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John Hwa

MD, PhD, FRACP
Professor of Medicine (Cardiology)

Contact Information

John Hwa, MD, PhD, FRACP

Lab Location

Office Location

Mailing Address

  • Cardiovascular Medicine

    PO Box 208017

    New Haven, CT 06520-8017

    United States

The Hwa Lab

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Research Summary

We study the role played by platelets in the pathogenesis of diseases including diabetes mellitus, NSCLC, neurodegenerative diseases and aging. We use a combination of approaches including molecular signaling, biochemistry, genomics and proteomics on both human subjects and animal models. The ultimate goal is to develop novel mechanistic based therapies.

Specialized Terms: Platelets; Thromboinflammation; Diabetes Mellitus; NSCLC:Aging

Extensive Research Description

The Hwa Laboratory research interests focuses on platelet metabolic reprogramming under stress conditions (e.g. hyperglycemia, oxidative stress) leading to thrombosis and critical intercellular communication with such cells as endothelial cells, vascular smooth muscle cells, and T-cells. Platelets play key roles in the regulation of vascular stress response, including hemostasis, immunoregulation, initiation of repair, and cessation of the repair process. Defective platelets thus contributes to vascular pathology including thromboinflammation, intimal hyperplasia, aneurysm formation, and immune dysregulation.

Our current studies can be broadly divided into the following major areas.

1) Platelet metabolic reprogramming in response to stress and aging

2) Platelet communication to other cells in health and disease

3) The Yale cardiovascular tissue repository collaborative effort

Coauthors

Research Interests

Blood Platelets; Carcinoma, Non-Small-Cell Lung; Cardiology; Diabetes Mellitus; Metabolism

Research Images

platelet uptake by vascular smooth muscle cell
Confocal and electron microscopy demonstrating whole platelet uptake by a vascular smooth muscle cell

