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Pro-Atherogenic Shear Stress and HIV Proteins Synergistically Upregulate Cathepsin K in Endothelial Cells

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Abstract

Major advances in highly active antiretroviral therapies (HAART) have extended the lives of people living with HIV, but there still remains an increased risk of death by cardiovascular diseases (CVD). HIV proteins have been shown to contribute to cardiovascular dysfunction with effects on the different cell types that comprise the arterial wall. In particular, HIV-1 transactivating factor (Tat) has been shown to bind to endothelial cells inducing a range of responses that contribute to vascular dysfunction. It is well established that hemodynamics also play an important role in endothelial cell mediated atherosclerotic development. When exposed to low or oscillatory shear stress, such as that found at branches and bifurcations, endothelial cells contribute to proteolytic vascular remodeling by upregulating cathepsins, potent elastases and collagenases that contribute to altered biomechanics and plaque formation. Mechanisms to understand the influence of Tat on shear stress mediated vascular remodeling have not been fully elucidated. Using an in vivo HIV-Tg mouse model and an in vitro cone and plate shear stress bioreactor to actuate physiologically relevant pro-atherogenic or atheroprotective shear stress on human aortic endothelial cells, we have shown synergism between HIV proteins and pro-atherogenic shear stress to increase endothelial cell expression of the powerful protease cathepsin K, and may implicate this protease in accelerated CVD in people living with HIV.

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Acknowledgments

This work was completed partially with funding from a Creative and Novel Ideas in HIV Research (CNIHR) grant sponsored by the National Institutes of Health CFAR programme and the International AIDS Society (MOP, RLS, and RLG), NIH Award Number DP2OD007433 from the Office of the Director, National Institutes of Health (MOP), and National Science Foundation Graduate Research Fellowships (IKP and LMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Office of the Director, National Institutes of Health or the National Institutes of Health.

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Authors and Affiliations

  1. George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA

    Ivana Kennedy Parker & Rudolph L. Gleason Jr.

  2. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 315 Ferst Drive, IBB 1308, Atlanta, GA, 30332, USA

    Ladeidra Monet Roberts, Laura Hansen, Rudolph L. Gleason Jr. & Manu O. Platt

  3. Department Medicine, Emory University/Atlanta VAMC, Atlanta, GA, USA

    Roy L. Sutliff

  4. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA

    Ivana Kennedy Parker, Laura Hansen, Rudolph L. Gleason Jr. & Manu O. Platt

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  1. Ivana Kennedy Parker
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  2. Ladeidra Monet Roberts
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Correspondence to Manu O. Platt.

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Associate Editor Scott I. Simon oversaw the review of this article.

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Parker, I.K., Roberts, L.M., Hansen, L. et al. Pro-Atherogenic Shear Stress and HIV Proteins Synergistically Upregulate Cathepsin K in Endothelial Cells. Ann Biomed Eng 42, 1185–1194 (2014). https://doi.org/10.1007/s10439-014-1005-9

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  • DOI: https://doi.org/10.1007/s10439-014-1005-9

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