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CARDIOVASCULAR

Role of Protein Kinase C in Endothelin-Induced Type I Collagen Expression in Cardiac Myofibroblasts Isolated from the Site of Myocardial Infarction

Department of Physiology, the Brody School of Medicine, East Carolina University, Greenville, North Carolina

The role of endothelin-1 (ET) in tissue remodeling/fibrogenesis has been demonstrated in various in vitro and in vivo models. Our previous studies have revealed ET-induced expression of type I collagen in cardiac myofibroblasts (myoFb). Here we report that protein kinase C (PKC) and mitogen-activated protein kinase/extracellular signal-regulated kinase-1/2 (MAPK/ERK1/2) play a role in ET-induced type I collagen expression using specific pharmacological inhibitors. The present study also reveals the expression of various isoforms of PKC including PKC, PKCI, PKCII, PKC, PKC, PKC, PKC, and PKC in cardiac myoFb. Our results from mRNA and protein studies demonstrate that calphostin-C, a PKC inhibitor, decreased the ET-induced type I collagen expression suggesting a role for the PKC pathway. Further treatment with rottlerin, a PKC isoform-specific inhibitor, demonstrated attenuation of 80 to 90% of type I collagen expression induced by ET. However, Go6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo [3,4-c]carbazole]], an inhibitor of Ca²⁺-dependent PKC isoforms (PKC and PKCI), showed little to no effect on ET-stimulated type I collagen expression. Furthermore, the MAPK inhibitor PD98059 (2'-amino-3'-methoxyflavone) attenuated ET-dependent activation of p44/42 MAPK (pERK1/2) and also down-regulated type I collagen expression. Similarly, rottlerin inhibited the activation of p44/42 MAPK (pERK) implicating the involvement of PKC and MAPK/ERK1/2 in ET-induced type I collagen expression. Our protein/DNA array and reverse transcription-polymerase chain reaction results from ET-treated samples showed a significant increase in Sp1 expression. PD98059 and rottlerin decreased ET-induced Sp1 expression, suggesting a possible interaction of Sp1 with PKC and MAPK in ET-induced type I collagen expression in cardiac myoFb.

Address correspondence to: Dr. Laxmansa C. Katwa, Department of Physiology, 6N-98, Brody Medical Sciences Bldg., East Carolina University Brody School of Medicine, 600 Moye Blvd., Greenville, NC 27834. E-mail: katwal{at}mail.ecu.edu

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