John Hwa
MD, PhD, FRACP
Professor of Medicine (Cardiology); Co-Director Yale Cooperative Center of Excellence in Hematology, Cardiovascular Medicine
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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
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Selected Publications
- Platelet-derived TLT-1 promotes tumor progression by suppressing CD8+ T cellsTyagi T, Jain K, Yarovinsky TO, Chiorazzi M, Du J, Castro C, Griffin J, Korde A, Martin KA, Takyar SS, Flavell RA, Patel AA, Hwa J. Platelet-derived TLT-1 promotes tumor progression by suppressing CD8+ T cells Journal Of Experimental Medicine 2022, 220: e20212218. PMID: 36305874, PMCID: PMC9814191, DOI: 10.1084/jem.20212218.
- Better together.Martin K, Hwa J. Better together. Science (New York, N.Y.) 2022, 378: 442. PMID: 36302027, DOI: 10.1126/science.adf4466.
- Unfolded Protein Response Differentially Modulates the Platelet PhenotypeJain 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.
- A guide to molecular and functional investigations of platelets to bridge basic and clinical sciencesTyagi T, Jain K, Gu S, Qiu M, Gu V, Melchinger H, Rinder H, Martin K, Gardiner E, Lee A, Tang W, Hwa J. A guide to molecular and functional investigations of platelets to bridge basic and clinical sciences Nature Cardiovascular Research 2022, 1: 223-237. DOI: 10.1038/s44161-022-00021-z.
- Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammationGu 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 2020, 18: 194-209. PMID: 33214651, PMCID: PMC7675396, DOI: 10.1038/s41569-020-00469-1.
- Insights into platelet pharmacology from a cryo-EM structure of the ABCC4 transporterSharda A, Gu S, Hwa J. Insights into platelet pharmacology from a cryo-EM structure of the ABCC4 transporter Nature Cardiovascular Research 2023, 1-3. DOI: 10.1038/s44161-023-00293-z.
- SOD2 in platelets: with age comes responsibilityJain K, Gu S, Hwa J. SOD2 in platelets: with age comes responsibility Journal Of Thrombosis And Haemostasis 2023, 21: 1077-1081. PMID: 36716965, DOI: 10.1016/j.jtha.2023.01.016.
- The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaquesKabir I, Zhang X, Dave J, Chakraborty R, Qu R, Chandran R, Ntokou A, Gallardo-Vara E, Aryal B, Rotllan N, Garcia-Milian R, Hwa J, Kluger Y, Martin K, Fernández-Hernando C, Greif D. The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques Nature Aging 2023, 1-18. DOI: 10.1038/s43587-022-00342-5.
- Gasdermin D-dependent platelet pyroptosis exacerbates NET formation and inflammation in severe sepsisSu 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.
- Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle PlasticityChakraborty 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.
- Sugar, Fat, and YAP: A Recipe for Vascular StiffnessMani 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.
- Gasdermin D inhibition confers antineutrophil mediated cardioprotection in acute myocardial infarctionJiang K, Tu Z, Chen K, Xu Y, Chen F, Xu S, Shi T, Qian J, Shen L, Hwa J, Wang D, Xiang Y. Gasdermin D inhibition confers antineutrophil mediated cardioprotection in acute myocardial infarction Journal Of Clinical Investigation 2022, 132: e151268. PMID: 34752417, PMCID: PMC8718151, DOI: 10.1172/jci151268.
- TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant VasculopathyOstriker 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.
- Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell DifferentiationZeng 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 2020, 143: 354-371. PMID: 33207953, DOI: 10.1161/circulationaha.120.049715.
- Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional studyGoshua 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.
- Reduced Platelet miR-223 Induction in Kawasaki Disease Leads to Severe Coronary Artery Pathology Through a miR-223/PDGFRβ Vascular Smooth Muscle Cell AxisZhang Y, Wang Y, Zhang L, Xia L, Zheng M, Zeng Z, Liu Y, Yarovinsky T, 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.
- CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activationEsteghamat 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.
- Mitochondrial MsrB2 serves as a switch and transducer for mitophagyLee SH, Lee S, Du J, Jain K, Ding M, Kadado AJ, Atteya G, Jaji Z, Tyagi T, Kim W, 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.
- Age associated non-linear regulation of redox homeostasis in the anucleate platelet: Implications for CVD risk patientsJain K, Tyagi T, Patell K, Xie Y, Kadado AJ, Lee SH, Yarovinsky T, Du J, Hwang J, Martin KA, Testani J, Ionescu CN, Hwa J. Age associated non-linear regulation of redox homeostasis in the anucleate platelet: Implications for CVD risk patients EBioMedicine 2019, 44: 28-40. PMID: 31130473, PMCID: PMC6604369, DOI: 10.1016/j.ebiom.2019.05.022.
- Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repairZeng 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 Journal Of Clinical Investigation 2019, 129: 1372-1386. PMID: 30645204, PMCID: PMC6391113, DOI: 10.1172/jci124508.
- LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and FibrosisXie 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.
- Inducing mitophagy in diabetic platelets protects against severe oxidative stressLee 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: 779-795. PMID: 27221050, PMCID: PMC4931291, DOI: 10.15252/emmm.201506046.
- The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated InflammationChae 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: 246-258. 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 factorXiang 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: 3377-3387. PMID: 25814526, PMCID: PMC4447857, DOI: 10.1182/blood-2015-01-620278.
- A Form of the Metabolic Syndrome Associated with Mutations in DYRK1BKeramati 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 New England Journal Of Medicine 2014, 370: 1909-1919. PMID: 24827035, PMCID: PMC4069260, DOI: 10.1056/nejmoa1301824.
- Aldose Reductase–Mediated Phosphorylation of p53 Leads to Mitochondrial Dysfunction and Damage in Diabetic PlateletsTang 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: 1598-1609. PMID: 24474649, PMCID: PMC3989377, DOI: 10.1161/circulationaha.113.005224.
- Ten-Eleven Translocation-2 (TET2) Is a Master Regulator of Smooth Muscle Cell PlasticityLiu 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: 2047-2057. PMID: 24077167, PMCID: PMC3899790, DOI: 10.1161/circulationaha.113.002887.
- Recessive mutations in DGKE cause atypical hemolytic-uremic syndromeLemaire 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: 531-536. PMID: 23542698, PMCID: PMC3719402, DOI: 10.1038/ng.2590.