Pressure overload inhibits glucocorticoid receptor transcriptional activity in cardiomyocytes and promotes pathological cardiac hypertrophy

Tomohiro Matsuhashi, Jin Endo, Yoshinori Katsumata, Tsunehisa Yamamoto, Noriaki Shimizu, Noritada Yoshikawa, Masaharu Kataoka, Sarasa Isobe, Hidenori Moriyama, Shinichi Goto, Keiichi Fukuda, Hirotoshi Tanaka, Motoaki Sano

Research output: Contribution to journalArticle

Abstract

Glucocorticoid receptor (GR) is abundantly expressed in cardiomyocytes. However, the role of GR in regulating cardiac hypertrophy and heart failure in response to pressure overload remains unclear. Cardiomyocyte-specific GR knockout (GRcKO) mice, mineralocorticoid receptor (MR) knockout (MRcKO), and GR and MR double KO (GRMRdcKO) mice were generated using the Cre-lox system. In response to pressure overload, GRcKO mice displayed worse cardiac remodeling compared to control (GR f/f ) mice, including a greater increase in heart weight to body weight ratio with a greater increase in cardiomyocytes size, a greater decline in left ventricular contractility, and higher reactivation of fetal genes. MRcKO mice showed a comparable degree of cardiac remodeling compared to control (MR f/f ) mice. The worse cardiac remodeling in pressure overloaded GRcKO mice is not due to compensatory activation of cardiomyocyte MR, since pressure overloaded GRMRdcKO mice displayed cardiac remodeling to the same extent as GRcKO mice. Pressure overload suppressed GR-target gene expression in the heart. Although plasma corticosterone levels and subcellular localization of GR (nuclear/cytoplasmic GR) were not changed, a chromatin immunoprecipitation assay revealed that GR recruitment onto the promoter of GR-target genes was significantly suppressed in response to pressure overload. Rescue of the expression of GR-target genes to the same extent as sham-operated hearts attenuated adverse cardiac remodeling in pressure-overloaded hearts. Thus, GR works as a repressor of adverse cardiac remodeling in response to pressure overload, but GR-mediated transcription is suppressed under pressure overload. Therapies that maintain GR-mediated transcription in cardiomyocytes under pressure overload can be a promising therapeutic strategy for heart failure.

Original languageEnglish
Pages (from-to)122-130
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume130
DOIs
Publication statusPublished - 2019 May 1

Fingerprint

Glucocorticoid Receptors
Cardiomegaly
Cardiac Myocytes
Pressure
Mineralocorticoid Receptors
Knockout Mice
Heart Failure
Genes
Chromatin Immunoprecipitation
Cytoplasmic and Nuclear Receptors
Corticosterone

Keywords

  • Cardiac hypertrophy
  • Glucocorticoid receptor
  • Heart failure
  • KLF15
  • Mineral corticoid receptor
  • mTORC1

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Pressure overload inhibits glucocorticoid receptor transcriptional activity in cardiomyocytes and promotes pathological cardiac hypertrophy. / Matsuhashi, Tomohiro; Endo, Jin; Katsumata, Yoshinori; Yamamoto, Tsunehisa; Shimizu, Noriaki; Yoshikawa, Noritada; Kataoka, Masaharu; Isobe, Sarasa; Moriyama, Hidenori; Goto, Shinichi; Fukuda, Keiichi; Tanaka, Hirotoshi; Sano, Motoaki.

In: Journal of Molecular and Cellular Cardiology, Vol. 130, 01.05.2019, p. 122-130.

Research output: Contribution to journalArticle

Matsuhashi, Tomohiro ; Endo, Jin ; Katsumata, Yoshinori ; Yamamoto, Tsunehisa ; Shimizu, Noriaki ; Yoshikawa, Noritada ; Kataoka, Masaharu ; Isobe, Sarasa ; Moriyama, Hidenori ; Goto, Shinichi ; Fukuda, Keiichi ; Tanaka, Hirotoshi ; Sano, Motoaki. / Pressure overload inhibits glucocorticoid receptor transcriptional activity in cardiomyocytes and promotes pathological cardiac hypertrophy. In: Journal of Molecular and Cellular Cardiology. 2019 ; Vol. 130. pp. 122-130.
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