title: Dehydroepiandrosterone restores right ventricular structure and function in rats with severe pulmonary arterial hypertension.
abstract: Current therapy of pulmonary arterial hypertension (PAH) is inadequate. Dehydroepiandrosterone (DHEA) effectively treats experimental pulmonary hypertension in chronically hypoxic and monocrotaline-injected rats. Contrary to these animal models, SU5416/hypoxia/normoxia-exposed rats develop a more severe form of occlusive pulmonary arteriopathy and right ventricular (RV) dysfunction that is indistinguishable from the human disorder. Thus, we tested the effects of DHEA treatment on PAH and RV structure and function in this model. Chronic (5 wk) DHEA treatment significantly, but moderately, reduced the severely elevated RV systolic pressure. In contrast, it restored the impaired cardiac index to normal levels, resulting in an improved cardiac function, as assessed by echocardiography. Moreover, DHEA treatment inhibited RV capillary rarefaction, apoptosis, fibrosis, and oxidative stress. The steroid decreased NADPH levels in the RV. As a result, the reduced reactive oxygen species production in the RV of these rats was reversed by NADPH supplementation. Mechanistically, DHEA reduced the expression and activity of Rho kinases in the RV, which was associated with the inhibition of cardiac remodeling-related transcription factors STAT3 and NFATc3. These results show that DHEA treatment slowed the progression of severe PAH in SU5416/hypoxia/normoxia-exposed rats and protected the RV against apoptosis and fibrosis, thus preserving its contractile function. The antioxidant activity of DHEA, by depleting NADPH, plays a central role in these cardioprotective effects.
authors.affiliation: Department of Pharmacology, University of South Alabama, Mobile, AL 36688, USA.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Alzoubi
authors.forename: Michie
authors.initials: M
authors.lastname: Toba
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Abe
authors.forename: Kealan D
authors.initials: KD
authors.lastname: O'Neill
authors.forename: Petra
authors.initials: P
authors.lastname: Rocic
authors.forename: Karen A
authors.initials: KA
authors.lastname: Fagan
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
mesh_terms: D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000627:therapeutic use*; D005355:Fibrosis; D015870:Gene Expression; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D000860:Hypoxia / Q000150:complications; D007211:Indoles / Q000633:toxicity; D008297:Male; D009249:NADP / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D011651:Pulmonary Artery / Q000473:pathology*; D011758:Pyrroles / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D018754:Ventricular Dysfunction / Q000188:drug therapy* / Q000209:etiology; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D007211:Indoles; D050778:NFATC Transcription Factors; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C445503:transcription factor NF-AT c3; D003687:Dehydroepiandrosterone; D009249:NADP; C116890:Semaxinib; D054460:rho-Associated Kinases
keywords: Rho kinase; SU5416; dehydroepiandrosterone; oxidative stress; pulmonary arterial hypertension; right ventricle