Publications by authors named "Craig N Morrell"

74 Publications

Sex-Specific Platelet Activation Through Protease-Activated Receptors Reverses in Myocardial Infarction.

Arterioscler Thromb Vasc Biol 2021 01 12;41(1):390-400. Epub 2020 Nov 12.

Aab Cardiovascular Research Institute, University of Rochester School of Medicine, Rochester, New York (B.S.K., H.S., A.M., D.Q.R., S.T., C.N.M., S.J.C.).

Objective: The platelet phenotype in certain patients and clinical contexts may differ from healthy conditions. We evaluated platelet activation through specific receptors in healthy men and women, comparing this to patients presenting with ST-segment-elevation myocardial infarction and non-ST-segment-elevation myocardial infarction. Approach and Results: We identified independent predictors of platelet activation through certain receptors and a murine MI model further explored these findings. Platelets from healthy women and female mice are more reactive through PARs (protease-activated receptors) compared with platelets from men and male mice. Multivariate regression analyses revealed male sex and non-ST-segment-elevation myocardial infarction as independent predictors of enhanced PAR1 activation in human platelets. Platelet PAR1 signaling decreased in women and increased in men during MI which was the opposite of what was observed during healthy conditions. Similarly, in mice, thrombin-mediated platelet activation was greater in healthy females compared with males, and lesser in females compared with males at the time of MI.

Conclusions: Sex-specific signaling in platelets seems to be a cross-species phenomenon. The divergent platelet phenotype in males and females at the time of MI suggests a sex-specific antiplatelet drug regimen should be prospectively evaluated.
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http://dx.doi.org/10.1161/ATVBAHA.120.315033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770120PMC
January 2021

Lung megakaryocytes are immune modulatory cells.

J Clin Invest 2021 Jan;131(1)

Aab Cardiovascular Research Institute and.

Although platelets are the cellular mediators of thrombosis, they are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered bone marrow-resident (BM-resident) cells. However, platelet-producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared with BM Mks. We therefore sought to define the immune functions of lung Mks. Using single-cell RNA sequencing of BM and lung myeloid-enriched cells, we found that lung Mks, which we term MkL, had gene expression patterns that are similar to antigen-presenting cells. This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment, as evidenced by BM Mks having an MkL-like phenotype under the influence of pathogen receptor challenge and lung-associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that MkL internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, MkL induced CD4+ T cell activation in an MHC II-dependent manner both in vitro and in vivo. These data indicated that MkL had key immune regulatory roles dictated in part by the tissue environment.
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http://dx.doi.org/10.1172/JCI137377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773372PMC
January 2021

Novel Mechanism of Microvesicle Regulation by the Antiviral Protein Tetherin During HIV Infection.

J Am Heart Assoc 2020 09 21;9(17):e015998. Epub 2020 Aug 21.

Department of Microbiology & Immunology University of Rochester Medical Center Rochester NY.

Background Microvesicles are cell membrane-derived vesicles that have been shown to augment inflammation. Specifically, monocyte-derived microvesicles (MDMVs), which can express the coagulation protein tissue factor, contribute to thrombus formation and cardiovascular disease. People living with HIV experience higher prevalence of cardiovascular disease and also exhibit increased levels of plasma microvesicles. The process of microvesicle release has striking similarity to budding of enveloped viruses. The surface protein tetherin inhibits viral budding by physically tethering budding virus particles to cells. Hence, we investigated the role of tetherin in regulating the release of MDMVs during HIV infection. Methods and Results The plasma of aviremic HIV-infected individuals had increased levels of tissue factor + MDMVs, as measured by flow cytometry, and correlated to reduced tetherin expression on monocytes. Superresolution confocal and electron microscopy showed that tetherin localized at the site of budding MDMVs. Mechanistic studies revealed that the exposure of monocytes to HIV-encoded Tat triggered tetherin loss and subsequent rise in MDMV production. Overexpression of tetherin in monocytes led to morphologic changes in the pseudopodia directly underneath the MDMVs. Further, tetherin knockout mice demonstrated a higher number of circulating MDMVs and less time to bleeding cessation. Conclusions Our studies define a novel regulatory mechanism of MDMV release through tetherin and explore its contribution to the procoagulatory state that is frequently observed in people with HIV. Such insights could lead to improved therapies for individuals infected with HIV and also for those with cardiovascular disease.
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http://dx.doi.org/10.1161/JAHA.120.015998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660781PMC
September 2020

Complement activation on endothelium initiates antibody-mediated acute lung injury.

J Clin Invest 2020 11;130(11):5909-5923

Department of Medicine, UCSF, San Francisco, California, USA.

