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November 26, 2020Työväentutkimus VuosikirjaOpen Access

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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Key result

A 48-hour exposure to the PKC activator PMA reduced α-smooth muscle actin staining by 56% and periostin mRNA levels by 60% compared with control in primary adult mouse cardiac fibroblasts.

Why the study?

Although protein kinase C (PKC) isoforms play a role in cardiac fibrosis, results are conflicting and the potential of targeting PKC pharmacologically to inhibit pathologic fibrosis has not been fully evaluated.

Population

Primary adult mouse cardiac fibroblasts

Comparison

Selected PKC agonists and inhibitors vs control

Design

In vitro preclinical laboratory study

Follow-up

48 hours

Authors

SKS. Tuuli KarhuUniversity of HelsinkiHRHeikki RuskoahoHeart Failure & TransplantVTVirpi TalmanUniversity of Helsinki

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Implication

Attenuates cardiac fibroblast activation in vitro; hypothesis-generating for PKC agonists in fibrosis.

Key Points

  • The study aims to explore how different protein kinase C isoforms regulate cardiac fibroblast behavior, particularly transdifferentiation and proliferation.
  • Utilized primary adult mouse cardiac fibroblasts in culture to assess the effects of PKC agonists and inhibitors on phenotype and gene expression.
  • Applied phorbol 12-myristate 13-acetate (PMA) and various PKC inhibitors to gauge changes in cell behavior and matrix synthesis.
  • Measured alterations in cell proliferation and expression of collagen-encoding genes via specific molecular techniques.
  • PMA reduced α-smooth muscle actin staining by 56% and periostin mRNA levels by 60%, indicating reduced transdifferentiation of cardiac fibroblasts (CFs).
  • 5-bromo-2’-deoxyuridine-positive CFs decreased by 33% with PMA, regulated distinctly by novel PKC isoforms for proliferation.
  • PMA downregulated collagen-encoding genes Col1a1 and Col3a1, demonstrating that PKC activation attenuates extracellular matrix synthesis.

Structured PICO

P
Population
In vitro study using primary adult mouse cardiac fibroblasts to investigate the effects of PKC agonists and inhibitors on fibrosis.
I
Intervention
PKC activator phorbol 12-myristate 13-acetate (PMA) at 10 nM, and partial PKC agonist bis(1-ethylpentyl) 5-(hydroxymethyl)isophthalate, with or without PKC inhibitors (Gö6983, Gö6976)
C
Comparator
Control
O
Outcome
Cardiac fibroblast phenotype (α-smooth muscle actin staining), proliferation (BrdU-positive cells), and gene expression (periostin, Col1a1, Col3a1)surrogate

Classical and novel protein kinase C (PKC) isoforms distinctly regulate cardiac fibroblast transdifferentiation and proliferation, suggesting PKC agonists may have potential as antifibrotic therapies.

Cite This Study

Karhu et al. (2020) studied Cardiac fibrosis. Phorbol 12-myristate 13-acetate (PMA) vs. Control was evaluated on α-smooth muscle actin staining intensity and periostin mRNA levels. A 48-hour exposure to the PKC activator PMA reduced α-smooth muscle actin staining by 56% and periostin mRNA levels by 60% compared with control in primary adult mouse cardiac fibroblasts.

synapsesocial.com/papers/6a61bacb5d85cff801c92129https://doi.org/10.1124/molpharm.120.000094
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