1. Pro-atherogenic shear stress and HIV proteins synergistically upregulate cathepsin K in endothelial cells.
- Author
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Parker IK, Roberts LM, Hansen L, Gleason RL Jr, Sutliff RL, and Platt MO
- Subjects
- Animals, Aorta metabolism, Aorta pathology, Atherosclerosis genetics, Cathepsin K genetics, Cells, Cultured, Endothelial Cells pathology, Gene Expression Regulation, Enzymologic genetics, HIV-1 genetics, Humans, Mice, Transgenic, Up-Regulation genetics, Vascular Remodeling genetics, tat Gene Products, Human Immunodeficiency Virus genetics, Atherosclerosis metabolism, Cathepsin K biosynthesis, Cathepsin K blood, Endothelial Cells metabolism, HIV-1 metabolism, Stress, Physiological, tat Gene Products, Human Immunodeficiency Virus metabolism
- 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.
- Published
- 2014
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