Antibodies targeting human leukocyte antigen (HLA)/major histocompatibility complex (MHC) proteins limit successful transplantation and transfusion, and their presence in blood products can cause lethal transfusion-related acute lung injury (TRALI). It is unclear which cell types are bound by these anti-leukocyte antibodies to initiate an immunologic cascade resulting in lung injury. We therefore conditionally removed MHC class I (MHC I) from likely cellular targets in antibody-mediated lung injury. Only the removal of endothelial MHC I reduced lung injury and mortality, related mechanistically to absent endothelial complement fixation and lung platelet retention. Restoration of endothelial MHC I rendered MHC I-deficient mice susceptible to lung injury. Neutrophil responses, including neutrophil extracellular trap (NET) release, were intact in endothelial MHC I-deficient mice, whereas complement depletion reduced both lung injury and NETs. Human pulmonary endothelial cells showed high HLA class I expression, and posttransfusion complement activation was increased in clinical TRALI. These results indicate that the critical source of antigen for anti-leukocyte antibodies is in fact the endothelium, which reframes our understanding of TRALI as a rapid-onset vasculitis. Inhibition of complement activation may have multiple beneficial effects of reducing endothelial injury, platelet retention, and NET release in conditions where antibodies trigger these pathogenic responses.
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http://dx.doi.org/10.1172/JCI138136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598054PMC
November 2020

The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function.

Nat Commun 2020 07 13;11(1):3479. Epub 2020 Jul 13.

Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.

Genetic factors contribute to the risk of thrombotic diseases. Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. Here we show that Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. We find that Slc44a2 null mice (Slc44a2(KO)) have increased bleeding times and delayed thrombosis compared to wild-type (Slc44a2(WT)) controls. Platelets from Slc44a2(KO) mice have impaired activation in response to thrombin. We discover that Slc44a2 mediates choline transport into mitochondria, where choline metabolism leads to an increase in mitochondrial oxygen consumption and ATP production. Platelets lacking Slc44a2 contain less ATP at rest, release less ATP when activated, and have an activation defect that can be rescued by exogenous ADP. Taken together, our data suggest that mitochondria require choline for maximum function, demonstrate the importance of mitochondrial metabolism to platelet activation, and reveal a mechanism by which Slc44a2 influences thrombosis.
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http://dx.doi.org/10.1038/s41467-020-17254-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359028PMC
July 2020

Essential Amino Acids-Essential in Arterial Thrombosis.

Circulation 2020 Jul 6;142(1):65-67. Epub 2020 Jul 6.

Aab Cardiovascular Research Institute (Z.T.H., C.N.M.), University of Rochester School of Medicine, New York.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046817DOI Listing
July 2020

Evaluation of the procoagulant properties of a newly developed platelet modified lysate product.

Transfusion 2020 Jul 15;60(7):1579-1589. Epub 2020 May 15.

Transfusion Medicine Division, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.

Background: Platelet transfusion is associated with logistical problems with the national storage guidelines of platelets. This results in decreased function in vivo as a result of the platelet storage lesion, and complications such as allergic or hemolytic reactions and thrombosis. We evaluated a new, freshly prepared platelet modified lysate (PML) product designed to be more procoagulant than fresh and stored platelets.

Methods: Fresh platelets were concentrated, sonicated, and centrifuged to produce PML. Samples of both washed and unwashed PML were evaluated for particle size, concentration, and activity, and then tested for clot kinetics and thrombin generation. PML samples were also stored at various temperatures for durations up to 6 months and evaluated for clot kinetics and thrombin generation throughout.

Results: PML showed significantly higher concentration of platelet microparticles, increased procoagulant properties, and increased thrombin generation as compared to fresh and stored platelets. In addition, PML maintained its clot kinetics over a 6-month storage period with variable storage conditions.

Conclusions: The newly proposed PML product is more procoagulant, stable, and has additional potential applications than currently available platelet products. Further studies will be performed to assess its functions in vivo and to assess thrombotic potential.
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http://dx.doi.org/10.1111/trf.15844DOI Listing
July 2020

Platelet-derived β2m regulates age related monocyte/macrophage functions.

Aging (Albany NY) 2019 12 18;11(24):11955-11974. Epub 2019 Dec 18.

Aab Cardiovascular Research Institute, University of Rochester School of Medicine, Box CVRI, Rochester, NY 14652, USA.

Platelets have central roles in both immune responses and development. Stimulated platelets express leukocyte adhesion molecules and release numerous immune modulatory factors that recruit and activate leukocytes, both at the sites of activation and distantly. Monocytes are innate immune cells with dynamic immune modulatory functions that change during the aging process, a phenomenon termed "inflammaging". We have previously shown that platelets are a major source of plasma beta-2 microglobulin (β2M) and that β2M induced a monocyte pro-inflammatory phenotype. Plasma β2M increases with age and is a pro-aging factor. We hypothesized that platelet derived β2M regulates monocyte phenotypes in the context of aging. Using wild-type (WT) and platelet specific β2M knockout mice (Plt-β2M) mice, we found that plasma β2M increased with age and correlated with increased circulating Ly6C monocytes. However, aged Plt-β2M mice had significantly fewer Ly6C monocytes compared to WT mice. Quantitative real-time PCR of circulating monocytes showed that WT mouse monocytes were more "pro-inflammatory" with age, while Plt-β2M derived monocytes adopted a "pro-reparative" phenotype. Older Plt-β2M mice had a significant decline in heart function compared to age matched WT mice, as well as increased cardiac fibrosis and pro-fibrotic markers. These data suggest that platelet-derived β2M regulates age associated monocyte polarization, and a loss of platelet derived β2M shifted monocytes and macrophages to a pro-reparative phenotype and increased pro-fibrotic cardiac responses. Platelet regulation of monocyte phenotypes via β2M may maintain a balance between inflammatory and reparative signals that affects age related physiologic outcomes.
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http://dx.doi.org/10.18632/aging.102520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949047PMC
December 2019

PAD4 and von Willebrand Factor Link Inflammation and Thrombosis.

