Atherosclerosis and associated cardiovascular disease (CVD) are the leading cause of morbidity and mortality in the US. Atherosclerosis is characterized by the accumulation of lipids in the artery wall, and is an inflammatory disease in which several immune effectors including macrophages play a central role. Obesity, insulin resistance, diabetes, and dyslipidemia are all major risk factors for CVD, but the mechanisms that link disordered metabolism to inflammation and the development of atherosclerosis remain to be elucidated. Our published work and preliminary data demonstrate that the double stranded RNA activated protein kinase, PKR, is activated in the context of obesity, where it plays a critica role in driving inflammation and the deterioration of glucose homeostasis. In macrophages, exposure to lipotoxic signals and lipoproteins activate PKR. In addition, PKR is a critical component for the activation of the NLRP3 inflammasome, and stress signaling pathways such as JNK, which are implicated in the pathogenesis of both diabetes and atherosclerosis. In addition, in supporting data presented in this proposal we demonstrate a significant protection against atherosclerotic plaque development in PKR-deficient mice. Based on these findings our overarching hypothesis is that by modulating inflammatory activity, insulin action, and protein synthesis, PKR links cellular stress and metabolic signals to chronic inflammation and atherosclerosis. The experiments described in this proposal will test that hypothesis by determining the role of PKR in the activation and function of macrophages, and by assessing the whole body and macrophage-specific requirement for PKR in the development of atherosclerosis in vivo. This contribution will expand our understanding of the link between nutrient stress and the development of cardiometabolic disease. The innovation of this work lies in investigating a novel approach to atherosclerosis therapy by identifying the mechanistic link between dyslipidemia and inflammatory activation of immune cells.

Public Health Relevance

The work proposed in these aims will determine the role for PKR in the development of atherosclerosis, specifically investigating the importance of PKR function in driving macrophage function in response to lipotoxicity. This work will provide novel insight into the molecular mechanisms that underlie the connection between metabolism, inflammation, and cardiometabolic disease, and thus may suggest new therapeutic strategies or targets. Cardiovascular disease is a leading cause of death and poses a major threat to human health. Hence, the development of novel, mechanism-based therapeutic approaches against atherosclerosis is highly relevant to public health and to the NIH mission.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125753-03
Application #
9171375
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Chen, Jue
Project Start
2014-11-15
Project End
2018-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Liu, Lunhua; Inouye, Karen Etsuko; Allman, Windy Rose et al. (2018) TACI-Deficient Macrophages Protect Mice Against Metaflammation and Obesity-Induced Dysregulation of Glucose Homeostasis. Diabetes 67:1589-1603
Hotamisligil, Gökhan S (2017) Inflammation, metaflammation and immunometabolic disorders. Nature 542:177-185
Hotamisligil, Gökhan S (2017) Foundations of Immunometabolism and Implications for Metabolic Health and Disease. Immunity 47:406-420
Yang, Ling; Licastro, Danilo; Cava, Edda et al. (2016) Long-Term Calorie Restriction Enhances Cellular Quality-Control Processes in Human Skeletal Muscle. Cell Rep 14:422-428
Ertunc, Meric Erikci; Hotamisligil, Gökhan S (2016) Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment. J Lipid Res 57:2099-2114
Yilmaz, Mustafa; Claiborn, Kathryn C; Hotamisligil, Gökhan S (2016) De Novo Lipogenesis Products and Endogenous Lipokines. Diabetes 65:1800-7
Arruda, Ana Paula; Hotamisligil, Gökhan S (2015) Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes. Cell Metab 22:381-97
Nakamura, Takahisa; Kunz, Ryan C; Zhang, Cai et al. (2015) A critical role for PKR complexes with TRBP in Immunometabolic regulation and eIF2? phosphorylation in obesity. Cell Rep 11:295-307
Youssef, Osama A; Safran, Sarah A; Nakamura, Takahisa et al. (2015) Potential role for snoRNAs in PKR activation during metabolic stress. Proc Natl Acad Sci U S A 112:5023-8
Yang, Ling; Calay, Ediz S; Fan, Jason et al. (2015) METABOLISM. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 349:500-6