Although Rho kinase (ROCK) is most well known for its role in regulating cytoskeletal proteins, several other functions of ROCK have been identified in recent years. One of these functions is in immune response and inflammation. Because of its unique ability to regulate such vital cellular functions as actin- myosin cytoskeleton, it is likely that ROCK will influence various leukocyte functions. Indeed, we have shown recently that inhibition of ROCK affects certain macrophage function. For example, our data suggest that migration as well as matrix invasion of macrophages are mediated by ROCK. Because of its ability to affect macrophage functions that are intimately involved in the atherogenic process, it is likely that ROCK plays an important role in immune-mediated atherosclerosis.
In aim 1, we will test the hypothesis that ROCK influences macrophage trafficking by using macrophages from mice with ROCK deficiency only in the macrophage. We will use both in vitro and in vivo approaches to demonstrate the effect of ROCK deficiency on the adhesive, migratory and matrix invasive properties of macrophages. We will also identify the signaling mechanisms that regulate ROCK-mediated macrophage chemotaxis. In addition we will characterize ROCK's role in extracellular matrix remodeling using both in vitro and in vivo approaches.
In aim 2, we will investigate the role of ROCK in two properties of macrophages that are essential to atherogenesis. By culturing macrophages derived from bone marrow of the above mice, we will examine the ability of the macrophages to phagocytose lipid and become foam cells in the presence or absence of ROCK. We will also examine the role of ROCK in lipid efflux from lipid-loaded cells. Mechanistic studies will attempt to identify the ROCK-mediated molecules that affect lipid loading. The other property of macrophages that will be studied is the role of ROCK in modulating the ability of these cells to become activated. Furthermore, the ability of the activated macrophages to perform their proinflammatory function will be assessed.
In aim 3, mice lacking ROCK specifically in macrophages will be crossed with the atherosclerosis-prone LDLR-/- mice. The extent of atherosclerosis and the morphology of atherosclerotic lesions in these mice will be compared to lesions in mice that have no deficiency of ROCK. Examination of lesions in these mice will reveal the role of macrophage-specific ROCK in atherosclerosis. Successful completion of these studies will likely implicate ROCK in several atherogenic processes and may lead to development of therapies aimed at inhibiting ROCK in macrophages to combat atherosclerosis.
|Hernández-Reséndiz, Sauri; Muñoz-Vega, Mónica; Contreras, Whendy E et al. (2018) Responses of Endothelial Cells Towards Ischemic Conditioning Following Acute Myocardial Infarction. Cond Med 1:247-258|
|Samangouei, Parisa; Crespo-Avilan, Gustavo E; Cabrera-Fuentes, Hector et al. (2018) MiD49 and MiD51: New mediators of mitochondrial fission and novel targets for cardioprotection. Cond Med 1:239-246|
|Chong, Jun; Bulluck, Heerajnarain; Yap, En Ping et al. (2018) Remote ischemic conditioning in ST-segment elevation myocardial infarction - an update. Cond Med 1:13-22|
|McCurdy, Sara; Liu, Chloe A; Yap, Jonathan et al. (2017) Potential role of IL-37 in atherosclerosis. Cytokine :|
|Kalkhoran, Siavash Beikoghli; Munro, Peter; Qiao, Fan et al. (2017) Unique morphological characteristics of mitochondrial subtypes in the heart: the effect of ischemia and ischemic preconditioning. Discoveries (Craiova) 5:|
|Baumer, Yvonne; McCurdy, Sara; Alcala, Martin et al. (2017) CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis. Atherosclerosis 256:105-114|
|Baumer, Yvonne; McCurdy, Sara; Weatherby, Tina M et al. (2017) Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis. Nat Commun 8:1129|
|Cabrera-Fuentes, Hector A; Aragones, Julian; Bernhagen, Jürgen et al. (2016) From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on ""New frontiers in cardiovascular research"". Basic Res Cardiol 111:69|
|Cabrera-Fuentes, Hector A; Alba-Alba, Corina; Aragones, Julian et al. (2016) Meeting report from the 2nd International Symposium on New Frontiers in Cardiovascular Research. Protecting the cardiovascular system from ischemia: between bench and bedside. Basic Res Cardiol 111:7|
|Mause, Sebastian F; Deck, Annika; Hennies, Mark et al. (2016) Validation of commercially available ELISAs for the detection of circulating sclerostin in hemodialysis patients. Discoveries (Craiova) 4:e55|
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