Pro-atherogenic shear stress and HIV proteins synergistically upregulate cathepsin K in endothelial cells.
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.
George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
Ivana Kennedy
IK
Parker
Ladeidra Monet
LM
Roberts
Laura
L
Hansen
Rudolph L
RL
Gleason
Roy L
RL
Sutliff
Manu O
MO
Platt
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D056657:Cathepsin K / Q000096:biosynthesis* / Q000097:blood* / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008822:Mice, Transgenic; D013312:Stress, Physiological; D015854:Up-Regulation / Q000235:genetics; D066253:Vascular Remodeling / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D054322:tat Gene Products, Human Immunodeficiency Virus; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse