Despite advances in surgical intervention and cholesterol-lowering drugs over the last few decades, atherosclerotic cardiovascular disease remains the leading cause of death worldwide. Atherosclerosis forms when modified low-density lipoproteins (LDL) accumulate in the subendothelial matrix of medium-sized arteries in areas of branch points, curvatures, and bifurcations, which generate a sustained inflammatory response in endothelial cells and drive leukocyte recruitment. Many of these infiltrating leukocytes become apoptotic, and while these dead cells are efficiently cleared by macrophages (termed “efferocytosis”) early in lesion formation, efferocytosis begins to fail as atherosclerosis progresses, resulting in an overabundance of post-apoptotic dead cells in an area of the atheroma called the necrotic core. In humans, plaques with large necrotic cores and thin fibrous caps are vulnerable to rupture, leading to myocardial infarction and stroke. Therefore, revealing the mechanisms by which efferocytosis fails as atherosclerosis progresses and how efferocytosis is restored during atherosclerosis regression are important objectives in the Yurdagul lab. With these goals in mind, we hope to identify new therapeutic approaches to curb atherosclerotic cardiovascular disease.

Nutrient Sensing of Apoptotic Cell-Derived Cargo by Macrophages

After an internalized apoptotic cell has been broken down to its basic cellular components within the phagolysosome, macrophages must either efflux these apoptotic cell-derived molecules to rid themselves from an overabundance of noxious materials or metabolize them into downstream products that are less toxic. Interestingly, some of these metabolites are instead beneficial to the macrophage and instruct a coordinated response to drive phagocytosis of more dead cells, termed “continual efferocytosis”. However, many questions remain surrounding the links between the metabolism of degraded apoptotic cells and continual efferocytosis, such as: (1) how does a macrophage sense the nutrients contained within the phagolysosome, (2) what metabolic pathways must be cued to properly handle apoptotic cell-derived cargo safely, and (3) how does nutrient-sensing of apoptotic cells and continual efferocytosis drive the resolution of inflammation and atherosclerosis regression. Our current research seeks to elucidate the cellular and molecular mechanisms underlying these functions and leverage these pathways to enhance inflammation resolution when it fails.

ODC-Dependent Putrescine Synthesis Regulates Smooth Muscle Cell Phenotype

Phenotypic modulation of vascular smooth muscle cells (SMCs), including changes in proliferation and migration, directly contribute to the progression of atherosclerosis, hypertension, and restenosis. Upon activation, vascular SMCs shift from a quiescent phenotype, characterized by a low rate of proliferation and exclusive expression of SMC-specific genes, towards a synthetic state, characterized by high rates of proliferation, a loss in expression of SMC-specific genes, and a heightened state of inflammation. Although this fibroproliferative remodeling expands plaque size, SMC-rich fibrous caps overlying large necrotic cores provide mechanical stability and lower the risk of rupture and sudden cardiac death. While the mechanisms that regulate smooth muscle cell phenotype during atherosclerosis progression are being defined, the role of SMC phenotypic modulation during regression remains largely unexplored. Our data indicate an essential role for polyamine metabolism in regulating fibrous cap formation, as we have shown that putrescine levels rise substantially during atherosclerosis regression and ODC-dependent putrescine synthesis governs SMC phenotype. Our current research aims to define the cellular and molecular mechanisms by which ODC-dependent putrescine synthesis regulates the stability of atherosclerotic plaques and identify theranostic platforms to deliver putrescine specifically to lesions in a manner that stabilizes rupture-prone plaques.

