocognitive impairments. We hypothesize that exposure of astrocytes to cocaine and the HIV protein Tat will disrupt LXR signaling. Alterations in these pathways will in turn, affect cholesterol bioavailability for neurons. Our data show that exposure of astrocytes to cocaine and HIV-Tat significantly decreases LXRβ levels, downstream signaling and bioavailability of cholesterol. Taken together, these data uncover novel alterations in a bioenergetic pathway in astrocytes exposed to cocaine and the HIV protein Tat. Results from these studies point to a new pathway in the CNS that may contribute to HAND in HIV+ cocaine user individuals.

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Section: Discussionmentioning

confidence: 99%

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cotto

Natarajaseenivasan

Ferrero

et al. 2018

Glia

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“…Increased ROS, together with the release of soluble cellular and host factors following HIV infection, results in induction of the ER stress response, leading to apoptosis in the vasculature (81). HIV also triggers ER stress through its interaction with host genes, resulting in an imbalance of ER calcium homeostasis (1).…”

Section: Potential Molecular Mechanismsmentioning

confidence: 99%

“…HIV also triggers ER stress through its interaction with host genes, resulting in an imbalance of ER calcium homeostasis (1). Several HIV proteins are known to contribute to calcium imbalance in endothelial cells and can trigger apoptosis through ER stress, thereby leading to endothelial dysfunction (81). Consistently, HIV Tat-mediated induction of human endothelial cell apoptosis involves ER stress and mitochondrial dysfunction.…”

Section: Potential Molecular Mechanismsmentioning

confidence: 99%

HIV-1–Associated Atherosclerosis

Kearns

Gordon

Burdo

et al. 2017

Journal of the American College of Cardiology

130

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Cardiovascular disease, including atherosclerosis and atherosclerosis-associated complications, is an increasing cause of morbidity and mortality in HIV patients in the post-antiretroviral therapy era. HIV alone accelerates atherosclerosis. Antiretroviral therapy, HIV-associated comorbidities, such as dyslipidemia, drug abuse, opportunistic infections, and lifestyle, are risk factors for HIV-associated atherosclerosis. However, our current understanding of HIV-associated atherogenesis is very limited and largely obtained from clinical observation. There is a pressing need to experimentally unravel the missing link between HIV and atherosclerosis. Understanding these mechanisms will help to better develop and design novel therapeutic interventions for the treatment of HIV-associated cardiovascular disease. HIV mainly infects T cells and macrophages resulting in the induction of oxidative and endoplasmic reticulem stress, the formation of the inflammasome, and the dysregulation of autophagy. These mechanisms may contribute to HIV-associated atherogenesis. In this review, we will summarize our current understanding and propose potential mechanisms of HIV-associated atherosclerosis.

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“…Following TAR binding, Tat is able to recruit the cellular apparatus that promotes chromatin‐remodelling and phosphorylation of RNA polymerase II. This enhances the processivity of the elongating polymerase and stimulates the assembly of new transcription complexes . Beyond its role on viral transcription, Tat has been proposed to modulate the expression of several other genes, to interact with a large number of host cell proteins, and to inhibit several cellular metabolic pathways .…”

Section: Introductionmentioning

confidence: 99%

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

Campestrini

Silveira

Pinto

2018

Cell Biochemistry & Function

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The HIV transactivator protein (Tat) is a multifunctional protein that plays a critical role in viral replication and contributes to several pathological symptoms of HIV‐1 infection, which has the loss of CD4+ T lymphocytes as one of its hallmark features. It has been shown that endoplasmic reticulum (ER) stress, including viral infections, is implicated in cellular dysfunction and cell death through activation of the unfolded protein response (UPR). Here, we demonstrate that the bystander stimulus of Tat on Jurkat cells resulted in time‐dependent overexpression of major UPR markers including ER chaperone BiP, ER stress sensors ATF6, PERK, and IRE1, as well as an increase in levels of downstream mediators eIF2α, ATF4, XBP‐1, and proapoptotic factors CHOP, GADD34, and BIM. This upregulation of UPR mediators was accompanied by decreased cell viability and increased apoptosis as evidenced by blue trypan dye exclusion and flow cytometry assays, respectively. Furthermore, we found that the Tat‐associated apoptosis of Jurkat cells led to the loss of mitochondrial membrane potential and caspase‐12 and ‐3 activation. Taken together, these results suggest that the exposure of HIV‐1 Tat leads to ER stress/UPR triggering which in turn contributes to apoptotic death in Jurkat cells. Significance of the study In the present work, we provide a substantial insight into the link between ER impairment and apoptotic death following a bystander HIV Tat stimulus, revealing an underlying ER‐mediated apoptotic mechanism which could explain the continuous depletion of uninfected CD4+ T lymphocytes observed in HIV‐related disease. Our findings reinforce the relevance of ER stress molecular responses in the course of HIV infection and may afford valuable information for the development of new therapeutic strategies to avoid CD4+ T lymphocyte loss and other disorders induced by circulant Tat.

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HIV Tat-Mediated Induction of Human Brain Microvascular Endothelial Cell Apoptosis Involves Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

Cited by 47 publications

References 44 publications

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

HIV-1–Associated Atherosclerosis

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

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