Exogenous Estrogen Preserves Distal Pulmonary Arterial Mechanics and Prevents Pulmonary Hypertension in Rats.
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ABSTRACT:
SUBMITTER: Philip JL
PROVIDER: S-EPMC6999110 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
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Exogenous Estrogen Preserves Distal Pulmonary Arterial Mechanics and Prevents Pulmonary Hypertension in Rats.
Philip Jennifer L JL Tabima Diana M DM Wolf Gregory D GD Frump Andrea L AL Cheng Tik-Chee TC Schreier David A DA Hacker Timothy A TA Lahm Tim T Chesler Naomi C NC
American journal of respiratory and critical care medicine 20200201 3
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Project description:BackgroundThe cardioprotective properties of sevoflurane have been reported in studies of the left ventricle. However, whether this volatile anesthetic would also be beneficial for pulmonary vascular remodeling and associated right ventricular hypertrophy (RVH) remained to be explored. Here, we investigated the potential benefit of sevoflurane to right heart function in experimental pulmonary arterial hypertension (PAH).MethodsAdult Wistar rats received one dose peritoneal injection of monocrotaline (MCT, 60 mg/kg) or the equal volume of normal saline. Two weeks later, rats were treated with sevoflurane or sham exposure. PAH status and cardiac function were assessed by echocardiography weekly, and the body weight (BW) was monitored every week. After 6 weeks of exercise, Fulton's index calculation, histological observation, IL-6 and TNF-α immunohistochemical analyses, evaluation of MDA, SOD and GSH-Px levels and NF-κB and MAPK active determination were performed in lung and RV tissue samples.ResultsMCT induced pulmonary vascular remodeling, RVH, increased Fulton's index (P<0.01), and right ventricular failure (RVF) in rats. Animals inhaled sevoflurane had an increased cardiac output (P<0.05) and lower incidence of RVF (P<0.05). Also, these animals had a reduced RVEDD, RVWTd and PAID (P<0.05), increased PV (P<0.05), reduced wall thickness and vascular wall area of pulmonary small vascular (vascular external diameter 50-150 um) (P<0.01), reduced RV fibrosis, and increased RV cardiomyocyte area (P<0.01). Furthermore, sevoflurane reduced IL-6 and TNF-α expression in lungs and heart (P<0.01), decreased level of MDA (P<0.01) and increased activity of SOD and GSH-Px (P<0.01). In addition, it decreased the activities of NF-κB and MAPK pathways (P<0.01).ConclusionSevoflurane reduces pulmonary vascular remodeling and RVH in PAH induced by MCT in rats. This effect is likely due to down-regulation of inflammatory factors IL-6 and TNF-α, reduced level of oxidative stress and the inhibition of NF-κB and MAPK pathways.
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Project description:Pulmonary arterial hypertension (PAH) is more prevalent in females. Paradoxically, female patients have better right ventricular (RV) function and higher survival rates than males. However, the effects of 17β-estradiol (E2) on RV function in PAH has not been studied. Twenty-four male rats were exposed to monocrotaline (MCT) to induce experimental PAH, while treated with E2 or vehicle respectively. Together with eight control rats, thirty-two rats were examined by echocardiography 4 weeks after drug administration. Echocardiographic measurement of RV function included: tricuspid annular plane systolic excursion (TAPSE), RV index of myocardial performance (RIMP), RV fractional area change (RVFAC) and tricuspid annular systolic velocity (s'). RV free wall longitudinal strain (RVLSFW) and RV longitudinal shortening fraction (RVLSF) were also used to quantify RV function. RV morphology was determined by echocardiographic and histological analysis. TAPSE, RVFAC and s' were reduced, and RIMP was elevated in the MCT-treated group and vehicle-treated group, when compared with control group (P < 0.01). TAPSE, RVFAC and s' in the E2 group were higher, while RIMP was lower than those in the MCT-treated group and vehicle-treated group (P < 0.01). Myocardial functional parameters (RVLSFW and RVLSF) were also higher in the E2 group. Enhanced serum E2 levels were closely correlated with the improvement in RV functional parameters and enhancement of serum BNP levels (P < 0.01 for all groups). RV function decreased significantly in male rats with MCT-induced PAH, while E2 exhibited a protective effect on RV function, suggesting that E2 is a critical modulator of sex differences in PAH.
