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Circulation. 2018 Oct 26. doi: 10.1161/CIRCULATIONAHA.118.036232. [Epub ahead of print]

Senescent Phenotype Induced by p90RSK-NRF2 Signaling Sensitizes Monocytes and Macrophages to Oxidative Stress in HIV+ Individuals: Implications for Atherogenesis.

Author information

1
Department of Microbiology and Immunology, University of Rochester, UNITED STATES.
2
Cardiology, University of Texas MD Anderson Cancer Center, UNITED STATES.
3
Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, UNITED STATES.
4
Cardiology, University of texas MDAnderson cancer center, UNITED STATES.
5
College of Pharmacy, Chungnam National University, KOREA, REPUBLIC OF.
6
Endocrine Neoplasia and Hormonal Disorders, UT MD Anderson Cancer Center, UNITED STATES.
7
Cariology, University of Texas MD Anderson Cancer Center, UNITED STATES.
8
Cardiology-Reserch, University of Texas MD Anderson Cancer Center, UNITED STATES.
9
CV Sciences, Houston Methodist Research Institute, UNITED STATES.
10
Cariology, UT MD Anderson Cancer Center, UNITED STATES.
11
UCSF, UNITED STATES.
12
Imaging Sciences, University of Rochester, UNITED STATES.
13
University of Rochester Medical Center, UNITED STATES.
14
Electrical & Computer Engineering, University of Rochester, UNITED STATES.
15
Biostatistics and Computational Biology, University of Rochester, UNITED STATES.
16
Department of Biostatistics and Computational Biology, University of Rochester, UNITED STATES.
17
Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, UNITED STATES.
18
University of Rochester, UNITED STATES.
19
Neuroscience, University of Rochester, UNITED STATES.
20
Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, UNITED STATES.
21
Neurology, University of Rochester, UNITED STATES.
22
Department of Cardiology, University of Texas MD Anderson Cancer Center, UNITED STATES.

Abstract

BACKGROUND:

The incidence of cardiovascular disease (CVD) is higher in HIV+ patients than it is in the average population, and combination antiretroviral therapy (cART) is a recognized risk factor for CVD. However, the molecular mechanisms that link cART and CVD are currently unknown. Our study explores the role of the activation of p90RSK, a reactive oxygen species (ROS)-sensitive kinase, in engendering senescent phenotype in macrophages and accelerating atherogenesis in patients undergoing cART.

METHODS:

Peripheral whole blood from cART-treated HIV+ individuals and non-treated HIV- individuals was treated with H2O2 (200 ┬ÁM) for 4 minutes, and p90RSK activity in CD14+ monocytes was measured. Plaque formation in the carotids were also analyzed in these individuals. Macrophage senescence was determined by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. The involvement of p90RSK-NRF2 signaling in cART-induced senescence was assessed by p90RSK specific inhibitor (FMK-MEA) or dominant negative p90RSK (DN-p90RSK), and NRF2 activator (NRF2A). Further, the severity of atherosclerosis was determined in myeloid cell-specific wild type and DN-p90RSK transgenic mice.

RESULTS:

Monocytes from HIV+ patients exhibited higher levels of p90RSK activity and were also more sensitive to ROS than monocytes from HIV- individuals. A multiple linear regression analysis involving cART, Reynolds CV risk score, and basal p90RSK activity revealed that cART and basal p90RSK activity were the two significant determinants of plaque formation. Many of the antiretroviral drugs individually activated p90RSK, which simultaneously triggered all components of the macrophage senescent phenotype. cART inhibited antioxidant response element reporter activity via ERK5 S496 phosphorylation. NRF2A reversed the H2O2-induced over-activation of p90RSK in cART-treated macrophages by countering the induction of senescent phenotype. Lastly, the data obtained from our gain- or loss-of-function mice conclusively showed the crucial role of p90RSK in inducing senescent phenotype in macrophages and atherogenesis.

CONCLUSIONS:

cART increased monocyte/macrophage sensitivity to ROS in HIV+ individuals by suppressing NRF2-ARE activity via p90RSK-mediated ERK5 S496 phosphorylation, which coordinately elicited senescent phenotypes and pro-inflammatory responses. As such, our report underscores the importance of p90RSK regulation in monocytes/macrophages as a viable biomarker and therapeutic target for preventing CVD, especially in HIV+ patients treated with cART.

KEYWORDS:

ERK5; cART; efferocytosis; p90RSK; telomere length

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