Estrogen receptor-a prevents right ventricular diastolic dysfunction and fibrosis in female rats

Tik Chee Cheng, Jennifer L. Philip, Diana M. Tabima, Santosh Kumari, Bakhtiyor Yakubov, Andrea L. Frump, Timothy A. Hacker, Alessandro Bellofiore, Rongbo Li, Xin Sun, Kara N. Goss, Tim Lahm, Naomi C. Chesler

Research output: Contribution to journalArticlepeer-review

Abstract

Although women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Estrogen receptor-a (ERa) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ERa in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERa removes female protection from adverse remodeling and is permissive for the development of a maladapted RV phenotype. Male and female rats with a loss-of-function mutation in ERa (ERaMut) and wild-type (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 wk post-PAB, WT and ERaMut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ERaMut PAB rats. Similarly, female, but not male, ERaMut exhibited increased RV fibrosis, comprised primarily of thick collagen fibers. There was an increased protein expression ratio of TIMP metallopeptidase inhibitor 1 (Timp1) to matrix metalloproteinase 9 (Mmp9) in female ERaMut compared with WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ERaMut RV revealed kallikrein-related peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ERa in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERa appears to be dispensable for RV adaptation in males. ERa may be a mediator of superior RV adaptation in female patients with PAH.

Original languageEnglish (US)
Pages (from-to)H1459-H1473
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume319
Issue number6
DOIs
StatePublished - Oct 2020
Externally publishedYes

Keywords

  • Adverse remodeling
  • Estrogen receptor-a
  • Pressure overload
  • Right ventricle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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