Estrogen maintains mitochondrial content and function in the right ventricle of rats with pulmonary hypertension.
The typical cause of death in pulmonary hypertension (PH) is right ventricular (RV) failure, with females showing better survival rates than males. Recently, metabolic shift and mitochondrial dysfunction have been demonstrated in RV failure secondary to PH In light of evidence showing that estrogen protects mitochondrial function and biogenesis in noncardiovascular systems, we hypothesized that the mechanism by which estrogen preserves RV function is via protection of mitochondrial content and oxidative capacity in PH We used a well-established model of PH (Sugen+Hypoxia) in ovariectomized female rats with/without estrogen treatment. RV functional measures were derived from pressure-volume relationships measured via RV catheterization in live rats. Citrate synthase activity, a marker of mitochondrial density, was measured in both RV and LV tissues. Respiratory capacity of mitochondria isolated from RV was measured using oxygraphy. We found that RV ventricular-vascular coupling efficiency decreased in the placebo-treated SuHx rats (0.78 ± 0.10 vs. 1.50 ± 0.13 in control,P< 0.05), whereas estrogen restored it. Mitochondrial density decreased in placebo-treated SuHx rats (0.12 ± 0.01 vs. 0.15 ± 0.01 U citrate synthase/mg in control,P< 0.05), and estrogen attenuated the decrease. Mitochondrial quality and oxidative capacity tended to be lower in placebo-treated SuHx rats only. The changes in mitochondrial biogenesis and function paralleled the expression levels of PGC-1αin RV Our results suggest that estrogen protects RV function by preserving mitochondrial content and oxidative capacity. This provides a mechanism by which estrogen provides protection in female PH patients and paves the way to develop estrogen and its targets as a novel RV-specific therapy for PH.
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin.
Aiping
A
Liu
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin.
Jennifer
J
Philip
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
Kalyan C
KC
Vinnakota
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
Francoise
F
Van den Bergh
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin.
Diana M
DM
Tabima
Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Timothy
T
Hacker
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
Daniel A
DA
Beard
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin naomi.chesler@wisc.edu.|Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Naomi C
NC
Chesler
D000818:Animals; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D001678:Organelle Biogenesis; D010052:Ovariectomy; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D016278:Ventricular Function, Right / Q000187:drug effects / Q000502:physiology*
D004958:Estradiol
Cardiopulmonary hemodynamics; mitochondria; sex differences