John H. Cleator, M.D., Ph.D.

Assistant Professor

john.cleator@vanderbilt.edu
Faculty Appointments
Assistant Professor of Medicine Assistant Professor of Pharmacology
Education
M.D., Medicine, Medical University of South Carolina, Charleston, South CarolinaPh.D., Molecular Pharmacology, Medical University of South Carolina, Charleston, South CarolinaB.S., The Citadel, Charleston, South Carolina
Office Address
382 PRB
Nashville, TN 37232
Research Description
The main focus is on defining the role of protease activated receptor regulation of platelet and vascular function and its impact on treating cardiovascular disease. Thrombin's effects on platelets, endothelial and vascular smooth muscle cells (VSMCs) are mediated primarily by activating protease activated receptor -1 (PAR-1). PAR-1 antagonists are currently being developed and tested as antiplatelet agents given during percutaneous coronary intervention (PCI) to prevent adverse events including myocardial infarction. Antagonizing the effects of PAR-1 on endothelium and vascular smooth muscle cells are largely unknown and could lead to further adverse events in certain clinical situations. For example, in vivo studies reveal that PAR-1 mediates endothelium-independent vasodilatation in the human forearm. If one extrapolates this to the coronary vasculature, blocking potential PAR-1 mediated coronary vasodilatation during PCI might lead to increased adverse events involving the microcirculation (coronary no reflow).

Another focus is examining the role of PARs in regulation of platelet function in patients treated with P2Y12 antagonists undergoing PCI. We have been studying platelet reactivity to thrombin through its receptors PAR1 and PAR4, and have found variability between normal and T2DM patients. In our published preliminary data, platelets from T2DM patients stimulated with thrombin show resistance to antagonism of P2Y12 receptors as compared to non-T2DM subjects 2. We have also observed variability between African American and Caucasian derived samples; samples from African American T2DM subjects do not exhibit this resistance, i.e. despite having T2DM; they are responsive to P2Y12 inhibition. Our published preliminary data derive from experiments in which a direct P2Y12 antagonist (2MEsAMP) was added ex vivo. We seek to determine if platelets from diabetic patients display resistance to oral P2Y12 receptor antagonists. The below are current ongoing projects in my laboratory:

1. Examining the in vivo role PAR-1 in a large animal model before and after inducing hypercholesterolemia and resultant endothelial dysfunction.
2. Determining if resistance to P2Y12 antagonists is altered platelets obtained from diabetic patients undergoing PCI.
3. Defining if PAR-1 single nucleotide polymorphisms are found in a BioVU subjects already identified to have recurrent ischemic events after PCI.
Research Keywords
Protease Activated Receptors (thrombin receptors) G-protein coupled receptors Regulation of coronary blood flow
Publications
Cleator JH, Wells CA, Dingus J, Kurtz DT, Hildebrandt JD. The N54-as Mutant Has Decreased Affinity for ß¿ and Suggests a Mechanism for Coupling Heterotrimeric G Protein Nucleotide Exchange with Subunit Dissociation. J. Pharmacol. Exp. Ther [print-electronic]. 2018 May; 365(2): 219-25. PMID: 29491039, PMCID: PMC5870480, PII: jpet.117.245779, DOI: 10.1124/jpet.117.245779, ISSN: 1521-0103.

Bergmeijer TO, Reny JL, Pakyz RE, Gong L, Lewis JP, Kim EY, Aradi D, Fernandez-Cadenas I, Horenstein RB, Lee MTM, Whaley RM, Montaner J, Gensini GF, Cleator JH, Chang K, Holmvang L, Hochholzer W, Roden DM, Winter S, Altman RB, Alexopoulos D, Kim HS, Déry JP, Gawaz M, Bliden K, Valgimigli M, Marcucci R, Campo G, Schaeffeler E, Dridi NP, Wen MS, Shin JG, Simon T, Fontana P, Giusti B, Geisler T, Kubo M, Trenk D, Siller-Matula JM, Ten Berg JM, Gurbel PA, Hulot JS, Mitchell BD, Schwab M, Ritchie MD, Klein TE, Shuldiner AR, . Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC). Am. Heart J [print-electronic]. 2018 Apr; 198: 152-9. PMID: 29653637, PMCID: PMC5903579, PII: S0002-8703(17)30398-8, DOI: 10.1016/j.ahj.2017.12.010, ISSN: 1097-6744.

