Deciphering the Role of HMGB1 in Diabetic Atherothrombosis, Platelet-VSMC Synergy in Disease Development

Presenter: Dr. Roberto Mota

Dr. Mota-Alvidrez’s research focuses on diabetic vasculopathies, particularly atherothrombosis studying the genetic and pathologic bases of atherosclerosis. Type-2 Diabetic (T2D) patients is a demographic that has high incidence of associated comorbidities such as obesity, dyslipidemia and atherosclerosis. These confounding factors increase risk of T2D patients to develop CAD and atherothrombosis which are fatal. Diabetic patients have direct association with CAD particularly in wide genome association studies in specific target mutations like HNF1A, CTRB1/2, APOE and HMGB1. The later, HMGB1, is a nuclear protein that regulates transcription in the nucleus and has major implications in chronic disease. Acetyl-HMGB1 is the extracellularly released form of HMGB1 with cytokine and chemokine activity that promotes inflammation. The receptor for advanced glycolysis end products (RAGE) is the preferred receptor for acetyl-HMGB1. RAGE becomes activated with an increase in receptor uptake after platelet activation, therefore we believe that inhibiting RAGE decreases platelet activation and signaling via the HMGB1 downstream pathway that will affect vascular smooth muscle cells (VSMC) in atherothrombosis development. Contrasting, RAGE transgenic mice have been shown to exacerbate vascular kidney disease and promote an inflammatory milieu in the systemic vasculature. Atherosclerosis is extensively evaluated, however the process of atherothrombosis which is often the final fatal disposition in T2D patients is not well understood.

Background Reading:

• Mota R., Buglak N., Maiochi S., Bahnson E. Targeting the Apoe Gene With Crispr/Cas9 In Zucker Rats: A New Rat Model of Atherosclerosis. Under review at Cardiovascular Research Journal from UNC Chapel Hill Department of Surgery.
• William E. Plautz, Shannon H. Haldeman, Mitchell R. Dyer, Jason L. Sperry, Francis X. Guyette, Patricia A. Loughran, Jurgis Alvikas, Adnan Hassoune, Lara Hoteit, Nijmeh Alsaadi, Brian S. Zuckerbraun, Marian A. Rollins-Raval, Jay S. Raval, Roberto I. Mota and Matthew D. Neal. Reduced Cleavage of von Willebrand Factor by ADAMTS13 Promotes Microangiopathic Acute Kidney Injury Following Trauma. Recently accepted
• Roberto I. Mota et al. “Chemokine Signaling Regulates Fibroblast Production of Extracellular Matrix Components through Modulation of TGF-b Signaling”. Currently under review at AJP, July 2021
• Lara Hoteit, Andrew-Paul Deeb, Elizabeth A. Andraska, Christof Kaltenmeier, Hamza O. Yazdani, Samer Tohme, Matthew D. Neal, Roberto I. Mota. “The Pathobiological basis for Thrombotic Complications in COVID-19: A Review of the Literature”. Currently under review at Current Pathobiology Reports