Membrane ERα attenuates myocardial fibrosis via RhoA/ROCK-mediated actin remodeling in ovariectomized female infarcted rats

Tsung-Ming Lee, Shinn Zong Lin, Nen Chung Chang

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

We have demonstrated that long-term 17β-estradiol attenuated fibrosis after myocardial infarction, but recent evidence suggests that estrogen mediates more rapid cellular effects. RhoA has been shown to play a role in the control of myocardial fibrosis by regulating the actin-regulatory protein cofilin. We sought to elucidate whether RhoA activity regulates estradiol-induced fibrosis after infarction in ovariectomized female rats. Twenty-four hours after coronary ligation, female Wistar rats were randomized into control or estradiol treatment for 4 weeks starting from 2 weeks after bilateral ovariectomy. There were similar infarct sizes among the infarcted groups. Myocardial fibrosis was significantly reduced, as measured by hydroxyproline content, Sirius Red staining and actin polymerization after administering estradiol. Estradiol treatment was associated with RhoA/Rho kinase inhibition evidenced by increased phosphorylation of RhoA and decreased phosphorylation of downstream factors including cofilin. Administration of PPT, a specific ERα agonist, or a membrane impermeable estrogen-albumin construct also inhibited cofilin phosphorylation, suggesting that cofilin phosphorylation is achieved through the recruitment of a membrane ERα. The ERβ-selective agonist, DPN, did not alter cofilin phosphorylation levels, but the ER antagonist, ICI 182,780 increased cofilin phosphorylation levels. G-15 (an inhibitor of G-protein coupled estrogen receptor) did not affect the phosphorylation as compared with estradiol alone. The inhibitor of Rho kinase, Y-27632, attenuated cofilin phosphorylation levels, similar to the effect produced by estradiol. These results indicate that chronic use of estradiol after infarction attenuates cardiac fibrosis by inhibiting RhoA/ROCK/cofilin pathway, which is exerted through membrane ERα-mediated receptor mechanism. Key Message: Postinfarction was associated with increased cardiac fibrosis. Myocardial fibrosis was significantly reduced after administering estradiol (E2). Administration of the membrane ERα agonist PPT or E2-BSA inhibited cofilin phosphorylation. Combination of E2 and Y-27632 did not enhance the attenuation of cofilin phosphorylation. Chronic use of E2 attenuated cardiac fibrosis by inhibiting the RhoA/ROCK/cofilin pathway via ERα.

Original languageEnglish
Pages (from-to)43-51
Number of pages9
JournalJournal of Molecular Medicine
Volume92
Issue number1
DOIs
Publication statusPublished - Jan 2014

Fingerprint

Actin Depolymerizing Factors
Actins
Fibrosis
Estradiol
Phosphorylation
Membranes
rho-Associated Kinases
Infarction
Estrogens
Hydroxyproline
Ovariectomy
G-Protein-Coupled Receptors
Polymerization
Estrogen Receptors
NAD
Ligation
Wistar Rats
Albumins

Keywords

  • Cofilin
  • Estrogen receptor
  • Fibrosis
  • Myocardial infarction
  • RhoA/ROCK

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Membrane ERα attenuates myocardial fibrosis via RhoA/ROCK-mediated actin remodeling in ovariectomized female infarcted rats. / Lee, Tsung-Ming; Lin, Shinn Zong; Chang, Nen Chung.

In: Journal of Molecular Medicine, Vol. 92, No. 1, 01.2014, p. 43-51.

