Distinct Regulation of Cardiac Fibroblast Proliferation and Transdifferentiation by Classical and Novel Protein Kinase C Isoforms : Possible Implications for New Antifibrotic Therapies

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dc.contributor.author Karhu, S. Tuuli
dc.contributor.author Ruskoaho, Heikki
dc.contributor.author Talman, Virpi
dc.date.accessioned 2021-02-02T07:22:01Z
dc.date.available 2021-02-02T07:22:01Z
dc.date.issued 2021-02-01
dc.identifier.citation Karhu , S T , Ruskoaho , H & Talman , V 2021 , ' Distinct Regulation of Cardiac Fibroblast Proliferation and Transdifferentiation by Classical and Novel Protein Kinase C Isoforms : Possible Implications for New Antifibrotic Therapies ' , Molecular pharmacology : an international journal , vol. 99 , no. 2 , pp. 104-113 . https://doi.org/10.1124/molpharm.120.000094
dc.identifier.other PURE: 159246477
dc.identifier.other PURE UUID: 488306b6-d845-4162-ac12-be00b8ef5aba
dc.identifier.other WOS: 000607847300002
dc.identifier.other ORCID: /0000-0002-2702-6505/work/88203142
dc.identifier.other ORCID: /0000-0001-8971-1359/work/88207918
dc.identifier.other ORCID: /0000-0001-8172-485X/work/88208818
dc.identifier.uri http://hdl.handle.net/10138/325633
dc.description.abstract Cardiac fibrosis is characterized by accumulation and activation of fibroblasts and excessive production of extracellular matrix, which results in myocardial stiffening and eventually leads to heart failure. Although previous work suggests that protein kinase C (PKC) isoforms play a role in cardiac fibrosis and remodeling, the results are conflicting. Moreover, the potential of targeting PKC with pharmacological tools to inhibit pathologic fibrosis has not been fully evaluated. Here we investigated the effects of selected PKC agonists and inhibitors on cardiac fibroblast (CF) phenotype, proliferation, and gene expression using primary adult mouse CFs, which spontaneously transdifferentiate into myofibroblasts in culture. A 48-hour exposure to the potent PKC activator phorbol 12-myristate 13-acetate (PMA) at 10 nM concentration reduced the intensity of a-smooth muscle actin staining by 56% and periostin mRNA levels by 60% compared with control. The decreases were inhibited with the pan-PKC inhibitor Gö6983 and the inhibitor of classical PKC isoforms Gö6976, suggesting that classical PKCs regulate CF transdifferentiation. PMA also induced a 33% decrease in 5-bromo-2’-deoxyuridine–positive CFs, which was inhibited with Gö6983 but not with Gö6976, indicating that novel PKC isoforms (nPKCs) regulate CF proliferation. Moreover, PMA downregulated the expression of collagen-encoding genes Col1a1 and Col3a1 nPKC-dependently, showing that PKC activation attenuates matrix synthesis in CFs. The partial PKC agonist isophthalate derivative bis(1-ethylpentyl) 5-(hydroxymethyl)isophthalate induced parallel changes in phenotype, cell cycle activity, and gene expression. In conclusion, our results reveal distinct PKC-dependent regulation of CF transdifferentiation and proliferation and suggest that PKC agonists exhibit potential as an antifibrotic treatment. en
dc.format.extent 10
dc.language.iso eng
dc.relation.ispartof Molecular pharmacology : an international journal
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject 317 Pharmacy
dc.subject PKC-ALPHA
dc.subject PHARMACOLOGICAL INHIBITION
dc.subject MYOCARDIAL-INFARCTION
dc.subject HEART-FAILURE
dc.subject DOMAIN
dc.subject EXPRESSION
dc.subject FIBROSIS
dc.subject EPSILON
dc.subject DIFFERENTIATION
dc.subject DYSFUNCTION
dc.title Distinct Regulation of Cardiac Fibroblast Proliferation and Transdifferentiation by Classical and Novel Protein Kinase C Isoforms : Possible Implications for New Antifibrotic Therapies en
dc.type Article
dc.contributor.organization Regenerative cardiac pharmacology
dc.contributor.organization Division of Pharmacology and Pharmacotherapy
dc.contributor.organization Drug Research Program
dc.contributor.organization Regenerative pharmacology group
dc.contributor.organization Divisions of Faculty of Pharmacy
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1124/molpharm.120.000094
dc.relation.issn 0026-895X
dc.rights.accesslevel openAccess
dc.type.version acceptedVersion
dc.type.version publishedVersion

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