Homophilic Interaction Between Transmembrane-JAM-A and Soluble JAM-A Regulates Thrombo-Inflammation: Implications for Coronary Artery Disease

Dominik Rath; Vera Rapp; Jessica Schwartz; Stefan Winter; Frederic Emschermann; Daniel Arnold; Johannes Rheinlaender; Manuela Büttcher; Michael Strebl; Michael B Braun; Konstanze Altgelt; Álvaro Petersen Uribe; Christoph Schories; Denis Canjuga; Elke Schaeffeler; Oliver Borst; Tilman E Schäffer; Harald Langer; Thilo Stehle; Matthias Schwab; Tobias Geisler; Meinrad Gawaz; Madhumita Chatterjee

doi:10.1016/j.jacbts.2022.03.003

Homophilic Interaction Between Transmembrane-JAM-A and Soluble JAM-A Regulates Thrombo-Inflammation: Implications for Coronary Artery Disease

JACC Basic Transl Sci. 2022 May 23;7(5):445-461. doi: 10.1016/j.jacbts.2022.03.003. eCollection 2022 May.

Authors

Dominik Rath¹, Vera Rapp¹, Jessica Schwartz¹, Stefan Winter², Frederic Emschermann¹, Daniel Arnold³, Johannes Rheinlaender³, Manuela Büttcher¹, Michael Strebl⁴, Michael B Braun⁴, Konstanze Altgelt¹, Álvaro Petersen Uribe¹, Christoph Schories¹, Denis Canjuga¹, Elke Schaeffeler², Oliver Borst^{1

5}, Tilman E Schäffer³, Harald Langer¹, Thilo Stehle⁴, Matthias Schwab^{2

6

7}, Tobias Geisler¹, Meinrad Gawaz¹, Madhumita Chatterjee¹

Affiliations

¹ Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany.
² Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany.
³ Institute of Applied Physics, University of Tübingen, Tübingen, Germany.
⁴ Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
⁵ DFG Heisenberg Group Thrombocardiology, Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany.
⁶ Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany.
⁷ Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.

Abstract

Genetic predisposition through F11R-single-nucleotide variation (SNV) influences circulatory soluble junctional adhesion molecule-A (sJAM-A) levels in coronary artery disease (CAD) patients. Homozygous carriers of the minor alleles (F11R-SNVs rs2774276, rs790056) show enhanced levels of thrombo-inflammatory sJAM-A. Both F11R-SNVs and sJAM-A are associated with worse prognosis for recurrent myocardial infarction in CAD patients. Platelet surface-associated JAM-A correlate with platelet activation markers in CAD patients. Activated platelets shed transmembrane-JAM-A, generating proinflammatory sJAM-A and JAM-A-bearing microparticles. Platelet transmembrane-JAM-A and sJAM-A as homophilic interaction partners exaggerate thrombotic and thrombo-inflammatory platelet monocyte interactions. Therapeutic strategies interfering with this homophilic interface may regulate thrombotic and thrombo-inflammatory platelet response in cardiovascular pathologies where circulatory sJAM-A levels are elevated.

Keywords: ACM, all-cause mortality; ACS, acute coronary syndrome; ADP, adenosine diphosphate; CAD, coronary artery disease; CCS, chronic coronary syndrome; CE, combined endpoint; HC, homozygous carriers; IS, ischemic stroke; JAM-A; JAM-A, junctional adhesion molecule-A; MI, myocardial infarction; SNV; SNV, single-nucleotide variation; TRAP, thrombin receptor activating peptide; coronary artery disease; platelet; sJAM-A, soluble junctional adhesion molecule-A; smJAM-A, soluble murine junctional adhesion molecule-A; thrombo-inflammation.