Vascular Smooth Muscle Lysyl Oxidase Mediated Increase in Vessel Stiffness and its Effect on Rho-Kinase Mechanosensors: A Novel Mechanism of Atherosclerosis in Chronic Kidney Disease?

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Cardiovascular disease is the leading cause of death in Chronic Kidney Disease (CKD). Arterial stiffness is increased in CKD, correlates with mortality, and is thought to be a key mediator of adverse cardiovascular events. However, the molecular mechanisms by which CKD causes increased arterial stiffness and how stiffness accelerates atherosclerosis is uncertain. Our novel preliminary data demonstrates that lysyl oxidase (LOX), an enzyme that crosslinks collagen and elastin, is up-regulated in vascular smooth muscle cells in CKD and could contribute to increased arterial stiffness. The increased stiffness in turn activates the rho-kinase isoform, ROCK1 which has been shown to increase migration and proliferation of vascular smooth muscle cells. These data suggest that atherosclerosis might be a consequence of stiffness and points to a primary, vascular smooth muscle cell dysfunction in CKD. The specific aims of this proposal are to (1) characterize the role of lysyl oxidase in mediating arterial stiffness in CKD, (2) define the role of ROCK1 in the regulation of smooth muscle migration and proliferation in response to stiffness, and (3) evaluate the role of lysyl oxidase and rho kinase in atherosclerosis in a CKD model in vivo. The successful completion of these specific aims will define the potential of targeting vessel stiffness as a potential mechanism to prevent vascular dysfunction of CKD. Vascular smooth muscle cells could be a new target for the prevention of cardiovascular complications in CKD patients and the basis for developing an independent line of research for Dr. Mohandas. Dr. Mohandas has completed a NIH sponsored T32 research fellowship, published 13 first or senior author papers and presented at national and international scientific meetings. He was recruited as a `Tenure Track Assistant Professor' at the University of Florida because of his outstanding track record and potential to be an independent physician scientist. To this end, a comprehensive but focused training program has been designed to enhance Dr. Mohandas' training in vascular physiology and molecular biology. This includes hands-on training in animal models of kidney disease, innovative genome editing tools, pressure arteriography, didactic coursework in cell signaling and vascular physiology, as well as seminars and journal clubs. Dr. Mark Segal, a highly regarded physician and expert in atherosclerosis and molecular biology, will serve as the candidate's mentor. An Advisory Committee has been assembled to aid the candidate in scientific and career development including Dr. Kirk Conrad (vascular physiology), Dr. Peter Sayeski (cell signaling), and Dr. Carl Pepine (experimental and clinical cardiovascular diseases). The outstanding environment of the University of Florida, rich in clinical and basic sciences, together with the scientific plan and comprehensive training program, will ensure the success of Dr. Mohandas as an independent investigator in the field of cardiovascular complications of kidney disease.