Epicardial adipose tissue (EAT) is present in close proximity to the adventitia of the coronary arteries and the underlying myocardium, and functions as both endocrine organ and inflammatory tissue, secreting hormones, cytokines and chemokines. Since atherosclerotic lesions result from inflammation and extracellular matrix formation that are exaggerated by obesity, there is a poor outcome in obese atherosclerotic patients following contrary intervention. We hypothesize that obesity-induced inflammatory phenotype of epicardial fat is exacerbated by vitamin D deficiency leading to endothelial dysfunction and enhanced intimal hyperplasia following coronary intervention.
Aim 1 : Our hypothesis predicts that high fructose and high fat diet will increase thickness and the inflammatory phenotype of EAT accompanied with impairment of coronary vasodilatation and increased reoccurrence of cardiovascular events following coronary artery intervention.
Aim 2 : Our hypothesis predicts that vitamin D deficiency will exacerbate and vitamin D supplementation will decrease thickness and the inflammatory phenotype of EAT and restore coronary vasodilatation and this will correlate with decreased reoccurrence of cardiovascular events following coronary artery intervention.
Aim 3 : Our hypothesis predicts that enhanced inflammatory phenotype of EAT in obese and atherosclerotic swine is due to increased translocation of NF-?B to the nucleus via increased transcription and translation of importin-?3 and decreased prohibitin and SOCS3, and vitamin D suppresses pro-inflammatory responses in EAT. Hypercholesterolemic swine on high fructose diet will undergo balloon angioplasty and stenting. Effect of vitamin D will be examined in vitamin D-deficient, -sufficient and supplemented swine fed with high cholesterol and high fructose diet. Epicardial fat thickness will be measured by cardiac CT. Angiogram and Optical Coherence Tomography will be done to assess cardiac function and quantify in-segment minimal luminal diameter and intimal hyperplasia. Endothelium-dependent and -independent coronary vasodilatation will be measured by intracoronary administration of adenosine and acetylcholine. Biochemical parameters in epicardial fat will include the changes in adipocyte size, M1/M2 macrophage polarity, T-lymphocyte subsets, levels of pro- and anti-inflammatory mediators and cytokines. Histologically, intimal thickness and intimal hyperplasia, lumen area, intima-media ratio, plaque development, and re-occlusion will be examined. The proposed studies will provide conceptual support of our hypothesis and position us to translate our investigation into a clinical study in obese patients with coronary artery disease.
The prevalence and significant rise in obesity is a major health problem. There is a poor outcome in obese patients with atherosclerosis following coronary intervention, such as angioplasty and intravascular stenting. Fat tissue on the anterior surface of the heart become inflamed due to obesity and this could be exacerbated by vitamin D deficiency, which is prevalent in our population. In this project, we proposed to examine the underlying cellular and molecular mechanisms of inflammation and vascular dysfunction in obese and hypercholesterolemic model and to determine if vitamin D supplementation will reduce fat deposits on outside of the heart and on re-narrowing of coronary arteries following angioplasty and stenting. The proposed studies will provide conceptual support of our hypothesis and position us to translate our investigation into a clinical study in patients with coronary artery disease.
|Chen, Songcang; Swier, Vicki J; Boosani, Chandra S et al. (2016) Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine. Arterioscler Thromb Vasc Biol 36:1651-9|
|Agarwal, Shreya; Kovilam, Oormila; Zach, Terence L et al. (2016) Immunopathogenesis and therapeutic approaches in pediatric celiac disease. Expert Rev Clin Immunol 12:857-69|
|Rai, Vikrant; Sharma, Poonam; Agrawal, Swati et al. (2016) Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research. Mol Cell Biochem :|
|Thankam, Finosh G; Dilisio, Matthew F; Dougherty, Kaitlin A et al. (2016) Triggering receptor expressed on myeloid cells and 5'adenosine monophosphate-activated protein kinase in the inflammatory response: a potential therapeutic target. Expert Rev Clin Immunol 12:1239-1249|
|Sur, Swastika; Agrawal, Devendra K (2016) Phosphatases and kinases regulating CDC25 activity in the cell cycle: clinical implications of CDC25 overexpression and potential treatment strategies. Mol Cell Biochem 416:33-46|
|Larson, Spencer P; Kovilam, Oormila; Agrawal, Devendra K (2016) Immunological basis in the pathogenesis of intrahepatic cholestasis of pregnancy. Expert Rev Clin Immunol 12:39-48|
|Swier, Vicki J; Tang, Lin; Radwan, Mohamed M et al. (2016) The role of high cholesterol-high fructose diet on coronary arteriosclerosis. Histol Histopathol 31:167-76|
|Kirkpatrick, Daniel R; McEntire, Dan M; Smith, Tyler A et al. (2016) Transmission pathways and mediators as the basis for clinical pharmacology of pain. Expert Rev Clin Pharmacol :1-25|
|Almalki, Sami G; Agrawal, Devendra K (2016) Effects of matrix metalloproteinases on the fate of mesenchymal stem cells. Stem Cell Res Ther 7:129|
|Hall, Sannette C; Agrawal, Devendra K (2016) Toll-like receptors, triggering receptor expressed on myeloid cells family members and receptor for advanced glycation end-products in allergic airway inflammation. Expert Rev Respir Med 10:171-84|
Showing the most recent 10 out of 41 publications