Huang Z, Sawyer DB, Troy EL, McEwen C, Cleator JH, Murphy A, Caggiano AO, Eisen A, Parry TJ. Species-specific effects of neuregulin-1ß (cimaglermin alfa) on glucose handling in animal models and humans with heart failure. Toxicol. Appl. Pharmacol [print-electronic]. 2017 Aug 8/2/2017; 332: 92-9. PMID: 28780372, PII: S0041-008X(17)30326-5, DOI: 10.1016/j.taap.2017.08.001, ISSN: 1096-0333.

Lee HJ, Jiang M, Wu Y, Shaffer CM, Cleator JH, Friedman EA, Lewis JP, Roden DM, Denny J, Xu H. A comparative study of different methods for automatic identification of clopidogrel-induced bleedings in electronic health records. AMIA Jt Summits Transl Sci Proc. 2017; 2017: 185-92. PMID: 28815128, PMCID: PMC5543340, ISSN: 2153-4063.

Peterson JF, Field JR, Unertl K, Schildcrout JS, Johnson DC, Shi Y, Danciu I, Cleator JH, Pulley JM, McPherson JA, Denny JC, Laposata M, Roden DM, Johnson KB. Physician response to implementation of genotype-tailored antiplatelet therapy. Clin. Pharmacol. Ther [print-electronic]. 2015 Dec 12/22/2015; PMID: 26693963, DOI: 10.1002/cpt.331, ISSN: 1532-6535.

Friedman EA, Texeira L, Delaney J, Weeke PE, Lynch DR, Kasasbeh E, Song Y, Harrell FE, Denny JC, Hamm HE, Roden DM, Cleator JH. Evaluation of the F2R IVS-14A/T PAR1 polymorphism with subsequent cardiovascular events and bleeding in patients who have undergone percutaneous coronary intervention. J. Thromb. Thrombolysis [print-electronic]. 2015 Oct 10/7/2015; PMID: 26446588, PII: 10.1007/s11239-015-1285-4, DOI: 10.1007/s11239-015-1285-4, ISSN: 1573-742X.

Galindo CL, Kasasbeh E, Murphy A, Ryzhov S, Lenihan S, Ahmad FA, Williams P, Nunnally A, Adcock J, Song Y, Harrell FE, Tran TL, Parry TJ, Iaci J, Ganguly A, Feoktistov I, Stephenson MK, Caggiano AO, Sawyer DB, Cleator JH. Anti-remodeling and anti-fibrotic effects of the neuregulin-1ß glial growth factor 2 in a large animal model of heart failure. J Am Heart Assoc. 2014 Oct; 3(5): e000773. PMID: 25341890, PMCID: PMC4323814, PII: jah3718, DOI: 10.1161/JAHA.113.000773, ISSN: 2047-9980.

Cleator JH, Duvernay MT, Holinstat M, Colowick NE, Hudson WJ, Song Y, Harrell FE, Hamm HE. Racial differences in resistance to P2Y12 receptor antagonists in type 2 diabetic subjects. J. Pharmacol. Exp. Ther [print-electronic]. 2014 Oct; 351(1): 33-43. PMID: 25052834, PMCID: PMC4165026, PII: jpet.114.215616, DOI: 10.1124/jpet.114.215616, ISSN: 1521-0103.

Holinstat M, Colowick NE, Hudson WJ, Blakemore D, Chen Q, Hamm HE, Cleator JH. Dichotomous effects of exposure to bivalirudin in patients undergoing percutaneous coronary intervention on protease-activated receptor-mediated platelet activation. J. Thromb. Thrombolysis. 2013 Feb; 35(2): 209-22. PMID: 23054462, PMCID: PMC3969264, DOI: 10.1007/s11239-012-0812-9, ISSN: 1573-742X.

Kasasbeh ES, Parvez B, Huang RL, Hasselblad MM, Glazer MD, Salloum JG, Cleator JH, Zhao DX. Learning curve in transradial cardiac catheterization: procedure-related parameters stratified by operators' transradial volume. J Invasive Cardiol. 2012 Nov; 24(11): 599-604. PMID: 23117316, ISSN: 1557-2501.

Delaney JT, Ramirez AH, Bowton E, Pulley JM, Basford MA, Schildcrout JS, Shi Y, Zink R, Oetjens M, Xu H, Cleator JH, Jahangir E, Ritchie MD, Masys DR, Roden DM, Crawford DC, Denny JC. Predicting clopidogrel response using DNA samples linked to an electronic health record. Clin. Pharmacol. Ther [print-electronic]. 2012 Feb; 91(2): 257-63. PMID: 22190063, PMCID: PMC3621954, PII: clpt2011221, DOI: 10.1038/clpt.2011.221, ISSN: 1532-6535.