Circ Res 2019 08 15;125(5):520-522. Epub 2019 Aug 15.

From the Aab Cardiovascular Research Institute (C.N.M., Z.T.H., D.N.P., P.M.), University of Rochester School of Medicine, Box CVRI, NY.

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http://dx.doi.org/10.1161/CIRCRESAHA.119.315601DOI Listing
August 2019

The Protective Role of Natriuretic Peptide Receptor 2 against High Salt Injury in the Renal Papilla.

Am J Pathol 2019 09 18;189(9):1721-1731. Epub 2019 Jun 18.

Aab Cardiovascular Research Institute, Hajim School of Engineering and Applied Sciences, University of Rochester, Rochester, New York. Electronic address:

Mutations in natriuretic peptide receptor 2 (Npr2) gene cause a rare form of short-limbed dwarfism, but its physiological effects have not been well studied. Human and mouse genetic data suggest that Npr2 in the kidney plays a role in salt homeostasis. Herein, we described anatomic changes within renal papilla of Npr2 knockout (Npr2) mice. Dramatic reduction was found in diuresis, and albuminuria was evident after administration of 1% NaCl in drinking water in Npr2 and heterozygous (Npr2) mice compared with their wild-type (Npr2) littermates. There was indication of renal epithelial damage accompanied by high numbers of red blood cells and inflammatory cells (macrophage surface glycoproteins binding to galectin-3) and an increase of renal epithelial damage marker (T-cell Ig and mucin domain 1) in Npr2 mice. Addition of 1% NaCl tended to increase apoptotic cells (cleaved caspase 3) in the renal papilla of Npr2 mice. In vitro, genetic silencing of the Npr2 abolished protective effects of C-type natriuretic peptide, a ligand for Npr2, against death of M-1 kidney epithelial cells exposed to 360 mmol/L NaCl. Finally, significantly lower levels of expression of the NPR2 protein were detected in renal samples of hypertensive compared with normotensive human subjects. Taken together, these findings suggest that Npr2 is essential to protect renal epithelial cells from high concentrations of salt and prevent kidney injury.
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http://dx.doi.org/10.1016/j.ajpath.2019.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724224PMC
September 2019

Acetylcholine Inhibits Platelet Activation.

J Pharmacol Exp Ther 2019 05 14;369(2):182-187. Epub 2019 Feb 14.

Aab Cardiovascular Research Institute, Department of Medicine (J.A.B., S.K.T., R.A.S., M.A.M., S.J.C., C.N.M., C.J.L.) and Department of Pharmacology and Physiology (L.E.T., D.I.Y.), University of Rochester Medical Center, Rochester, New York.

Platelets are key mediators of thrombosis. Many agonists of platelet activation are known, but fewer endogenous inhibitors of platelets, such as prostacyclin and nitric oxide (NO), have been identified. Acetylcholinesterase inhibitors, such as donepezil, can cause bleeding in patients, but the underlying mechanisms are not well understood. We hypothesized that acetylcholine is an endogenous inhibitor of platelets. We measured the effect of acetylcholine or analogs of acetylcholine on human platelet activation ex vivo. Acetylcholine and analogs of acetylcholine inhibited platelet activation, as measured by P-selectin translocation and glycoprotein IIb IIIa conformational changes. Conversely, we found that antagonists of the acetylcholine receptor, such as pancuronium, enhance platelet activation. Furthermore, drugs inhibiting acetylcholinesterase, such as donepezil, also inhibit platelet activation, suggesting that platelets release acetylcholine. We found that NO mediates acetylcholine inhibition of platelets. Our data suggest that acetylcholine is an endogenous inhibitor of platelet activation. The cholinergic system may be a novel target for antithrombotic therapies.
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http://dx.doi.org/10.1124/jpet.118.253583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439456PMC
May 2019

Platelet-derived β2M regulates monocyte inflammatory responses.

JCI Insight 2019 03 7;4(5). Epub 2019 Mar 7.

Aab Cardiovascular Research Institute.

β-2 Microglobulin (β2M) is a molecular chaperone for the major histocompatibility class I (MHC I) complex, hemochromatosis factor protein (HFE), and the neonatal Fc receptor (FcRn), but β2M may also have less understood chaperone-independent functions. Elevated plasma β2M has a direct role in neurocognitive decline and is a risk factor for adverse cardiovascular events. β2M mRNA is present in platelets at very high levels, and β2M is part of the activated platelet releasate. In addition to their more well-studied thrombotic functions, platelets are important immune regulatory cells that release inflammatory molecules and contribute to leukocyte trafficking, activation, and differentiation. We have now found that platelet-derived β2M is a mediator of monocyte proinflammatory differentiation through noncanonical TGFβ receptor signaling. Circulating monocytes from mice lacking β2M only in platelets (Plt-β2M-/-) had a more proreparative monocyte phenotype, in part dependent on increased platelet-derived TGFβ signaling in the absence of β2M. Using a mouse myocardial infarction (MI) model, Plt-β2M-/- mice had limited post-MI proinflammatory monocyte responses and, instead, demonstrated early proreparative monocyte differentiation, profibrotic myofibroblast responses, and a rapid decline in heart function compared with WT mice. These data demonstrate a potentially novel chaperone-independent, monocyte phenotype-regulatory function for platelet β2M and that platelet-derived 2M and TGFβ have opposing roles in monocyte differentiation that may be important in tissue injury responses.
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http://dx.doi.org/10.1172/jci.insight.122943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483513PMC
March 2019

The Platelet Napoleon Complex-Small Cells, but Big Immune Regulatory Functions.

