Beneficial effect of dehydroepiandrosterone on pulmonary hypertension in a rodent model of pulmonary hypertension in infants

Abstract

Background: Pulmonary hypertension (PH) is a disease that affects the adult or infant population. Dehydroepiandrosterone (DHEA), a steroid hormone, has been previously shown to prevent and to reverse PH in an adult rat model. We thus investigated its effect in a rat-pup model of chronic hypoxic PH. Methods: Animals were maintained for 3 wk in a hypobaric chamber to induce PH, with or without concomitant treatment with DHEA (30 mg/kg every alternate day). results: DHEA significantly reduced mean pulmonary artery pressure (measured by right cardiac catheterization), pulmonary artery remodeling (evaluated by histology), and rightventricular hypertrophy (measured by echography and by the Fulton index). At the level of the pulmonary artery smooth muscle cell (PASMC), DHEA increased activity and expression of the large-conductance Ca2+-activated potassium channel (BK Ca ) (assessed by means of the patch clamp technique). DHEA also inhibited both serotonin-and KCl-induced contraction and smooth muscle cell proliferation. conclusion: Collectively, these results indicate that DHEA prevents PH in infant rats and may therefore be clinically relevant for the management of PH in human infants. P ulmonary hypertension (PH) is a disease that affects both adults and infants. PH is characterized by increased pulmonary vascular pressure and resistance, which can lead, in rare cases in infants, to right-ventricular failure and ultimately to death (1). Increased reactivity to agonists and remodeling of small pulmonary arteries (PAs) are landmarks of PH (2,3). In infants, there are a variety of PH phenotypes, some of which are specific to this age group: (i) PH secondary to congenital heart disease with a left-right shunt, (ii) persistent PH of the newborn due to the absence of a drop in neonatal pulmonary resistance, (iii) acute or chronic pulmonary disease induced by hypoxemia, and (iv) idiopathic forms (4,5). Pharmacological treatments that mainly aim at vasodilating PAs, e.g., prostanoid analog, endothelin receptor antagonists, or phosphodiesterase inhibitors (2,6), still need to be comprehensively evaluated in pediatric patients. It is thus essential to develop new treatments to prevent and/or reverse PH in this population.Dehydroepiandrosterone (DHEA) is the most abundant adrenal steroid, and serum concentration of its sulfate ester is approximately 20-fold higher than that of any other circulating steroid hormone (7,8). In different models of adult rats with PH, we (9) and others (10,11) have shown that DHEA prevents and reverses PH and the resulting right-ventricular (RV) hypertrophy as well as small PA remodeling. However, similar studies have not been performed in newborn or infant animals. We have thus investigated the effect of DHEA in a model of infant rats in which PH was induced. We have observed that chronic treatment with DHEA (30 mg/kg every alternate day) is able to prevent PH and its associated cardiovascular alterations such as RV hypertrophy, pulmonary vascular hyperreactivity, and smooth muscle cell proliferat...

Activation of PPARγ by baicalin attenuates pulmonary hypertension in an infant rat model by suppressing HMGB1/RAGE signaling

“…The animal model protocol of PH infant rats was carried out in accordance with a previous study . Fifteen days after birth, female Wistar rats with their neonatal pups were divided into five groups evenly and randomly.…”

“…The phenotypes of PH in infants can be divided into four subtypes: (a) congenital heart disease related (infants often with left–right shunt congenital heart diseases; (b) acute or chronic hypoxia related; (c) neonatal developmental defect related; and (d) idiopathic forms . Remodeling of the small pulmonary arteries is the leading manifestation of the pathology of PH , and it was reported that airway inflammation played important roles in this process, contributing to the development of PH . However, the exact mechanism is still not clear.…”

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

“…At the cellular level, DHEA reduces hypoxia-induced accumulation of hypoxia-inducible factor 1α (HIF)-1α in human pulmonary artery endothelial cells (hPAECs) [35] and stimulates NO release in bovine endothelial cells (ECs) [36]. In animals, preventive and/or rescue treatments with DHEA or DHEA-S are effective in CH-PH [37][38][39], MCT-PH [40,41], fetal pulmonary circulation in sheep [42], the rat model of PH in infants [43], and in Sugen 5416 + hypoxia (Su-Hx)-induced PH [44]. DHEA also attenuates PH in patients with chronic obstructive pulmonary disease [45].…”

2-Methoxyestradiol in Pulmonary Arterial Hypertension: A New Disease Modifier

“…The delicate balance between DHEA and DHEA-S is controlled by the relative activity of sulfotransferase (DHEA → DHEA-S) and sulfatase (DHEA-S → DHEA) [26]. Both DHEA and DHEA-S are protective in experimental models of pulmonary hypertension [27][28][29][30][31] including models of angioproliferative PH [32,33]. Recently, lower DHEA-S and higher E2 levels have been linked to a greater risk of PAH and worse hemodynamics, functional status, and greater risk of death [34,35].…”