Novel Antiplatelet Activity of Minocycline Involves Inhibition of MLK3-p38 Mitogen Activated Protein Kinase Axis.
Platelets play an essential role in hemostasis and wound healing by facilitating thrombus formation at sites of injury. Platelets also mediate inflammation and contain several pro-inflammatory molecules including cytokines and chemokines that mediate leukocyte recruitment and activation. Not surprisingly, platelet dysfunction is known to contribute to several inflammatory disorders. Antiplatelet therapies, such as aspirin, adenosine diphosphate (ADP) antagonists, glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, and anticoagulants such as warfarin, dampen platelet activity at the risk of unwarranted bleeding. Thus, the development of drugs that reduce platelet-mediated inflammation without interfering with thrombus formation is of importance to combat platelet-associated disorders. We have shown here for the first time that the tetracycline antibiotic, minocycline, administered to HIV-infected individuals reduces plasma levels of soluble CD40L and platelet factor 4 levels, host molecules predominately released by platelets. Minocycline reduced the activation of isolated platelets in the presence of the potent platelet activator, thrombin, as measured by ELISA and flow cytometry. Platelet degranulation was reduced upon exposure to minocycline as shown by mepacrine retention and flow cytometry. However, minocycline had no effect on spreading, aggregation, GPIIb/IIIa activation, or in vivo thrombus formation. Lastly, immunoblot analysis suggests that the antiplatelet activity of minocycline is likely mediated by inhibition of mixed lineage kinase 3 (MLK3)-p38 MAPK signaling axis and loss of p38 activity. Our findings provide a better understanding of platelet biology and a novel repurposing of an established antibiotic, minocycline, to specifically reduce platelet granule release without affecting thrombosis, which may yield insights in generating novel, specific antiplatelet therapies.
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
Joseph W
JW
Jackson
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
Meera V
MV
Singh
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
Vir B
VB
Singh
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
Letitia D
LD
Jones
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
Gregory A
GA
Davidson
Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
Sara
S
Ture
Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
Craig N
CN
Morrell
Department of Neurology, University of Rochester Medical Center, Rochester, New York, United States of America.
Giovanni
G
Schifitto
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
Sanjay B
SB
Maggirwar
D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008911:Minocycline / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D020930:MAP Kinase Kinase Kinases; D008911:Minocycline; D010975:Platelet Aggregation Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11