Selected Publications

  • Sugar, Fat, and YAP: A Recipe for Vascular Stiffness.Mani A, Hwa J, Martin KA. Sugar, Fat, and YAP: A Recipe for Vascular Stiffness. Circulation Research 2022, 130: 868-870. PMID: 35298300, PMCID: PMC9112226, DOI: 10.1161/CIRCRESAHA.122.320880.
  • Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity.Chakraborty R, Ostriker AC, Xie Y, Dave JM, Gamez-Mendez A, Chatterjee P, Abu Y, Valentine J, Lezon-Geyda K, Greif DM, Schulz VP, Gallagher PG, Sessa WC, Hwa J, Martin KA. Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity. Circulation 2022, 145: 1720-1737. PMID: 35502657, DOI: 10.1161/CIRCULATIONAHA.121.057599.
  • Unfolded Protein Response Differentially Modulates the Platelet Phenotype.Jain K, Tyagi T, Du J, Hu X, Patell K, Martin KA, Hwa J. Unfolded Protein Response Differentially Modulates the Platelet Phenotype. Circulation Research 2022, 131: 290-307. PMID: 35862006, PMCID: PMC9357223, DOI: 10.1161/CIRCRESAHA.121.320530.
  • Gasdermin D-dependent platelet pyroptosis exacerbates NET formation and inflammation in severe sepsis.Su M, Chen C, Li S, Li M, Zeng Z, Zhang Y, Xia L, Li X, Zheng D, Lin Q, Fan X, Wen Y, Liu Y, Chen F, Luo W, Bu Y, Qin J, Guo M, Qiu M, Sun L, Liu R, Wang P, Hwa J, Tang WH. Gasdermin D-dependent platelet pyroptosis exacerbates NET formation and inflammation in severe sepsis. Nature Cardiovascular Research 2022, 1: 732-747. PMID: 35967457, PMCID: PMC9362711, DOI: 10.1038/s44161-022-00108-7.
  • Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation.Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, Kwan JM, Krause DS, Lee AI, Halene S, Martin KA, Chun HJ, Hwa J. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nature Reviews. Cardiology 2021, 18: 194-209. PMID: 33214651, PMCID: PMC7675396, DOI: 10.1038/s41569-020-00469-1.
  • Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation.Zeng Z, Xia L, Fan S, Zheng J, Qin J, Fan X, Liu Y, Tao J, Liu Y, Li K, Ling Z, Bu Y, Martin KA, Hwa J, Liu R, Tang WH. Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation. Circulation 2021, 143: 354-371. PMID: 33207953, DOI: 10.1161/CIRCULATIONAHA.120.049715.
  • TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.Ostriker AC, Xie Y, Chakraborty R, Sizer AJ, Bai Y, Ding M, Song WL, Huttner A, Hwa J, Martin KA. TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy. Circulation 2021, 144: 455-470. PMID: 34111946, PMCID: PMC8643133, DOI: 10.1161/CIRCULATIONAHA.120.050553.
  • Reduced Platelet miR-223 Induction in Kawasaki Disease Leads to Severe Coronary Artery Pathology Through a miR-223/PDGFRβ Vascular Smooth Muscle Cell Axis.Zhang Y, Wang Y, Zhang L, Xia L, Zheng M, Zeng Z, Liu Y, Yarovinsky TO, Ostriker AC, Fan X, Weng K, Su M, Huang P, Martin KA, Hwa J, Tang WH. Reduced Platelet miR-223 Induction in Kawasaki Disease Leads to Severe Coronary Artery Pathology Through a miR-223/PDGFRβ Vascular Smooth Muscle Cell Axis. Circulation Research 2020, 127: 855-873. PMID: 32597702, PMCID: PMC7486265, DOI: 10.1161/CIRCRESAHA.120.316951.
  • Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study.Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, Baluha A, Bar N, Bona RD, Burns AJ, Dela Cruz CS, Dumont A, Halene S, Hwa J, Koff J, Menninger H, Neparidze N, Price C, Siner JM, Tormey C, Rinder HM, Chun HJ, Lee AI. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. The Lancet. Haematology 2020, 7: e575-e582. PMID: 32619411, PMCID: PMC7326446, DOI: 10.1016/S2352-3026(20)30216-7.
  • LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis.Xie Y, Ostriker AC, Jin Y, Hu H, Sizer AJ, Peng G, Morris AH, Ryu C, Herzog EL, Kyriakides T, Zhao H, Dardik A, Yu J, Hwa J, Martin KA. LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis. Circulation 2019, 139: 679-693. PMID: 30586711, PMCID: PMC6371979, DOI: 10.1161/CIRCULATIONAHA.118.034615.
  • Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair.Zeng Z, Xia L, Fan X, Ostriker AC, Yarovinsky T, Su M, Zhang Y, Peng X, Xie Y, Pi L, Gu X, Chung SK, Martin KA, Liu R, Hwa J, Tang WH. Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair. The Journal Of Clinical Investigation 2019, 129: 1372-1386. PMID: 30645204, PMCID: PMC6391113, DOI: 10.1172/JCI124508.
  • Mitochondrial MsrB2 serves as a switch and transducer for mitophagy.Lee SH, Lee S, Du J, Jain K, Ding M, Kadado AJ, Atteya G, Jaji Z, Tyagi T, Kim WH, Herzog RI, Patel A, Ionescu CN, Martin KA, Hwa J. Mitochondrial MsrB2 serves as a switch and transducer for mitophagy. EMBO Molecular Medicine 2019, 11: e10409. PMID: 31282614, PMCID: PMC6685081, DOI: 10.15252/emmm.201910409.
  • CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation.Esteghamat F, Broughton JS, Smith E, Cardone R, Tyagi T, Guerra M, Szabó A, Ugwu N, Mani MV, Azari B, Kayingo G, Chung S, Fathzadeh M, Weiss E, Bender J, Mane S, Lifton RP, Adeniran A, Nathanson MH, Gorelick FS, Hwa J, Sahin-Tóth M, Belfort-DeAguiar R, Kibbey RG, Mani A. CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation. Nature Genetics 2019, 51: 1233-1243. PMID: 31358993, PMCID: PMC6675645, DOI: 10.1038/s41588-019-0470-3.
  • Inducing mitophagy in diabetic platelets protects against severe oxidative stress.Lee SH, Du J, Stitham J, Atteya G, Lee S, Xiang Y, Wang D, Jin Y, Leslie KL, Spollett G, Srivastava A, Mannam P, Ostriker A, Martin KA, Tang WH, Hwa J. Inducing mitophagy in diabetic platelets protects against severe oxidative stress. EMBO Molecular Medicine 2016, 8: 779-95. PMID: 27221050, PMCID: PMC4931291, DOI: 10.15252/emmm.201506046.
  • The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation.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, Bothwell AL. The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity 2016, 44: 246-58. PMID: 26872695, PMCID: PMC4758884, DOI: 10.1016/j.immuni.2016.01.008.
  • Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor.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, Hwa J. Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood 2015, 125: 3377-87. PMID: 25814526, PMCID: PMC4447857, DOI: 10.1182/blood-2015-01-620278.
  • Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets.Tang WH, Stitham J, Jin Y, Liu R, Lee SH, Du J, Atteya G, Gleim S, Spollett G, Martin K, Hwa J. Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets. Circulation 2014, 129: 1598-609. PMID: 24474649, PMCID: PMC3989377, DOI: 10.1161/CIRCULATIONAHA.113.005224.
  • A form of the metabolic syndrome associated with mutations in DYRK1B.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, Mani A. A form of the metabolic syndrome associated with mutations in DYRK1B. The New England Journal Of Medicine 2014, 370: 1909-1919. PMID: 24827035, PMCID: PMC4069260, DOI: 10.1056/NEJMoa1301824.
  • Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity.Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, Hwa J, Yu J, Martin KA. Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation 2013, 128: 2047-57. PMID: 24077167, PMCID: PMC3899790, DOI: 10.1161/CIRCULATIONAHA.113.002887.
  • Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.Lemaire M, Frémeaux-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, Nürnberg G, Altmüller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nürnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nature Genetics 2013, 45: 531-6. PMID: 23542698, PMCID: PMC3719402, DOI: 10.1038/ng.2590.
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