Annu Rev Immunol 2019 04 28;37:125-144. Epub 2018 Nov 28.

Aab Cardiovascular Research Institute, University of Rochester School of Medicine, Rochester, New York 14642, USA; email:

Platelets have dual physiologic roles as both cellular mediators of thrombosis and immune modulatory cells. Historically, the thrombotic function of platelets has received significant research and clinical attention, but emerging research indicates that the immune regulatory roles of platelets may be just as important. We now know that in addition to their role in the acute thrombotic event at the time of myocardial infarction, platelets initiate and accelerate inflammatory processes that are part of the pathogenesis of atherosclerosis and myocardial infarction expansion. Furthermore, it is increasingly apparent from recent studies that platelets impact the pathogenesis of many vascular inflammatory processes such as autoimmune diseases, sepsis, viral infections, and growth and metastasis of many types of tumors. Therefore, we must consider platelets as immune cells that affect all phases of immune responses.
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http://dx.doi.org/10.1146/annurev-immunol-042718-041607DOI Listing
April 2019

Platelet CD36 signaling through ERK5 promotes caspase-dependent procoagulant activity and fibrin deposition in vivo.

Blood Adv 2018 11;2(21):2848-2861

Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI.

Dyslipidemia is a risk factor for clinically significant thrombotic events. In this condition, scavenger receptor CD36 potentiates platelet reactivity through recognition of circulating oxidized lipids. CD36 promotes thrombosis by activating redox-sensitive signaling molecules, such as the MAPK extracellular signal-regulated kinase 5 (ERK5). However, the events downstream of platelet ERK5 are not clear. In this study, we report that oxidized low-density lipoprotein (oxLDL) promotes exposure of procoagulant phosphatidylserine (PSer) on platelet surfaces. Studies using pharmacologic inhibitors indicate that oxLDL-CD36 interaction-induced PSer exposure requires apoptotic caspases in addition to the downstream CD36-signaling molecules Src kinases, hydrogen peroxide, and ERK5. Caspases promote PSer exposure and, subsequently, recruitment of the prothrombinase complex, resulting in the generation of fibrin from the activation of thrombin. Caspase activity was observed when platelets were stimulated with oxLDL. This was prevented by inhibiting CD36 and ERK5. Furthermore, oxLDL potentiates convulxin/glycoprotein VI-mediated fibrin formation by platelets, which was prevented when CD36, ERK5, and caspases were inhibited. Using 2 in vivo arterial thrombosis models in apoE-null hyperlipidemic mice demonstrated enhanced arterial fibrin accumulation upon vessel injury. Importantly, absence of ERK5 in platelets or mice lacking CD36 displayed decreased fibrin accumulation in high-fat diet-fed conditions comparable to that seen in chow diet-fed animals. These findings suggest that platelet signaling through CD36 and ERK5 induces a procoagulant phenotype in the hyperlipidemic environment by enhancing caspase-mediated PSer exposure.
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http://dx.doi.org/10.1182/bloodadvances.2018025411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234364PMC
November 2018

Hypoxia and Ischemia Promote a Maladaptive Platelet Phenotype.

Arterioscler Thromb Vasc Biol 2018 07 3;38(7):1594-1606. Epub 2018 May 3.

From the Aab Cardiovascular Research Institute (S.J.C., S.K.T., R.A.S., A.M., D.P., D.J.F., K.L.M., C.N.M.).

Objective: Reduced blood flow and tissue oxygen tension conditions result from thrombotic and vascular diseases such as myocardial infarction, stroke, and peripheral vascular disease. It is largely assumed that while platelet activation is increased by an acute vascular event, chronic vascular inflammation, and ischemia, the platelet activation pathways and responses are not themselves changed by the disease process. We, therefore, sought to determine whether the platelet phenotype is altered by hypoxic and ischemic conditions.

Approach And Results: In a cohort of patients with metabolic and peripheral artery disease, platelet activity was enhanced, and inhibition with oral antiplatelet agents was impaired compared with platelets from control subjects, suggesting a difference in platelet phenotype caused by the disease. Isolated murine and human platelets exposed to reduced oxygen (hypoxia chamber, 5% O) had increased expression of some proteins that augment platelet activation compared with platelets in normoxic conditions (21% O). Using a murine model of critical limb ischemia, platelet activity was increased even 2 weeks postsurgery compared with sham surgery mice. This effect was partly inhibited in platelet-specific ERK5 (extracellular regulated protein kinase 5) knockout mice.

Conclusions: These findings suggest that ischemic disease changes the platelet phenotype and alters platelet agonist responses because of changes in the expression of signal transduction pathway proteins. Platelet phenotype and function should, therefore, be better characterized in ischemic and hypoxic diseases to understand the benefits and limitations of antiplatelet therapy.
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http://dx.doi.org/10.1161/ATVBAHA.118.311186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023774PMC
July 2018

The platelet phenotype in patients with ST-segment elevation myocardial infarction is different from non-ST-segment elevation myocardial infarction.

