Atherosclerosis is an Inflammatory Disease: Does it Matter? Atherosclerosis is an Inflammatory Disease: Does it Matter?
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1 12 th Annual Cardiovascular Disease Prevention Symposium February 8, 2013 Atherosclerosis is an Inflammatory Disease: Does it Matter? Ira Tabas, M.D., Ph.D. Richard J. Stock Professor of Medicine, Cell Biology, and Physiology 12 th Annual Cardiovascular Disease Prevention Symposium February 8, 2013 Atherosclerosis is an Inflammatory Disease: Does it Matter? No Conflicts of Interest to Disclose Tabas et al., Circulation, 2007
2 Tabas et al., Circulation, 2007 Tabas et al., Circulation, 2007 Tabas et al., Circulation, 2007
3 Amplified LP retention Plaque necrosis mature DC Tabas et al., Circulation, 2007 Amplified LP retention Plaque necrosis mature DC Tabas et al., Circulation, 2007 Inflammation The Key Biological Response to Lipoprotein Retention
4 Defective Inflammation Resolution The Response That Promotes Plaque Progression PERSISTENT LP amplified LP RETENTION retention LP tissue tissue (s) Plaque necrosis with cholesterol crystals mast cell T cell dendritic mature Mφ cell dying Mφ DC Resolving Inflammation
5 Resolving Inflammation Resolving Inflammation Resolving Inflammation
6 Resolving Inflammation Non-resolving Inflammation Non-resolving Inflammation
7 Non-resolving Inflammation Non-resolving Inflammation Atherosclerosis ApoB LP retention Persistent and amplified apob LP retention
8 Hallmarks of Defective Inflammation Resolution in Atherosclerosis Hallmarks of Defective Inflammation Resolution in Atherosclerosis S Hallmarks of Defective Inflammation Resolution in Atherosclerosis S
9 Hallmarks of Defective Inflammation Resolution in Atherosclerosis S inflammation Hallmarks of Defective Inflammation Resolution in Atherosclerosis S inflammation Hallmarks of Defective Inflammation Resolution in Atherosclerosis S oxidative stress inflammation
10 Hallmarks of Defective Inflammation Resolution in Atherosclerosis S oxidative stress inflammation defective efferocytosis necrosis Hallmarks of Defective Inflammation Resolution in Atherosclerosis S oxidative stress inflammation defective efferocytosis necrosis additional S Therapeutic Opportunities in Atherosclerosis? S oxidative stress inflammation defective efferocytosis necrosis additional S
11 Therapeutic Opportunities in Atherosclerosis? S lower apob lipoproteins or block retention oxidative stress inflammation defective efferocytosis necrosis additional S 25 4S % with CAD event LIPID CARE HPS WOSCOPS HPS AFCAPS LDL-C (mg/dl) 25 4S % with CAD event LIPID CARE HPS WOSCOPS HPS AFCAPS LDL-C (mg/dl) ATVB 2012
12 Therapeutic Opportunities in Atherosclerosis? oxidative stress inflammation defective efferocytosis necrosis additional S dampen inflammation and restore homeostasis S efferocytosis fibrous cap oxidative stress Barriers to Therapeutic Translation in Chronic Inflammatory Diseases Host Defense and the Therapeutic Window Nature's Solution Specialized proresolving mediators (SPMs)
13 Specialized Proresolving Mediators (SPMs): The Push and Pull of Pro-Inflammatory and Pro-Resolving Mediators Pro-inflammatory mediators Leukotrienes Cytokines Chemokines Fight infection Specialized Proresolving Mediators (SPMs): The Push and Pull of Pro-Inflammatory and Pro-Resolving Mediators Endogenous SPMs Annexin A1 IL-10 Lipoxins Resolvins Homeostasis Pro-inflammatory mediators Leukotrienes Cytokines Chemokines Fight infection Specialized Proresolving Mediators (SPMs): The Push and Pull of Pro-Inflammatory and Pro-Resolving Mediators Temper pro-inflammatory signals but are not immunosuppressive Enhance efferocytosis and tissue repair Endogenous SPMs Annexin A1 IL-10 Lipoxins Resolvins Homeostasis Pro-inflammatory mediators Leukotrienes Cytokines Chemokines Fight infection
14 Specialized Proresolving Mediators (SPMs): The Push and Pull of Pro-Inflammatory and Pro-Resolving Mediators Temper pro-inflammatory signals but are not immunosuppressive Enhance efferocytosis and tissue repair Endogenous SPMs Annexin A1 IL-10 Lipoxins Resolvins Homeostasis Pro-inflammatory mediators Leukotrienes Cytokines Chemokines Fight infection Annexin A1 IL-10 Lipoxins Resolvins Inflammatory Disease Leukotrienes Cytokines Chemokines Specialized Proresolving Mediators (SPMs): The Push and Pull of Pro-Inflammatory and Pro-Resolving Mediators Temper pro-inflammatory signals but are not immunosuppressive Enhance efferocytosis and tissue repair Endogenous SPMs Annexin A1 IL-10 Lipoxins Resolvins Homeostasis Pro-inflammatory mediators Leukotrienes Cytokines Chemokines Fight infection? Rx with exogenous SPMs Annexin A1 IL-10 Lipoxins Resolvins Inflammatory Disease Leukotrienes Cytokines Chemokines The Potential of SPM Therapy in Atherosclerosis therapeutic SPMs S efferocytosis fibrous cap oxidative stress oxidative stress inflammation defective efferocytosis necrosis additional S
15 Atherosclerosis is an Inflammatory Disease: Does it Matter? Atherosclerosis is an Inflammatory Disease: Does it Matter? Yes but only if viewed in the context of the balance between inflammation and its resolution and the narrow therapeutic window limited by compromising host defense
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