Selected Publications

1. Seeley EH, Liu Z, Yuan S, Stroope C, Cockerham E, Rashdan NA, Delgadillo LF, Finney AC, Kumar D, Das S, Razani B, Liu W, Traylor J, Orr AW, Rom O*, Pattillo CB*, Yurdagul A Jr*. Spatially Resolved Metabolites in Stable and Unstable Human Atherosclerotic Plaques Identified by Mass Spectrometry Imaging (2023). Arterioscler. Thromb. Vasc. Biol. PMID: 37381983. *Selected for Commentary by ATVB.
2. Kumar D, Pandit R, Yurdagul A Jr. Mechanisms of Continual Efferocytosis by Macrophages and its Role in Mitigating Atherosclerosis (2023). Immunometabolism. PMID: 36710920.
3. Yurdagul A Jr. Crosstalk Between Macrophages and Vascular Smooth Muscle Cells in Atherosclerotic Plaque Stability (2022). Arterioscler. Thromb. Vasc. Biol. PMID: 35172605.
4. Yurdagul A Jr. Metabolic Consequences of Efferocytosis and its Impact on Atherosclerosis (2021). Immunometabolism. PMID: 33927896.
5. Yurdagul A Jr*, Kong N, Gerlach BD, Wang X, Ampomah P, Kuriakose G, Tao W, Shi J, Tabas I (2021). ODC-Dependent Putrescine Synthesis Maintains MerTK Expression to Drive Resolution. Arterioscler. Thromb. Vasc. Biol.  PMID: 33406854. *Co-Corresponding Author. **Selected as the cover of the journal issue.
6. Tao Wei*, Yurdagul A Jr*, Kong N, Li W, Wang X, Doran AC, Feng C, Wang J, Islam MA, Farokhzad OC, Tabas I, Shi J. siRNA Nanoparticles Targeting CaMKIIγ in Lesional Macrophages Improve Atherosclerotic Plaque Stability in Mice (2020). Science Translational Medicine. PMID: 32718990. *Co-first Author. ** Selected as the cover of the journal issue. Commentary: Research Highlight-Nanoparticles to Target Lesional Macrophages in Atherosclerotic Mice. Nature Reviews Cardiology (2020). Preview-Macrophage Targeted Gene Therapy to Improve Atherosclerotic Plaque Stability. Matter.
7. Yurdagul A Jr*, Subramanian M, Wang X, Crown SB, Ilkayeva O, Darville L, Kolluru G, Rymond CC, Gerlach BD, Zheng Z, Kuriakose G, Kevil CG, Koomen JM, Cleveland JL, Muoio DM, Tabas I. Macrophage Metabolism of Apoptotic Cell-Derived Arginine Promotes Continual Efferocytosis and Resolution of Injury (2020). Cell Metabolism. PMID: 32004476. *Co-Corresponding Author. *Selected by Faculty Opinions. Commentaries: Editors’ Choice. Boosting Arginine Metabolism to Regress Atherosclerosis? Science Translational Medicine. Preview. Appetite for Arginine: Metabolic Control of Macrophage Hunger. Cell Metabolism.
8. Doran AC, Yurdagul A Jr, Tabas I. Efferocytosis in Health and Disease (2019). Nature Reviews Immunology. PMID: 31822793.
9. Back M, Yurdagul A Jr, Tabas I, Oorni K, Kovanen PT. Inflammation and its Resolution in Atherosclerosis: Mediators and Therapeutic Opportunities (2019). Nature Reviews Cardiology. PMID: 30846875. *Selected by Faculty of 1000.
10. Wang Y.*, Subramanian M.*, Yurdagul A Jr*, Barbosa-Lorenzi VC, Cai B, de Juan-Sanz J, Ryan TA, Nomura M, Maxfield FR., Tabas IA. Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages (2017). Cell. *Co-first author. *Selected by Faculty of 1000

Complete List of my Published Work in MyBibliography: LEARN MORE
 

September 2023 - Drs. Rom and Yurdagul received the Chancellor's Pathways Research Award to pursue the role of dysregulated putrescine metabolism in metabolic dysfunction-associated steatohepatitis (MASH).

June 2023 - Congratulations to Dr. Dhananjay Kumar for obtaining the CCDS Malcolm Feist Postdoctoral Fellowship Award.

June 2023 - Our manuscript titled "Spatially Resolved Metabolites in Stable and Unstable Human Atherosclerotic Plaques Identified by Mass Spectrometry Imaging" was published in ATVB and was selected for a Commentary.

March 2023 - The Yurdagul Laboratory was awarded an NIH R01 Award to study dysregulations in polyamine metabolism during atherosclerosis.

February 2023 - Dr. Yurdagul was selected as a finalist for the 2023 Irvine H. Page Junior Faculty Research Award by the ATVB Council of the American Heart Association.

June 2022 - The Yurdagul Laboratory and Ari Cohen at Ochsner Health System, in collaboration with the Rom laboratory at LSU Health Shreveport, have received the Collaborative Intramural Research Program (CIRP) Award to investigate the role of dysregulated polyamine homeostasis in NASH progression.

April 2022 - Dr. Yurdagul received the Institution's Research Rising Star Award at the Annual Research Celebration.

Post-doctoral Fellows

A Postdoctoral Fellowship position is immediately available in the laboratory of Dr. Arif Yurdagul Jr. studying the role of polyamine metabolism in smooth muscle cell function and identifying the mechanisms of nutrient sensing by macrophages during the clearance of dead cells, particularly in the context of atherosclerosis progression and regression. The Yurdagul lab, located in the Department of Molecular and Cellular Physiology at LSU Health Shreveport, has a long-standing interest in the mechanisms linking signaling pathways and cell metabolism during atherosclerosis progression and regression. In association with the LSU Center for Cardiovascular Diseases and Sciences (CCDS), the fellows will be exposed to extensive training and networking opportunities in vascular biology, immunology, metabolism, career development workshops through the local Post-Doctoral Association, and opportunities for intramural fellowships through the CCDS. Postdoctoral Fellows interested in conducting research in the Yurdagul lab should review the current laboratory research directions and contact Dr. Yurdagul at arif.yurdagul@lsuhs.edu.

Graduate Students

Graduate students interested in conducting research in the Yurdagul lab should review the current laboratory research directions and contact Dr. Yurdagul at arif.yurdagul@lsuhs.edu.

Undergraduate Research Assistants

The Yurdagul laboratory has a number of research projects available for undergraduate students who are interested in gaining research experience and learning new techniques. Most positions are available in the summer. Those who are interested should contact Dr. Yurdagul directly at arif.yurdagul@lsuhs.edu.

Medical Students, Residents, and Fellows

The Yurdagul laboratory has a number of research projects available for any Medical Students, Residents, and Fellows. Those who are interested should contact Dr. Yurdagul directly at arif.yurdagul@lsuhs.edu.