Transl Res 2018 05 2;195:1-12. Epub 2017 Dec 2.

Aab Cardiovascular Research Institute, University of Rochester School of Medicine, Rochester, New York; Department of Medicine, Division of Cardiology, University of Rochester School of Medicine, Rochester, New York; Department of Surgery, University of Rochester School of Medicine, Rochester, New York. Electronic address:

It is assumed that platelets in diseased conditions share similar properties to platelets in healthy conditions, although this has never been examined in detail for myocardial infarction (MI). We examined platelets from patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) compared with platelets from healthy volunteers to evaluate for differences in platelet phenotype and function. Platelet activation was examined and postreceptor signal transduction pathways were assessed. Platelet-derived plasma biomarkers were evaluated by receiver operator characteristic curve analysis. Maximum platelet activation through the thromboxane receptor was greater in STEMI than in NSTEMI but less through protease-activated receptor 1. Extracellular-signal related-kinase 5 activation, which can activate platelets, was increased in platelets from subjects with STEMI and especially in platelets from patients with NSTEMI. Matrix metalloproteinase 9 (MMP9) protein content and enzymatic activity were several-fold greater in platelets with MI than in control. Mean plasma MMP9 concentration in patients with MI distinguished between STEMI and NSTEMI (area under curve [AUC] 75% [confidence interval (CI) 60-91], P = 0.006) which was superior to troponin T (AUC 66% [CI 48-85, P = 0.08), predicting STEMI with 80% sensitivity (95% CI 56-94), 90% specificity (CI 68-99), 70% AUC (CI 54-86, P < 0.0001), and NSTEMI with 50% sensitivity (CI 27-70), 90% specificity (CI 68-99), 70% AUC (CI 54-86, P = 0.03). Platelets from patients with STEMI and NSTEMI show differences in platelet surface receptor activation and postreceptor signal transduction, suggesting the healthy platelet phenotype in which antiplatelet agents are often evaluated in preclinical studies is different from platelets in patients with MI.
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http://dx.doi.org/10.1016/j.trsl.2017.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898983PMC
May 2018

Platelet factor 4 increases bone marrow B cell development and differentiation.

Immunol Res 2017 10;65(5):1089-1094

Aab Cardiovascular Research Institute, University of Rochester Medical Center, Box CVRI, 601 Elmwood Ave, Rochester, NY, 14642, USA.

Platelet factor 4 (PF4) is a megakaryocyte-/platelet-derived chemokine with diverse functions as a regulator of vascular and immune biology. PF4 has a central role in vessel injury responses, innate immune cell responses, and T-helper cell differentiation. We have now discovered that PF4 has a direct role in B cell differentiation in the bone marrow. Mice lacking PF4 (PF4 mice) had fewer developing B cells in the bone marrow beginning after the pre-pro-B cell stage of differentiation. In vitro, PF4 increased the differentiation of hematopoietic progenitors to B cell lineage cells, indicating that PF4 has a direct effect on B cell differentiation. STAT5 activation is essential in early B cell development and PF4 increased the phosphorylation of STAT5. Taken together, these data demonstrate that PF4 has an important role in increasing B cell differentiation in the bone marrow environment.
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http://dx.doi.org/10.1007/s12026-017-8951-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693646PMC
October 2017

miR-451 limits CD4 T cell proliferative responses to infection in mice.

Immunol Res 2017 08;65(4):828-840

Aab Cardiovascular Research Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA.

MicroRNAs (miRNAs) are major regulators of cell responses, particularly in stressed cell states and host immune responses. Some miRNAs have a role in pathogen defense, including regulation of immune responses to Plasmodium parasite infection. Using a nonlethal mouse model of blood stage malaria infection, we have found that miR-451 mice infected with Plasmodium yoelii XNL cleared infection at a faster rate than did wild-type (WT) mice. MiR-451 mice had an increased leukocyte response to infection, with the protective phenotype primarily driven by CD4 T cells. WT and miR-451 CD4 T cells had similar activation responses, but miR-451 CD4 cells had significantly increased proliferation, both in vitro and in vivo. Myc is a miR-451 target with a central role in cell cycle progression and cell proliferation. CD4 T cells from miR-451 mice had increased postactivation Myc expression. RNA-Seq analysis of CD4 cells demonstrated over 5000 differentially expressed genes in miR-451 mice postinfection, many of which are directly or indirectly Myc regulated. This study demonstrates that miR-451 regulates T cell proliferative responses in part via a Myc-dependent mechanism.
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http://dx.doi.org/10.1007/s12026-017-8919-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545071PMC
August 2017

Platelets: killers of parasites or patients?

Authors:
Craig N Morrell

Blood 2017 03;129(12):1571-1572

UNIVERSITY OF ROCHESTER SCHOOL OF MEDICINE AND DENTISTRY.

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http://dx.doi.org/10.1182/blood-2017-01-764621DOI Listing
March 2017

Platelet CD36 promotes thrombosis by activating redox sensor ERK5 in hyperlipidemic conditions.

