PT  - JOURNAL ARTICLE
AU  - Vishnu Chintalgattu
AU  - Laxmansa C. Katwa
TI  - Role of Protein Kinase Cδ in Endothelin-Induced Type I Collagen Expression in Cardiac Myofibroblasts Isolated from the Site of Myocardial Infarction
AID  - 10.1124/jpet.104.070151
DP  - 2004 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 691--699
VI  - 311
IP  - 2
4099  - http://jpet.aspetjournals.org/content/311/2/691.short
4100  - http://jpet.aspetjournals.org/content/311/2/691.full
SO  - J Pharmacol Exp Ther2004 Nov 01; 311
AB  - 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 Cδ (PKCδ) 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 PKCα, PKCβI, PKCβII, PKCγ, PKCδ, PKCϵ, PKCη, and PKCζ 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 PKCδ 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 (PKCα and PKCβI), 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 PKCδ and MAPK in ET-induced type I collagen expression in cardiac myoFb. The American Society for Pharmacology and Experimental Therapeutics