Platelet Extracellular Regulated Protein Kinase 5 Is a Redox Switch and Triggers Maladaptive Platelet Responses and Myocardial Infarct Expansion.
BACKGROUND
Platelets have a pathophysiologic role in the ischemic microvascular environment of acute coronary syndromes. In comparison with platelet activation in normal healthy conditions, less attention is given to mechanisms of platelet activation in diseased states. Platelet function and mechanisms of activation in ischemic and reactive oxygen species-rich environments may not be the same as in normal healthy conditions. Extracellular regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase family member activated in hypoxic, reactive oxygen species-rich environments and in response to receptor-signaling mechanisms. Prior studies suggest a protective effect of ERK5 in endothelial and myocardial cells after ischemia. We present evidence that platelets express ERK5 and that platelet ERK5 has an adverse effect on platelet activation via selective receptor-dependent and receptor-independent reactive oxygen species-mediated mechanisms in ischemic myocardium.


RESULTS
Using isolated human platelets and a mouse model of myocardial infarction (MI), we found that platelet ERK5 is activated post-MI and that platelet-specific ERK5(-/-) mice have less platelet activation, reduced MI size, and improved post-MI heart function. Furthermore, the expression of downstream ERK5-regulated proteins is reduced in ERK5(-/-) platelets post-MI.


CONCLUSIONS
ERK5 functions as a platelet activator in ischemic conditions, and platelet ERK5 maintains the expression of some platelet proteins after MI, leading to infarct expansion. This demonstrates that platelet function in normal healthy conditions is different from platelet function in chronic ischemic and inflammatory conditions. Platelet ERK5 may be a target for acute therapeutic intervention in the thrombotic and inflammatory post-MI environment.
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.).
Scott J
SJ
Cameron
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.).
Sara K
SK
Ture
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.).
Deanne
D
Mickelsen
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.).
Enakshi
E
Chakrabarti
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.).
Kristina L
KL
Modjeski
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.).
Scott
S
McNitt
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.).
Michael
M
Seaberry
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.).
David J
DJ
Field
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.).
Nhat-Tu
NT
Le
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.).
Jun-Ichi
J
Abe
From Aab Cardiovascular Research Institute, University of Rochester School of Medicine, NY (S.J.C., S.K.T., D.M., E.C., K.L.M., M.S., D.J.F., C.N.M.); Department of Medicine (S.J.C., C.N.M.) and Heart Research Follow-Up Program (S.M.), Division of Cardiology, University of Rochester School of Medicine, NY; and Department of Cardiology Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston (N.-T.L., J.-i.A.). Craig_Morrell@URMC.Rochester.edu.
Craig N
CN
Morrell
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7 / Q000096:biosynthesis* / Q000172:deficiency; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology*; D010084:Oxidation-Reduction; D015539:Platelet Activation / Q000502:physiology*
D048054:Mitogen-Activated Protein Kinase 7
blood platelets; echocardiography; infarction; microcirculation