Blood 2017 05 23;129(21):2917-2927. Epub 2017 Mar 23.

Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI.

Atherothrombosis is a process mediated by dysregulated platelet activation that can cause life-threatening complications and is the leading cause of death by cardiovascular disease. Platelet reactivity in hyperlipidemic conditions is enhanced when platelet scavenger receptor CD36 recognizes oxidized lipids in oxidized low-density lipoprotein (oxLDL) particles, a process that induces an overt prothrombotic phenotype. The mechanisms by which CD36 promotes platelet activation and thrombosis remain incompletely defined. In this study, we identify a mechanism for CD36 to promote thrombosis by increasing activation of MAPK extracellular signal-regulated kinase 5 (ERK5), a protein kinase known to be exquisitely sensitive to redox stress, through a signaling pathway requiring Src kinases, NADPH oxidase, superoxide radical anion, and hydrogen peroxide. Pharmacologic inhibitors of ERK5 blunted platelet activation and aggregation in response to oxLDL and targeted genetic deletion of ERK5 in murine platelets prevented oxLDL-induced platelet deposition on immobilized collagen in response to arterial shear. Importantly, in vivo thrombosis experiments after bone marrow transplantation from platelet-specific ERK5 null mice into hyperlipidemic apolipoprotein E null mice showed decreased platelet accumulation and increased thrombosis times compared with mice transplanted with ERK5 expressing control bone marrows. These findings suggest that atherogenic conditions critically regulate platelet CD36 signaling by increasing superoxide radical anion and hydrogen peroxide through a mechanism that promotes activation of MAPK ERK5.
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http://dx.doi.org/10.1182/blood-2016-11-750133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445574PMC
May 2017

Associations between ambient wood smoke and other particulate pollutants and biomarkers of systemic inflammation, coagulation and thrombosis in cardiac patients.

Environ Res 2017 04 4;154:352-361. Epub 2017 Feb 4.

Department of Public Health Sciences, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, USA; Department of Environmental Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, USA. Electronic address:

Background: Increased particulate air pollution has been associated with both an increased risk of myocardial infarction (MI) and adverse changes in cardiac biomarkers. Up to 30% of ambient wintertime fine particles (PM) in Rochester, NY are from wood burning. Our study examined associations between ambient levels of a marker of wood smoke (Delta-C) and other particulate air pollutants and biomarkers of inflammation, coagulation and thrombosis.

Methods: We measured blood concentrations of C-reactive protein (CRP), D-dimer, fibrinogen, P-selectin, platelet factor 4 (PF-4), von Willebrand factor (vWF), and myeloperoxidase (MPO) of 135 patients undergoing cardiac catheterization during the winters of 2011-2013. We coupled these data with hourly ambient concentrations of Delta-C, black carbon (BC; marker of traffic pollution), and ultrafine (10-100nm; UFP), accumulation mode (100-500nm; AMP), and fine particles (<2.5µm; PM). Using linear regression models, we estimated the change in each biomarker associated with increased pollutant concentrations at intervals between 1 and 96h preceding blood collection.

Results: Each 0.13µg/m increase in Delta-C concentration in the prior 12h was associated with a 0.91% increase in fibrinogen levels (95% CI=0.23%, 1.59%), but unexpectedly in the prior 48h, each 0.17µg/m increase in Delta-C concentration was associated with a 2.75% decrease in MPO levels (95% CI=-5.13%,-0.37%). We did not see associations between Delta-C concentrations and any other biomarkers. Interquartile range (IQR) increases in PM BC, UFP, and AMP concentrations were generally associated with increased CRP and fibrinogen, but not PF4, D-dimer, vWF, or P-selectin.

Conclusions: In a population of cardiac patients, we noted adverse changes in fibrinogen associated with increased concentrations of a marker of wood smoke. Increases in PM, BC, AMP, and UFP concentrations in the previous 96h were also associated with adverse changes in markers of systemic inflammation and coagulation, but not with markers of endothelial cell dysfunction or platelet activation.
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http://dx.doi.org/10.1016/j.envres.2017.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5375102PMC
April 2017

Novel Thrombotic Function of a Human SNP in STXBP5 Revealed by CRISPR/Cas9 Gene Editing in Mice.

Arterioscler Thromb Vasc Biol 2017 Feb 29;37(2):264-270. Epub 2016 Dec 29.

From the Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester Medical Center, NY (Q.M.Z., K.A.K., S.T., M.A.M., C.N.M., J.M.M., C.J.L.); Division of Intramural Research, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, and NHLBI Framingham Heart Study, Framingham, MA (M.-H.C., A.D.J., C.J.O.D.); and Cardiovascular Division, Massachusetts General Hospital, Harvard Medical School, Boston (C.J.O.D.).

Objective: To identify and characterize the effect of a SNP (single-nucleotide polymorphism) in the STXBP5 locus that is associated with altered thrombosis in humans. GWAS (genome-wide association studies) have identified numerous SNPs associated with human thrombotic phenotypes, but determining the functional significance of an individual candidate SNP can be challenging, particularly when in vivo modeling is required. Recent GWAS led to the discovery of STXBP5 as a regulator of platelet secretion in humans. Further clinical studies have identified genetic variants of STXBP5 that are linked to altered plasma von Willebrand factor levels and thrombosis in humans, but the functional significance of these variants in STXBP5 is not understood.

