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Hwa Lab Research

The degree of mitochondrial dysfunction, resulting from hyperglycemia, is key to development of platelet hyperactivity or apoptosis.

Dr. Hwa’s overall interests have been on translational studies (from bench to bedside) in the broad area of cardiovascular disease. Over his career, he has studied how mutations affect the functions of G-protein coupled receptors (GPCRs), how these receptors influence platelet function, and how hyperglycemia causes platelet dysfunction in diabetes mellitus (DM), exacerbating cardiovascular disease. Dr Hwa received his Medical Degree with first class honors from the University of Sydney in Australia. He completed residency in Internal Medicine and a Fellowship in Cardiology at the Royal Prince Alfred Hospital in Sydney. He then pursued graduate studies (Department of Molecular Cardiology at the Cleveland Clinic and the Department of Physiology and Biophysics at Case Western Reserve University) where he developed his interests in the structure and function of G-protein coupled receptors (GPCRs) under the mentorship of Robert M. Graham MD and Dianne Perez PhD. Dr Hwa was then awarded a Howard Hughes Physician Postdoctoral Fellowship to further study structure and function of GPCRs at MIT in the laboratory of Nobel Laureate, H. Gobind Khorana. At MIT, using a mass spectrometry approach, Dr. Hwa discovered how naturally occurring mutations in rhodopsin mutations lead to Retinitis Pigmentosa by locking the receptor in a misfolded conformation through abnormal disulfide bond formation1.

As a junior faculty member at Dartmouth Medical School, Dr. Hwa further demonstrated naturally occurring mutations in the prostacyclin receptor (a GPCR found on smooth muscle and platelets) were associated with increased cardiovascular events and increased atherosclerosis burden2. These studies helped highlight the cardioprotective effect of prostacyclin as well as the consequences of prostacyclin inhibition in the cardiovascular pathophysiology of NSAIDs. Dr. Hwa was then recruited to the Section of Cardiovascular Medicine at Yale in 2009 where his lab pursued studies on platelet signaling in diabetes mellitus. In 2011, his laboratory discovered a novel pathway in platelets through which hyperglycemia promotes platelet hyperactivity in diabetics. This pathway linked hyperglycemia-induced aldose reductase activity and ROS production, to release of thromboxane and platelet hyperactivity3. This was followed in 2014 by a study demonstrating that diabetic hyperglycemia could also induce platelet apoptosis and enhanced thrombosis through mitochondrial dysfunction and rupture via a p53/Bclxl mediated pathway4. In 2015, members of Dr. Hwa’s laboratory demonstrated that the hyperglycemia and aldose reductase pathway reduced miR-24 production in endothelial cells leading to dysregulation of VWF production and secretion and thrombosis5. In addition to providing new insights into the molecular mechanisms underlying the enhanced thrombotic cardiovascular events in diabetes mellitus, the Hwa lab studies have provided novel targets for therapies to treat and prevent thrombosis in diabetic patients.

The Hwa laboratory has also been involved with many exciting collaborative efforts in assessing the contributions of GPCRs 6-8, platelets 9, 10, and genetic mutations 9, 11, to disease. This has been facilitated by a large blood and tissue repository from cardiovascular and diabetic patients that Dr. Hwa started at Dartmouth, and has continued at Yale. These collaborative studies have provided novel insights into the important unrecognized roles played by GPCRs and platelets in systemic disease pathophysiology.

References

  1. Hwa J, Klein-Seetharaman J and Khorana HG. Structure and function in rhodopsin: Mass spectrometric identification of the abnormal intradiscal disulfide bond in misfolded retinitis pigmentosa mutants. Proc Natl Acad Sci U S A. 2001;98:4872-6.
  2. Arehart E, Stitham J, Asselbergs FW, Douville K, MacKenzie T, Fetalvero KM, Gleim S, Kasza Z, Rao Y, Martel L, Segel S, Robb J, Kaplan A, Simons M, Powell RJ, Moore JH, Rimm EB, Martin KA and Hwa J. Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation: potential implications for cyclooxygenase-2 inhibition. Circ Res. 2008;102:986-93.
  3. Tang WH, Stitham J, Gleim S, Di Febbo C, Porreca E, Fava C, Tacconelli S, Capone M, Evangelista V, Levantesi G, Wen L, Martin K, Minuz P, Rade J, Patrignani P and Hwa J. Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane. J Clin Invest. 2011;121:4462-76.
  4. Tang WH, Stitham J, Jin Y, Liu R, Lee SH, Du J, Atteya G, Gleim S, Spollett G, Martin K and Hwa J. Aldose Reductase-Mediated Phosphorylation of p53 Leads to Mitochondrial Dysfunction, and Damage in Diabetic Platelets. Circulation. 2014.
  5. Xiang Y, Cheng J, Wang D, Hu X, Xie Y, Stitham J, Atteya G, Du J, Tang WH, Lee SH, Leslie K, Spollett G, Liu Z, Herzog E, Herzog RI, Lu J, Martin KA and Hwa J. Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood. 2015;125:3377-87.
  6. Ogden SK, Fei DL, Schilling NS, Ahmed YF, Hwa J and Robbins DJ. G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling. Nature. 2008;456:967-70.
  7. Kang Y, Kim J, Anderson JP, Wu J, Gleim SR, Kundu RK, McLean DL, Kim JD, Park H, Jin SW, Hwa J, Quertermous T and Chun HJ. Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development. Circ Res. 2013;113:22-31.
  8. Fetalvero KM, Zhang P, Shyu M, Young BT, Hwa J, Young RC and Martin KA. Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition. J Clin Invest. 2008;118:3966-79.
  9. Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji W, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C and Lifton RP. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45:531-6.
  10. Chae WJ, Ehrlich AK, Chan PY, Teixeira AM, Henegariu O, Hao L, Shin JH, Park JH, Tang WH, Kim ST, Maher SE, Goldsmith-Pestana K, Shan P, Hwa J, Lee PJ, Krause DS, Rothlin CV, McMahon-Pratt D and Bothwell AL. The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity. 2016;44:246-258.
  11. Keramati AR, Fathzadeh M, Go GW, Singh R, Choi M, Faramarzi S, Mane S, Kasaei M, Sarajzadeh-Fard K, Hwa J, Kidd KK, Babaee Bigi MA, Malekzadeh R, Hosseinian A, Babaei M, Lifton RP and Mani A. A form of the metabolic syndrome associated with mutations in DYRK1B. N Engl J Med. 2014;370:1909-19.