New (re)purpose for an old drug: purinergic modulation may extinguish the COVID-19 thromboinflammatory firestorm
Yogendra Kanthi,1,2 Jason S. Knight,3 Yu Zuo,3 and David J. Pinsky1,4
1Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
2Section of Vascular Thrombosis and Inflammation, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
3Division of Rheumatology, Department of Internal Medicine and
4Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
Address correspondence to: Yogendra Kanthi, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Room 5-5130, Bethesda, Maryland 20892, USA. Phone: 734.998.7955; Email: yogen.kanthi@nih.gov. Or to: Jason S. Knight, University of Michigan, 5560 MSRB2, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA. Phone: 734.936.3257; Email: jsknight@umich.edu. Or to: David J. Pinsky, University of Michigan, 2141 Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA. Phone: 734.936.3500; Email: dpinsky@umich.edu.
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1Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
2Section of Vascular Thrombosis and Inflammation, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
3Division of Rheumatology, Department of Internal Medicine and
4Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
Address correspondence to: Yogendra Kanthi, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Room 5-5130, Bethesda, Maryland 20892, USA. Phone: 734.998.7955; Email: yogen.kanthi@nih.gov. Or to: Jason S. Knight, University of Michigan, 5560 MSRB2, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA. Phone: 734.936.3257; Email: jsknight@umich.edu. Or to: David J. Pinsky, University of Michigan, 2141 Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA. Phone: 734.936.3500; Email: dpinsky@umich.edu.
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1Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
2Section of Vascular Thrombosis and Inflammation, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
3Division of Rheumatology, Department of Internal Medicine and
4Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
Address correspondence to: Yogendra Kanthi, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Room 5-5130, Bethesda, Maryland 20892, USA. Phone: 734.998.7955; Email: yogen.kanthi@nih.gov. Or to: Jason S. Knight, University of Michigan, 5560 MSRB2, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA. Phone: 734.936.3257; Email: jsknight@umich.edu. Or to: David J. Pinsky, University of Michigan, 2141 Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA. Phone: 734.936.3500; Email: dpinsky@umich.edu.
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1Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
2Section of Vascular Thrombosis and Inflammation, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
3Division of Rheumatology, Department of Internal Medicine and
4Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
Address correspondence to: Yogendra Kanthi, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Room 5-5130, Bethesda, Maryland 20892, USA. Phone: 734.998.7955; Email: yogen.kanthi@nih.gov. Or to: Jason S. Knight, University of Michigan, 5560 MSRB2, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA. Phone: 734.936.3257; Email: jsknight@umich.edu. Or to: David J. Pinsky, University of Michigan, 2141 Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA. Phone: 734.936.3500; Email: dpinsky@umich.edu.
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Published June 12, 2020 - More info
JCI Insight. 2020;5(14):e140971. https://doi.org/10.1172/jci.insight.140971.
© 2020 American Society for Clinical Investigation
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Targeting purinergic signaling to prevent thromboinflammation
Purinergic signaling represents a critical checkpoint in the self-amplifying thromboinflammatory loop of endothelial dysfunction and hyperactivation of neutrophils, monocytes, and platelets. Activated and injured cells release their stores of ATP and ADP, creating a purinergic cloud in the extracellular space, where these nucleotides function in an autocrine and paracrine fashion as “danger” signals for neighboring and downstream tissues. Activation of extracellular ATP receptors (such as P2X7) on monocytes and neutrophils engages the canonical NLRP3 inflammasome, resulting in exuberant IL-1β production (12, 13). Moreover, blockade of this pathway prevents accretion of venous and arterial thrombi in mice (14–16). Similarly, thienopyridine antagonists of the ADP P2Y12 receptor are used clinically to suppress platelet activation in patients with cardiovascular disease (17).
CD39 and CD73, the dominant vascular ectonucleotidases, sequentially phosphohydrolyze these nucleotides to generate adenosine, which sustains homeostasis and a quiescent, antiinflammatory microenvironment. Furthermore, efficient activation of the extracellular adenosine receptor 2A (A2AR) by the FDA-approved drug dipyridamole tempers both neutrophil ROS formation and NET release in a cAMP- and PKA-dependent manner, while preventing intraluminal vascular thrombi in mice (18, 19). Dipyridamole also protects the endothelium from ROS generation and acquiring a tissue factor–rich procoagulant phenotype induced by TNF-α (20–22). Dipyridamole potentiates homeostatic adenosine receptor signaling through at least 2 mechanisms: (a) inhibition of ectonucleoside reuptake and (b) stabilization of intracellular cAMP via inhibition of cytoplasmic phosphodiesterase activity (Figure 1). Dipyridamole is an old and relatively safe drug, with FDA-approved indications for use in combination with aspirin to prevent recurrent strokes and in combination with vitamin K antagonists for thromboprophylaxis following mechanical heart valve replacement (23). Dipyridamole was once one of the fifty most prescribed drugs in the US (24), with a favorable safety profile and a bleeding risk similar to that of aspirin.
Figure 1Dipyridamole’s mechanisms of action and potential role in the treatment of COVID-19. (A) Dipyridamole potentiates homeostatic adenosine receptor signaling by preventing reuptake of ectonucleoside (i) and by stabilizing the intracellular cAMP pools via inhibition of cytoplasmic phosphodiesterase (PDE) activity (ii). (B) Left unchecked, purinergic signaling exacerbates both inflammation and thrombosis; therefore, dipyridamole has the potential to inhibit multiple processes that have been recently linked to COVID-19 severity. Illustrated by Rachel Davidowitz.
In addition to its antithrombotic properties, human and animal studies have demonstrated that dipyridamole both induces synthesis of antiviral type I IFNs and protects against harmful inflammatory responses in the context of endotoxemia (25, 26). Intriguingly, dipyridamole has recently been shown to inhibit SARS-CoV-2 replication in vitro, likely via direct interaction with the SARS-CoV-2 replication complex at concentrations below those achieved in plasma with FDA-approved dosing. In a small study in China, dipyridamole significantly suppressed D-dimer elevation and improved platelet counts in patients with COVID-19; however, larger studies are needed to evaluate clinical outcomes (27).
