17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension

dc.contributor.authorLahm, Tim
dc.contributor.authorFrump, Andrea L.
dc.contributor.authorAlbrecht, Marjorie E.
dc.contributor.authorFisher, Amanda J.
dc.contributor.authorCook, Todd G.
dc.contributor.authorJones, Thomas J.
dc.contributor.authorYakubov, Bakhtiyor
dc.contributor.authorWhitson, Jordan
dc.contributor.authorFuchs, Robyn K.
dc.contributor.authorLiu, Aiping
dc.contributor.authorChesler, Naomi C.
dc.contributor.authorBrown, M. Beth
dc.contributor.departmentMedicine, School of Medicineen_US
dc.date.accessioned2018-02-26T21:10:05Z
dc.date.available2018-02-26T21:10:05Z
dc.date.issued2016-08-01
dc.description.abstract17β-Estradiol (E2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 μg·kg−1·day−1) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E2 repletion after OVX markedly improved RV function. E2's effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E2's mechanisms may lead to novel RV-directed therapies.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationLahm, T., Frump, A. L., Albrecht, M. E., Fisher, A. J., Cook, T. G., Jones, T. J., … Brown, M. B. (2016). 17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension. American Journal of Physiology - Lung Cellular and Molecular Physiology, 311(2), L375–L388. https://doi.org/10.1152/ajplung.00132.2016en_US
dc.identifier.issn1040-0605en_US
dc.identifier.urihttps://hdl.handle.net/1805/15282
dc.language.isoen_USen_US
dc.publisherAPS Journalsen_US
dc.relation.isversionof10.1152/ajplung.00132.2016en_US
dc.relation.journalAmerican Journal of Physiology - Lung Cellular and Molecular Physiologyen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectapoptosisen_US
dc.subjectautophagyen_US
dc.subjectendothelial nitric oxide synthaseen_US
dc.subjectfibrosisen_US
dc.subjectsugen/hypoxiaen_US
dc.title17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertensionen_US
dc.typeArticleen_US
ul.alternative.fulltexthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142461/en_US
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