Cheng 2020 Am J Physiol Heart Circ Physiol
|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 [Epub ahead of print].|
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 (ERα) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ERα in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERα 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 ERα (ERαMut) and wildtype (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 weeks post-PAB, WT and ERαMut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ERαMut PAB rats. Similarly, female, but not male, ERαMut 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 ERαMut compared to WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ERαMut RV revealed Kallikrein related-peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ERα in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERα appears to be dispensable for RV adaptation in males. ERα may be a mediator of superior RV adaptation in female patients with PAH.
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