Approach And Results: We used CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated 9) techniques to produce a precise mouse model carrying a human coding SNP rs1039084 (encoding human p. N436S) in the STXBP5 locus associated with decreased thrombosis. Mice carrying the orthologous human mutation (encoding p. N437S in mouse STXBP5) have lower plasma von Willebrand factor levels, decreased thrombosis, and decreased platelet secretion compared with wild-type mice. This thrombosis phenotype recapitulates the phenotype of humans carrying the minor allele of rs1039084. Decreased plasma von Willebrand factor and platelet activation may partially explain the decreased thrombotic phenotype in mutant mice.

Conclusions: Using precise mammalian genome editing, we have identified a human nonsynonymous SNP rs1039084 in the STXBP5 locus as a causal variant for a decreased thrombotic phenotype. CRISPR/Cas9 genetic editing facilitates the rapid and efficient generation of animals to study the function of human genetic variation in vascular diseases.
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http://dx.doi.org/10.1161/ATVBAHA.116.308614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269475PMC
February 2017

A novel TRPV4-specific agonist inhibits monocyte adhesion and atherosclerosis.

Oncotarget 2016 Jun;7(25):37622-37635

Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

TRPV4 ion channel mediates vascular mechanosensitivity and vasodilation. Here, we sought to explore whether non-mechanical activation of TRPV4 could limit vascular inflammation and atherosclerosis. We found that GSK1016790A, a potent and specific small-molecule agonist of TRPV4, induces the phosphorylation and activation of eNOS partially through the AMPK pathway. Moreover, GSK1016790A inhibited TNF-α-induced monocyte adhesion to human endothelial cells. Mice given GSK1016790A showed increased phosphorylation of eNOS and AMPK in the aorta and decreased leukocyte adhesion to TNF-α-inflamed endothelium. Importantly, oral administration of GSK1016790A reduced atherosclerotic plaque formation in ApoE deficient mice fed a Western-type diet. Together, the present study suggests that pharmacological activation of TRPV4 may serve as a potential therapeutic approach to treat atherosclerosis.
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http://dx.doi.org/10.18632/oncotarget.9376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122337PMC
June 2016

Glutamate Receptor Interacting Protein 1 Mediates Platelet Adhesion and Thrombus Formation.

PLoS One 2016 15;11(9):e0160638. Epub 2016 Sep 15.

Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY, United States of America.

Thrombosis-associated pathologies, such as myocardial infarction and stroke, are major causes of morbidity and mortality worldwide. Because platelets are necessary for hemostasis and thrombosis, platelet directed therapies must balance inhibiting platelet function with bleeding risk. Glutamate receptor interacting protein 1 (GRIP1) is a large scaffolding protein that localizes and organizes interacting proteins in other cells, such as neurons. We have investigated the role of GRIP1 in platelet function to determine its role as a molecular scaffold in thrombus formation. Platelet-specific GRIP1-/- mice were used to determine the role of GRIP1 in platelets. GRIP1-/- mice had normal platelet counts, but a prolonged bleeding time and delayed thrombus formation in a FeCl3-induced vessel injury model. In vitro stimulation of WT and GRIP1-/- platelets with multiple agonists showed no difference in platelet activation. However, in vivo platelet rolling velocity after endothelial stimulation was significantly greater in GRIP1-/- platelets compared to WT platelets, indicating a potential platelet adhesion defect. Mass spectrometry analysis of GRIP1 platelet immunoprecipitation revealed enrichment of GRIP1 binding to GPIb-IX complex proteins. Western blots confirmed the mass spectrometry findings that GRIP1 interacts with GPIbα, GPIbβ, and 14-3-3. Additionally, in resting GRIP1-/- platelets, GPIbα and 14-3-3 have increased interaction compared to WT platelets. GRIP1 interactions with the GPIb-IX binding complex are necessary for normal platelet adhesion to a stimulated endothelium.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160638PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025166PMC
August 2017

Role of Axl in T-Lymphocyte Survival in Salt-Dependent Hypertension.

Arterioscler Thromb Vasc Biol 2016 08 30;36(8):1638-1646. Epub 2016 Jun 30.

Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY USA.

Objective: Survival of immune and nonimmune cells relies on Axl, a receptor tyrosine kinase, which is implicated in hypertension. Activated T lymphocytes are involved in regulation of high blood pressure. The goal of the study was to investigate the role of Axl in T-lymphocyte functions and its contribution to salt-dependent hypertension.

Approach And Results: We report increased apoptosis in peripheral blood from Axl(-/-) mice because of lower numbers of white blood cells mostly lymphocytes. In vitro studies showed modest reduction in interferon gamma production in Axl(-/-) type 1 T helper cells. Axl did not affect basic proliferation capacity or production of interleukin 4 in Axl(-/-) type 2 T helper cells. However, competitive repopulation of Axl(-/-) bone marrow or adoptive transfer of Axl(-/-) CD4(+) T cells to Rag1(-/-) mice showed robust effect of Axl on T lymphocyte expansion in vivo. Adoptive transfer of Axl(-/-) CD4(+) T cells was protective in a later phase of deoxycorticosterone-acetate and salt hypertension. Reduced numbers of CD4(+) T cells in circulation and in perivascular adventitia decreased vascular remodeling and increased vascular apoptosis in the late phase of hypertension.

