- Internal Medicine
Clinical Scholar, Surgery - Vascular Surgery
Board Certification: American Board of Internal Medicine, Internal Medicine (2021)
Residency: Scripps Clinic Internal Medicine Residency Program (2020) CA
Medical Education: University of Oklahoma College of Medicine (2016) OK
Dynamic changes in chromatin accessibility are associated with the atherogenic transitioning of vascular smooth muscle cells.
AIMS: De-differentiation and activation of pro-inflammatory pathways are key transitions vascular smooth muscle cells (SMCs) make during atherogenesis. Here, we explored the upstream regulators of this 'atherogenic transition'.METHODS AND RESULTS: Genome-wide sequencing studies, including ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) and RNA-seq, were performed on cells isolated from both murine SMC-lineage tracing models of atherosclerosis and human atherosclerotic lesions. At the bulk level, alterations in chromatin accessibility were associated with the atherogenic transitioning of lesional SMCs, especially in relation to genes that govern differentiation status and complement-dependent inflammation. Using computational biology, we observed that a transcription factor previously related to coronary artery disease, ATF3 (Activating transcription factor 3), was predicted to be an upstream regulator of genes altered during the transition. At the single-cell level, our results indicated that ATF3 is a key repressor of SMC transitioning towards the subset of cells that promote vascular inflammation by activating the complement cascade. The expression of ATF3 and complement component C3 were negatively correlated in SMCs from human atherosclerotic lesions, suggesting translational relevance. Phenome-wide association studies indicated that genetic variation that results in reduced expression of ATF3 is correlated with an increased risk for atherosclerosis, and the expression of ATF3 was significantly downregulated in humans with advanced vascular disease.CONCLUSION: Our study indicates that the plasticity of atherosclerotic SMCs may in part be explained by dynamic changes in their chromatin architecture, which in turn may contribute to their maladaptive response to inflammation-induced stress.TRANSLATIONAL PERSPECTIVE: The recent CANTOS and COLCOT trials have shown that targeting inflammatory pathways lowers the risk of major adverse cardiovascular events. However, more specific targets are needed to avoid immunosuppressive side effects. Our data identify an upstream regulator of pro-inflammatory SMCs, ATF3, which is involved in the initial atherogenic transitioning of lesional SMCs. Restoring ATF3 activity may prevent the de-differentiation of SMCs and offer a novel translational approach for the suppression of complement-dependent inflammation in atherosclerotic lesions.
View details for DOI 10.1093/cvr/cvab347
View details for PubMedID 34849613
Varicose Veins and Chronic Venous Disease.
2021; 39 (4): 567-581
Chronic venous disease is a worldwide problem associated with significant morbidity and is expected to increase in prevalence as the current population ages. This is a comprehensive review of the anatomy, pathophysiology, genomics, clinical classification, and treatment modalities of chronic venous disease.
View details for DOI 10.1016/j.ccl.2021.06.009
View details for PubMedID 34686268
Bench-to-Bedside in Vascular Medicine: Optimizing the Translational Pipeline for Patients With Peripheral Artery Disease.
2021; 128 (12): 1927-1943
Peripheral arterial disease is a growing worldwide problem with a wide spectrum of clinical severity and is projected to consume >$21 billion per year in the United States alone. While vascular researchers have brought several therapies to the clinic in recent years, few of these approaches have leveraged advances in high-throughput discovery screens, novel translational models, or innovative trial designs. In the following review, we discuss recent advances in unbiased genomics and broader omics technology platforms, along with preclinical vascular models designed to enhance our understanding of disease pathobiology and prioritize targets for additional investigation. Furthermore, we summarize novel approaches to clinical studies in subjects with claudication and ischemic ulceration, with an emphasis on streamlining and accelerating bench-to-bedside translation. By providing a framework designed to enhance each aspect of future clinical development programs, we hope to enrich the pipeline of therapies that may prevent loss of life and limb for those with peripheral arterial disease.
View details for DOI 10.1161/CIRCRESAHA.121.318265
View details for PubMedID 34110900