Zhao DX, Leacche M, Balaguer JM, Boudoulas KD, Damp JA, Greelish JP, Byrne JG, , Ahmad RM, Ball SK, Cleator JH, Deegan RJ, Eagle SS, Fong PP, Fredi JL, Hoff SJ, Jennings HS, McPherson JA, Piana RN, Pretorius M, Robbins MA, Slosky DA, Thompson A. Routine intraoperative completion angiography after coronary artery bypass grafting and 1-stop hybrid revascularization results from a fully integrated hybrid catheterization laboratory/operating room. J. Am. Coll. Cardiol. 2009 Jan 1/20/2009; 53(3): 232-41. PMID: 19147039, PII: S0735-1097(08)03463-3, DOI: 10.1016/j.jacc.2008.10.011, ISSN: 1558-3597.

Cleator JH, Vaughan DE. Clinical implications of the contrasting effects of in vivo thrombin receptor activation (protease-activated receptor type 1) on the human vasculature [editorial]. J. Am. Coll. Cardiol. 2008 May 5/6/2008; 51(18): 1757-9. PMID: 18452781, PII: S0735-1097(08)00693-1, DOI: 10.1016/j.jacc.2008.01.037, ISSN: 1558-3597.

Holinstat M, Voss B, Bilodeau ML, McLaughlin JN, Cleator J, Hamm HE. PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. J. Biol. Chem [print-electronic]. 2006 Sep 9/8/2006; 281(36): 26665-74. PMID: 16837456, PMCID: PMC3035573, PII: M602174200, DOI: 10.1074/jbc.M602174200, ISSN: 0021-9258.

Cleator JH, Zhu WQ, Vaughan DE, Hamm HE. Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP. Blood [print-electronic]. 2006 Apr 4/1/2006; 107(7): 2736-44. PMID: 16332977, PMCID: PMC1895372, PII: 2004-07-2698, DOI: 10.1182/blood-2004-07-2698, ISSN: 0006-4971.

Holinstat, M, Voss, B, Bilodeau, M, Zhu, WQ, McLaughlin, J, Cleator, JH, Hamm, HE.. PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. JBC. 2006; 281((Sep)): 26665 – 26674.

Dingus J, Wells CA, Campbell L, Cleator JH, Robinson K, Hildebrandt JD. G Protein betagamma dimer formation: Gbeta and Ggamma differentially determine efficiency of in vitro dimer formation. Biochemistry. 2005 Sep 9/6/2005; 44(35): 11882-90. PMID: 16128590, DOI: 10.1021/bi0504254, ISSN: 0006-2960.

McLaughlin JN, Mazzoni MR, Cleator JH, Earls L, Perdigoto AL, Brooks JD, Muldowney JA, Vaughan DE, Hamm HE. Thrombin modulates the expression of a set of genes including thrombospondin-1 in human microvascular endothelial cells. J. Biol. Chem [print-electronic]. 2005 Jun 6/10/2005; 280(23): 22172-80. PMID: 15817447, PII: M500721200, DOI: 10.1074/jbc.M500721200, ISSN: 0021-9258.

Cleator JH, Ravenell R, Kurtz DT, Hildebrandt JD. A dominant negative Galphas mutant that prevents thyroid-stimulating hormone receptor activation of cAMP production and inositol 1,4,5-trisphosphate turnover: competition by different G proteins for activation by a common receptor. J. Biol. Chem [print-electronic]. 2004 Aug 8/27/2004; 279(35): 36601-7. PMID: 15234971, PII: M406232200, DOI: 10.1074/jbc.M406232200, ISSN: 0021-9258.

Cook LA, Schey KL, Cleator JH, Wilcox MD, Dingus J, Hildebrandt JD. Identification of a region in G protein gamma subunits conserved across species but hypervariable among subunit isoforms. Protein Sci. 2001 Dec; 10(12): 2548-55. PMID: 11714923, PMCID: PMC2374038, DOI: 10.1110/ps.ps.26401, ISSN: 0961-8368.

Cleator JH, Mehta ND, Kurtz DT, Hildebrandt JD. The N54 mutant of Galphas has a conditional dominant negative phenotype which suppresses hormone-stimulated but not basal cAMP levels. FEBS Lett. 1999 Jan 1/25/1999; 443(2): 205-8. PMID: 9989606, PII: S0014-5793(98)01704-9, ISSN: 0014-5793.