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Atherosclerotic Risk of Branched Chain Amino Acids in a Tissue Engineered Blood Vessel Model

组织工程血管模型中支链氨基酸的动脉粥样硬化风险

基本信息

批准号：
10753482
负责人：
Ellery Jensen Jones
金额：
$ 0.89万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10753482
关键词：
Acceleration Address Adhesions Affect Amino Acids Arterial Fatty Streak Atherosclerosis Autophagocytosis Autophagosome Biological Biological Assay Biological Models Blood Blood Vessels Branched-Chain Amino Acids Cardiovascular Diseases Cardiovascular system Cause of Death Cells Chondroitin Sulfates Clinical Collaborations Collagen Dermal Development Diabetes Mellitus Disease Disease Progression Disease model Encapsulated Endothelium Environment Event Extracellular Matrix Fibroblasts Foam Cells Functional disorder Glucose Goals Health Heart Diseases Heart failure Human Hydrogels Impairment Incidence Inflammation Inflammatory Insulin Resistance Isoleucine Lesion Leucine Leukocytes Link Lipids Lipoprotein Binding Low-Density Lipoproteins Medial Mediating Metabolic Metabolic Diseases Metabolic syndrome Minority Groups Mitochondria Modeling Molecular Myocardial Infarction Onset of illness Orthopedics Outcome Study Oxidative Stress Pathologic Pathology Patients Perfusion Phenotype Physiological Physiology Prevalence Proteins Proteoglycan Reactive Oxygen Species Recovery Research Risk Role Serum Stress Stroke System Testing Tissue Engineering United States Valine Vasodilation Western Blotting Woman amino acid metabolism atherogenesis atherosclerosis risk cardiovascular risk factor cell growth chondroitin sulfate glycosaminoglycan cytokine disability disease phenotype endothelial dysfunction fabrication human tissue in vitro Model interest low and middle-income countries member metabolomics monocyte mouse model negative affect neonatal human novel novel therapeutics oxidized low density lipoprotein polysulfated glycosaminoglycan prevent therapeutic target vascular inflammation

项目摘要

Elevated levels of the branched chain amino acids (BCAA) leucine, isoleucine, and valine are highly correlated with the development of CVD and adverse cardiovascular events, such as heart attacks. Some mechanisms linking BCAA, metabolic disease and heart failure have been documented. However, it remains unclear if BCAAs directly interact with vascular cells to enable CVD onset and progression. Mouse models that have been developed to study CVD and BCAA both have limitations in their applicability to human physiology. Current in vitro models of atherosclerosis are limited to early stages of atherogenesis, and it is challenging to recapitulate more advanced atherosclerotic changes. To address this issue, we will develop a model of an intermediate atherosclerotic lesion using a human tissue engineered blood vessel system (TEBV) model with a disease-pathology collagen extracellular matrix enriched with the glycosaminoglycan chondroitin sulfate (CS), treated with modified low-density lipoprotein (LDL). We will use collagen TEBVs treated with modified LDL as a model for early atherosclerosis. These platforms will be used as a platform to study BCAA mechanism in CVD. The TEBV model is made of collagen or CS-collagen vessels with encapsulated human neonatal dermal fibroblasts serving as the medial cells in the vascular wall and an endothelialized inner lumen of endothelial colony-forming cells (ECFCs). It is perfused with medium at a rate of 2 mL/minute and can be cultured for up to 6 weeks. We have demonstrated that the CS-enriched vessels have an enhanced sensitivity to the inflammatory effects of modified LDL and demonstrate increased vessel vasoactive dysfunction and endothelial-leukocyte interactions compared to collagen TEBVs. We have also demonstrated that elevations of the BCAA within the physiological milieu are sufficient to induce an atherosclerotic phenotype in the endothelium. Preliminary results demonstrate that treatment of ECFCs with elevated BCAA and oxidized low- density lipoprotein causes increased mitochondrial oxidative stress, as well as decreased expression of LC3B, an autophagosome protein. This induced early atherosclerotic events in the TEBV system: impaired endothelium-controlled vasodilation and leukocyte adhesion to the endothelium. Autophagic flux will be further assayed via Western Blot for LC3-I to LC3-II conversion. Vascular cells, especially the endothelium, may be sensitive to the effects of elevated BCAA because they do not significantly contribute to BCAA metabolism, leading to intracellular buildup of metabolites and mitochondrial stress. This will be tested via metabolomic analysis of BCAA and their downstream metabolites in the vascular cells. Using the TEBVs, we will determine the role of BCAA in early versus intermediate atherosclerosis. At the end of the study, we will have an intermediate lesion model of atherosclerosis, the mechanisms linking BCAA to cardiovascular events will become clearer, and potential therapeutic targets for atherosclerosis will be identified.

支链氨基酸（BCAA）亮氨酸、异亮氨酸和缬氨酸水平升高是高度相关的