Cheng 2020 Am J Physiol Heart Circ Physiol

From Bioblast
Publications in the MiPMap
Cheng TC, Philip JL, Tabima DM, Kumari S, Yakubov B, Frump AL, Hacker TA, Bellofiore A, Li R, Sun X, Goss KN, Lahm T, Chesler N (2020) Estrogen receptor alpha prevents right ventricular diastolic dysfunction and fibrosis in female rats . Am J Physiol Heart Circ Physiol 319:H1459-73.

ยป PMID: 33064565 Open Access

Cheng Tik-Chee, Philip Jennifer L, Tabima Diana Marcela, Kumari Santosh, Yakubov Bakhtiyor, Frump Andrea L, Hacker Timothy A, Bellofiore Alessandro, Li Rongbo, Sun Xin, Goss Kara N, Lahm Tim, Chesler Naomi (2020) Am J Physiol Heart Circ Physiol

Abstract: While women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Estrogen receptor alpha (ERฮฑ) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ERฮฑ in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERฮฑ removes female protection from adverse remodeling and is permissive for development of a maladapted RV phenotype. Male and female rats with a loss-of-function mutation in ERฮฑ (ERฮฑMut) and wildtype (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 weeks post-PAB, WT and ERฮฑMut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ERฮฑMut PAB rats. Similarly, female, but not male, ERฮฑMut 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 ERฮฑMut compared to WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ERฮฑMut RV revealed Kallikrein related-peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ERฮฑ in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERฮฑ appears to be dispensable for RV adaptation in males. ERฮฑ may be a mediator of superior RV adaptation in female patients with PAH. โ€ข Keywords: Adverse Remodeling, Estrogen receptor alpha, Pressure overload, Right ventricle โ€ข Bioblast editor: Plangger M โ€ข O2k-Network Lab: US NC Durham Li PA

Labels: MiParea: Respiration, Genetic knockout;overexpression, Gender  Pathology: Cardiovascular 

Organism: Rat  Tissue;cell: Heart  Preparation: Permeabilized tissue 

Coupling state: LEAK, OXPHOS  Pathway: N, S, CIV, ROX  HRR: Oxygraph-2k 


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