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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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

Title: Distinct Regulation of Cardiac Fibroblast Proliferation and Transdifferentiation by Classical and Novel Protein Kinase C Isoforms : Possible Implications for New Antifibrotic Therapies
Author: Karhu, S. Tuuli; Ruskoaho, Heikki; Talman, Virpi
Other contributor: University of Helsinki, Regenerative cardiac pharmacology
University of Helsinki, Regenerative pharmacology group
University of Helsinki, Division of Pharmacology and Pharmacotherapy




Date: 2021-02-01
Language: eng
Number of pages: 10
Belongs to series: Molecular pharmacology : an international journal
ISSN: 0026-895X
DOI: https://doi.org/10.1124/molpharm.120.000094
URI: http://hdl.handle.net/10138/325633
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.
Subject: 317 Pharmacy
PKC-ALPHA
PHARMACOLOGICAL INHIBITION
MYOCARDIAL-INFARCTION
HEART-FAILURE
DOMAIN
EXPRESSION
FIBROSIS
EPSILON
DIFFERENTIATION
DYSFUNCTION
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