Conclusions: These findings suggest that Axl is critical for survival of T lymphocytes, especially during vascular remodeling in hypertension.
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http://dx.doi.org/10.1161/ATVBAHA.116.307848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096552PMC
August 2016

Novel Antiplatelet Activity of Minocycline Involves Inhibition of MLK3-p38 Mitogen Activated Protein Kinase Axis.

PLoS One 2016 6;11(6):e0157115. Epub 2016 Jun 6.

Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157115PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894566PMC
August 2017

Resveratrol preserves the function of human platelets stored for transfusion.

Br J Haematol 2016 Mar 18;172(5):794-806. Epub 2015 Dec 18.

Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

Stored platelets undergo biochemical, structural and functional changes that lead to decreased efficacy and safety of platelet transfusions. Not only do platelets acquire markers of activation during storage, but they also fail to respond normally to agonists post-storage. We hypothesized that resveratrol, a cardioprotective antioxidant, could act as a novel platelet storage additive to safely prevent unwanted platelet activation during storage, while simultaneously preserving normal haemostatic function. Human platelets treated with resveratrol and stored for 5 d released less thromboxane B2 and prostaglandin E2 compared to control platelets. Resveratrol preserved the ability of platelets to aggregate, spread and respond to thrombin, suggesting an improved ability to activate post-storage. Utilizing an in vitro model of transfusion and thromboelastography, clot strength was improved with resveratrol treatment compared to conventionally stored platelets. The mechanism of resveratrol's beneficial actions on stored platelets was partly mediated through decreased platelet apoptosis in storage, resulting in a longer half-life following transfusion. Lastly, an in vivo mouse model of transfusion demonstrated that stored platelets are prothrombotic and that resveratrol delayed vessel occlusion time to a level similar to transfusion with fresh platelets. We show resveratrol has a dual ability to reduce unwanted platelet activation during storage, while preserving critical haemostatic function.
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http://dx.doi.org/10.1111/bjh.13862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764392PMC
March 2016

A Novel Anti-Inflammatory Effect for High Density Lipoprotein.

PLoS One 2015 17;10(12):e0144372. Epub 2015 Dec 17.

Departments of Medicine, Division of Cardiology, University of Rochester School of Medicine, Box 679, 601 Elmwood Avenue, Rochester, NY, 14652, United States of America.

High density lipoprotein has anti-inflammatory effects in addition to mediating reverse cholesterol transport. While many of the chronic anti-inflammatory effects of high density lipoprotein (HDL) are attributed to changes in cell adhesion molecules, little is known about acute signal transduction events elicited by HDL in endothelial cells. We now show that high density lipoprotein decreases endothelial cell exocytosis, the first step in leukocyte trafficking. ApoA-I, a major apolipoprotein of HDL, mediates inhibition of endothelial cell exocytosis by interacting with endothelial scavenger receptor-BI which triggers an intracellular protective signaling cascade involving protein kinase C (PKC). Other apolipoproteins within the HDL particle have only modest effects upon endothelial exocytosis. Using a human primary culture of endothelial cells and murine apo-AI knockout mice, we show that apo-AI prevents endothelial cell exocytosis which limits leukocyte recruitment. These data suggest that high density lipoprotein may inhibit diseases associated with vascular inflammation in part by blocking endothelial exocytosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144372PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683005PMC
June 2016

Axl modulates immune activation of smooth muscle cells in vein graft remodeling.

Am J Physiol Heart Circ Physiol 2015 Sep 14;309(6):H1048-58. Epub 2015 Aug 14.

Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York; and Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York;

The pathophysiological mechanisms of the immune activation of smooth muscle cells are not well understood. Increased expression of Axl, a receptor tyrosine kinase, was recently found in arteries from patients after coronary bypass grafts. In the present study, we hypothesized that Axl-dependent immune activation of smooth muscle cells regulates vein graft remodeling. We observed a twofold decrease in intimal thickening after vascular and systemic depletion of Axl in vein grafts. Local depletion of Axl had the greatest effect on immune activation, whereas systemic deletion of Axl reduced intima due to an increase in apoptosis in vein grafts. Primary smooth muscle cells isolated from Axl knockout mice had reduced proinflammatory responses by prevention of the STAT1 pathway. The absence of Axl increased suppressor of cytokine signaling (SOCS)1 expression in smooth muscle cells, a major inhibitory protein for STAT1. Ultrasound imaging suggested that vascular depletion of Axl reduced vein graft stiffness. Axl expression determined the STAT1-SOCS1 balance in vein graft intima and progression of the remodeling. The results of this investigation demonstrate that Axl promotes STAT1 signaling via inhibition of SOCS1 in activated smooth muscle cells in vein graft remodeling.
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http://dx.doi.org/10.1152/ajpheart.00495.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591360PMC
September 2015

Platelet Extracellular Regulated Protein Kinase 5 Is a Redox Switch and Triggers Maladaptive Platelet Responses and Myocardial Infarct Expansion.

Circulation 2015 Jul 1;132(1):47-58. Epub 2015 May 1.

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.).

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.

Methods And 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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.015656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532543PMC
July 2015