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Project description:RationalePulmonary hypertension (PH) is characterized by progressive increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and death. Current treatments only temporarily reduce severity of the disease, and an ideal therapy is still lacking.ObjectivesEstrogen pretreatment has been shown to attenuate development of PH. Because PH is not often diagnosed early, we examined if estrogen can rescue preexisting advanced PH.MethodsPH was induced in male rats with monocrotaline (60 mg/kg). At Day 21, rats were either treated with 17-β estradiol or estrogen (E2, 42.5 μg/kg/d), estrogen receptor-β agonist (diarylpropionitrile, 850 μg/kg/d), or estrogen receptor α-agonist (4,4',4"-[4-Propyl-(1H)-pyrazole-1,3,5-triyl] trisphenol, 850 μg/kg/d) for 10 days or left untreated to develop RV failure. Serial echocardiography, cardiac catheterization, immunohistochemistry, Western blot, and real-time polymerase chain reaction were performed.Measurements and main resultsEstrogen therapy prevented progression of PH to RV failure and restored lung and RV structure and function. This restoration was maintained even after removal of estrogen at Day 30, resulting in 100% survival at Day 42. Estradiol treatment restored the loss of blood vessels in the lungs and RV. In the presence of angiogenesis inhibitor TNP-470 (30 mg/kg) or estrogen receptor-β antagonist (PHTPP, 850 μg/kg/d), estrogen failed to rescue PH. Estrogen receptor-β selective agonist was as effective as estrogen in rescuing PH.ConclusionsEstrogen rescues preexisting severe PH in rats by restoring lung and RV structure and function that are maintained even after removal of estrogen. Estrogen-induced rescue of PH is associated with stimulation of cardiopulmonary neoangiogenesis, suppression of inflammation, fibrosis, and RV hypertrophy. Furthermore, estrogen rescue is likely mediated through estrogen receptor-β.
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Project description:Rationale: Antenatal factors, such as chorioamnionitis, preeclampsia, and postnatal injury, are associated with an increased risk for bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) after preterm birth. IGF-1 (insulin-like growth factor-1) is markedly decreased in normal preterm infants, but whether IGF-1 treatment can prevent BPD or PH is unknown.Objectives: To evaluate whether postnatal treatment with rhIGF-1 (recombinant human IGF-1)/BP3 (binding peptide 3) improves lung growth and prevents PH in two antenatal models of BPD induced by intraamniotic exposure to endotoxin (ETX) or sFlt-1 (soluble fms-like tyrosine kinase 1), and in a postnatal model due to prolonged hyperoxia.Methods: ETX or sFlt-1 were administered into the amniotic sac of pregnant rats at Embryonic Day 20 to simulate antenatal models of chorioamnionitis and preeclampsia, respectively. Pups were delivered by cesarean section at Embryonic Day 22 and treated with rhIGF-1/BP3 (0.02-20 mg/kg/d intraperitoneal) or buffer for 2 weeks. Study endpoints included radial alveolar counts (RACs), vessel density, and right ventricular hypertrophy (RVH). Direct effects of rhIGF-1/BP3 (250 ng/ml) on fetal lung endothelial cell proliferation and tube formation and alveolar type 2 cell proliferation were studied by standard methods in vitro.Measurements and Main Results: Antenatal ETX and antenatal sFlt-1 reduced RAC and decreased RVH in infant rats. In both models, postnatal rhIGF-1/BP3 treatment restored RAC and RVH to normal values when compared with placebo injections. rhIGF-1/BP3 treatment also preserved lung structure and prevented RVH after postnatal hyperoxia. In vitro studies showed that rhIGF-1/BP3 treatment increased lung endothelial cell and alveolar type 2 cell proliferation.Conclusions: Postnatal rhIGF-1/BP3 treatment preserved lung structure and prevented RVH in antenatal and postnatal BPD models. rhIGF-1/BP3 treatment may provide a novel strategy for the prevention of BPD in preterm infants.
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Project description:BackgroundThe role of interventricular mechanics in pediatric pulmonary arterial hypertension (PAH) and its relation to right ventricular (RV) dysfunction has been largely overlooked. Here, we characterize the impact of maintained pressure overload in the RV-pulmonary artery (PA) axis on myocardial strain and left ventricular (LV) mechanics in pediatric PAH patients in comparison to a preclinical PA-banding (PAB) mouse model. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children.MethodsBalanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) images of 18 PAH and 17 healthy (control) pediatric subjects were retrospectively analyzed using CMR feature-tracking (FT) software to compute measurements of myocardial strain. Furthermore, myocardial tagged-CMR images were also analyzed for each subject using harmonic phase flow analysis to derive LV torsion rate. Within 48 h of CMR, PAH patients underwent right heart catheterization (RHC) for measurement of PA/RV pressures, and to compute RV end-systolic elastance (RV_Ees, a measure of load-independent contractility). Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. bSSFP-CMR, tagged CMR, and intra-cardiac catheterization were performed on 12 PAB and 9 control mice (Sham) 7 weeks after surgery with identical post-processing as in the aforementioned patient studies. RV_Ees was assessed via the single beat method.ResultsLV torsion rate was significantly reduced under hypertensive conditions in both PAB mice (p = 0.004) and pediatric PAH patients (p < 0.001). This decrease in LV torsion rate correlated significantly with a decrease in RV_Ees in PAB (r = 0.91, p = 0.05) and PAH subjects (r = 0.51, p = 0.04). In order to compare combined metrics of LV torsion rate and strain parameters principal component analysis (PCA) was used. PCA revealed grouping of PAH patients with PAB mice and control subjects with Sham mice. Similar to LV torsion rate, LV global peak circumferential, radial, and longitudinal strain were significantly (p < 0.05) reduced under hypertensive conditions in both PAB mice and children with PAH.ConclusionsThe PAB mouse model resembles PAH-associated myocardial mechanics and may provide a potential model to study mechanisms of RV/LV interdependency.
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