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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:699.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Protein Kinase C Differentially Regulates Platelet Functional Responses

Ramya Chari; Todd Getz; Bela Nagy, Jr; Kamala Bhavaraju; Yingying Mao; Yamini Saraswathy Bynagari; Swaminathan Murugappan; Keiko Nakayama; Satya P. Kunapuli

From the Department of Physiology (R.C., T.G., B.N., K.B., Y.M., Y.S.B., S.M., S.P.K.), Pharmacology (S.P.K.), and the Sol Sherry Thrombosis Research Center (S.M., S.P.K.), Temple University School of Medicine, Philadelphia, Pa; and the Division of Developmental Genetics (K.N.), Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Correspondence to Satya P. Kunapuli, PhD, Department of Physiology, Temple University Medical School, Rm 217 MRB, 3420 N Broad Street, Philadelphia, PA 19140. E-mail spk{at}temple.edu

Objective— Protein Kinase C delta (PKC) is expressed in platelets and activated downstream of protease-activated receptors (PAR)s and glycoprotein VI (GPVI) receptors. The purpose of this study was to investigate the role of PKC in platelets.

Methods and Results— We evaluated the role of PKC in platelets using two approaches—pharmacological and molecular genetic approach. In human platelets pretreated with isoform selective antagonistic RACK peptide ( V1-1)TAT, and in the murine platelets lacking PKC, PAR4-mediated dense granule secretion was inhibited, whereas GPVI-mediated dense granule secretion was potentiated. These effects were statistically significant in the absence and presence of thromboxane A₂ (TXA₂). Furthermore, TXA₂ generation was differentially regulated by PKC. However, PKC had a small effect on platelet P-selectin expression. Calcium- and PKC-dependent pathways independently activate fibrinogen receptor in platelets. When calcium pathways are blocked by dimethyl-BAPTA, AYPGKF-induced aggregation in PKC null mouse platelets and in human platelets pretreated with ( V1-1)TAT, was inhibited. In a FeCl₃-induced injury in vivo thrombosis model, PKC^–/– mice occluded similar to their wild-type littermates.

Conclusions— Hence, we conclude that PKC differentially regulates platelet functional responses such as dense granule secretion and TXA₂ generation downstream of PARs and GPVI receptors, but PKC deficiency does not affect the thrombus formation in vivo.

These studies using pharmacological inhibitors as well as knockout mice show that PKC differentially regulates PAR- and GPVI-mediated dense granule secretion and TXA₂ generation. However, in a murine model of FeCl₃-induced carotid artery injury model, lack of PKC did not affect thrombus formation in vivo

Key Words: platelets • thrombosis • protein kinase C • fibrinogen • secretion

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