Article

Annals of Biomedical Engineering

, Volume 42, Issue 6, pp 1185-1194

First online:

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

  • Ivana Kennedy ParkerAffiliated withGeorge W. Woodruff School of Mechanical Engineering, Georgia Institute of TechnologyPetit Institute for Bioengineering and Bioscience, Georgia Institute of Technology
  • , Ladeidra Monet RobertsAffiliated withWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology
  • , Laura HansenAffiliated withWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of TechnologyPetit Institute for Bioengineering and Bioscience, Georgia Institute of Technology
  • , Rudolph L. GleasonJr.Affiliated withGeorge W. Woodruff School of Mechanical Engineering, Georgia Institute of TechnologyWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of TechnologyPetit Institute for Bioengineering and Bioscience, Georgia Institute of Technology
  • , Roy L. SutliffAffiliated withDepartment Medicine, Emory University/Atlanta VAMC
  • , Manu O. PlattAffiliated withWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of TechnologyPetit Institute for Bioengineering and Bioscience, Georgia Institute of Technology Email author 

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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.

Keywords

Cathepsin HIV Tat Arterial remodeling Shear stress Endothelial cells