Research output: Contribution to journalArticle

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N2 - We have demonstrated that long-term 17β-estradiol attenuated fibrosis after myocardial infarction, but recent evidence suggests that estrogen mediates more rapid cellular effects. RhoA has been shown to play a role in the control of myocardial fibrosis by regulating the actin-regulatory protein cofilin. We sought to elucidate whether RhoA activity regulates estradiol-induced fibrosis after infarction in ovariectomized female rats. Twenty-four hours after coronary ligation, female Wistar rats were randomized into control or estradiol treatment for 4 weeks starting from 2 weeks after bilateral ovariectomy. There were similar infarct sizes among the infarcted groups. Myocardial fibrosis was significantly reduced, as measured by hydroxyproline content, Sirius Red staining and actin polymerization after administering estradiol. Estradiol treatment was associated with RhoA/Rho kinase inhibition evidenced by increased phosphorylation of RhoA and decreased phosphorylation of downstream factors including cofilin. Administration of PPT, a specific ERα agonist, or a membrane impermeable estrogen-albumin construct also inhibited cofilin phosphorylation, suggesting that cofilin phosphorylation is achieved through the recruitment of a membrane ERα. The ERβ-selective agonist, DPN, did not alter cofilin phosphorylation levels, but the ER antagonist, ICI 182,780 increased cofilin phosphorylation levels. G-15 (an inhibitor of G-protein coupled estrogen receptor) did not affect the phosphorylation as compared with estradiol alone. The inhibitor of Rho kinase, Y-27632, attenuated cofilin phosphorylation levels, similar to the effect produced by estradiol. These results indicate that chronic use of estradiol after infarction attenuates cardiac fibrosis by inhibiting RhoA/ROCK/cofilin pathway, which is exerted through membrane ERα-mediated receptor mechanism. Key Message: Postinfarction was associated with increased cardiac fibrosis. Myocardial fibrosis was significantly reduced after administering estradiol (E2). Administration of the membrane ERα agonist PPT or E2-BSA inhibited cofilin phosphorylation. Combination of E2 and Y-27632 did not enhance the attenuation of cofilin phosphorylation. Chronic use of E2 attenuated cardiac fibrosis by inhibiting the RhoA/ROCK/cofilin pathway via ERα.

AB - We have demonstrated that long-term 17β-estradiol attenuated fibrosis after myocardial infarction, but recent evidence suggests that estrogen mediates more rapid cellular effects. RhoA has been shown to play a role in the control of myocardial fibrosis by regulating the actin-regulatory protein cofilin. We sought to elucidate whether RhoA activity regulates estradiol-induced fibrosis after infarction in ovariectomized female rats. Twenty-four hours after coronary ligation, female Wistar rats were randomized into control or estradiol treatment for 4 weeks starting from 2 weeks after bilateral ovariectomy. There were similar infarct sizes among the infarcted groups. Myocardial fibrosis was significantly reduced, as measured by hydroxyproline content, Sirius Red staining and actin polymerization after administering estradiol. Estradiol treatment was associated with RhoA/Rho kinase inhibition evidenced by increased phosphorylation of RhoA and decreased phosphorylation of downstream factors including cofilin. Administration of PPT, a specific ERα agonist, or a membrane impermeable estrogen-albumin construct also inhibited cofilin phosphorylation, suggesting that cofilin phosphorylation is achieved through the recruitment of a membrane ERα. The ERβ-selective agonist, DPN, did not alter cofilin phosphorylation levels, but the ER antagonist, ICI 182,780 increased cofilin phosphorylation levels. G-15 (an inhibitor of G-protein coupled estrogen receptor) did not affect the phosphorylation as compared with estradiol alone. The inhibitor of Rho kinase, Y-27632, attenuated cofilin phosphorylation levels, similar to the effect produced by estradiol. These results indicate that chronic use of estradiol after infarction attenuates cardiac fibrosis by inhibiting RhoA/ROCK/cofilin pathway, which is exerted through membrane ERα-mediated receptor mechanism. Key Message: Postinfarction was associated with increased cardiac fibrosis. Myocardial fibrosis was significantly reduced after administering estradiol (E2). Administration of the membrane ERα agonist PPT or E2-BSA inhibited cofilin phosphorylation. Combination of E2 and Y-27632 did not enhance the attenuation of cofilin phosphorylation. Chronic use of E2 attenuated cardiac fibrosis by inhibiting the RhoA/ROCK/cofilin pathway via ERα.

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