cAMP-induced actin cytoskeleton remodelling inhibits MKL1-dependent expression of the chemotactic and pro-proliferative factor, CCN1.

Journal article

Duggirala, A., Kimura TE, Sala-Newby GB, Johnson JL, Wu YJ, Newby AC and Bond M 2014. cAMP-induced actin cytoskeleton remodelling inhibits MKL1-dependent expression of the chemotactic and pro-proliferative factor, CCN1. Journal of molecular and cellular cardiology. Vol 79 (Feb 2015), pp. 157 - 168. https://doi.org/10.1016/j.yjmcc.2014.11.012
AuthorsDuggirala, A., Kimura TE, Sala-Newby GB, Johnson JL, Wu YJ, Newby AC and Bond M
Abstract

Elevation of intracellular cAMP concentration has numerous vascular protective effects that are in part mediated via actin cytoskeleton-remodelling and subsequent regulation of gene expression. However, the mechanisms are incompletely understood. Here we investigated whether cAMP-induced actin-cytoskeleton remodelling modulates VSMC behaviour by inhibiting expression of CCN1. In cultured rat VSMC, CCN1-silencing significantly inhibited BrdU incorporation and migration in a wound healing assay. Recombinant CCN1 enhanced chemotaxis in a Boyden chamber. Adding db-cAMP, or elevating cAMP using forskolin, significantly inhibited CCN1 mRNA and protein expression in vitro; transcriptional regulation was demonstrated by measuring pre-spliced CCN1 mRNA and CCN1-promoter activity. Forskolin also inhibited CCN1 expression in balloon injured rat carotid arteries in vivo. Inhibiting RhoA activity, which regulates actin-polymerisation, by cAMP-elevation or pharmacologically with C3-transferase, or inhibiting its downstream kinase, ROCK, with Y27632, significantly inhibited CCN1 expression. Conversely, expression of constitutively active RhoA reversed the inhibitory effects of forskolin on CCN1 mRNA. Furthermore, CCN1 mRNA levels were significantly decreased by inhibiting actin-polymerisation with latrunculin B or increased by stimulating actin-polymerisation with Jasplakinolide. We next tested the role of the actin-dependent SRF co-factor, MKL1, in CCN1 expression. Forskolin inhibited nuclear translocation of MKL1 and binding of MKL1 to the CCN1 promoter. Constitutively-active MKL1 enhanced basal promoter activity of wild-type but not SRE-mutated CCN1; and prevented forskolin inhibition. Furthermore, pharmacological MKL-inhibition with CCG-1423 significantly inhibited CCN1 promoter activity as well as mRNA and protein expression. Our data demonstrates that cAMP-induced actin-cytoskeleton remodelling regulates expression of CCN1 through MKL1: it highlights a novel cAMP-dependent mechanism controlling VSMC behaviour.

Keywords3'-5'-Cyclic adenosine monophosphate; CAMP; CCN1; Cyr61; MKL1; VSMC
Year2014
JournalJournal of molecular and cellular cardiology
Journal citationVol 79 (Feb 2015), pp. 157 - 168
PublisherElseiver
ISSN0022-2828
1095-8584
Digital Object Identifier (DOI)https://doi.org/10.1016/j.yjmcc.2014.11.012
Web address (URL)https://europepmc.org/articles/PMC4312355
https://www.sciencedirect.com/science/article/pii/S0022282814003721?via%3Dihub
https://www.scopus.com/record/display.uri?eid=2-s2.0-84913569105&origin=resultslist&sort=plf-f&src=s&st1=cAMP-induced+actin+cytoskeleton+remodelling+inhibits+MKL1-dependent+expression+of+the+chemotactic+and+pro-proliferative+factor%2cCCN1.&sid=12960913e1f09183bffa7e7725b97ff6&sot=b&sdt=b&sl=148&s=TITLE-ABS-KEY%28cAMP-induced+actin+cytoskeleton+remodelling+inhibits+MKL1-dependent+expression+of+the+chemotactic+and+pro-proliferative+factor%2c+CCN1.%29&relpos=0&citeCnt=10&searchTerm=
https://pubmed.ncbi.nlm.nih.gov/25446180/
Output statusPublished
Publication dates
Online18 Nov 2014
Feb 2015
Publication process dates
Accepted12 Nov 2014
Deposited08 Jun 2023
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https://repository.derby.ac.uk/item/9z274/camp-induced-actin-cytoskeleton-remodelling-inhibits-mkl1-dependent-expression-of-the-chemotactic-and-pro-proliferative-factor-ccn1

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