Browsing by Author "Wang, Longfei"

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    Insights into the pulmonary vascular complications of heart failure with preserved ejection fraction
    (Wiley, 2019-02) Lai, Yen‐Chun; Wang, Longfei; Gladwin, Mark T.; Medicine, School of Medicine
    Pulmonary hypertension in the setting of heart failure with preserved ejection fraction (PH-HFpEF) is a growing public health problem that is increasing in prevalence. While PH-HFpEF is defined by a high mean pulmonary artery pressure, high left ventricular end-diastolic pressure and a normal ejection fraction, some HFpEF patients develop PH in the presence of pulmonary vascular remodelling with a high transpulmonary pressure gradient or pulmonary vascular resistance. Ageing, increased left atrial pressure and stiffness, mitral regurgitation, as well as features of metabolic syndrome, which include obesity, diabetes and hypertension, are recognized as risk factors for PH-HFpEF. Qualitative studies have documented that patients with PH-HFpEF develop more severe symptoms than those with HFpEF and are associated with more significant exercise intolerance, frequent hospitalizations, right heart failure and reduced survival. Currently, there are no effective therapies for PH-HFpEF, although a number of candidate drugs are being evaluated, including soluble guanylate cyclase stimulators, phosphodiesterase type 5 inhibitors, sodium nitrite and endothelin receptor antagonists. In this review we attempt to provide an updated overview of recent findings pertaining to the pulmonary vascular complications in HFpEF in terms of clinical definitions, epidemiology and pathophysiology. Mechanisms leading to pulmonary vascular remodelling in HFpEF, a summary of pre-clinical models of HFpEF and PH-HFpEF, and new candidate therapeutic strategies for the treatment of PH-HFpEF are summarized.
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    Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction
    (American Heart Association, 2021) Satoh, Taijyu; Wang, Longfei; Espinosa-Diez, Cristina; Wang, Bing; Hahn, Scott A.; Noda, Kentaro; Rochon, Elizabeth R.; Dent, Matthew R.; Levine, Andrea; Baust, Jeffrey J.; Wyman, Samuel; Wu, Yijen L.; Triantafyllou, Georgios A.; Tang, Ying; Reynolds, Mike; Shiva, Sruti; St. Hilaire, Cynthia; Gomez, Delphine; Goncharov, Dmitry A.; Goncharova, Elena A.; Chan, Stephen Y.; Straub, Adam C.; Lai, Yen-Chun; McTiernan, Charles F.; Gladwin, Mark T.; Medicine, School of Medicine
    Background: Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells. Methods: We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress. Results: Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. Conclusions: In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.
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    Salt Content Distribution and Paleoclimatic Significance of the Lop Nur “Ear” Feature: Results from Analysis of EO-1 Hyperion Imagery
    (MDPI, 2017-08) Zhang, Tingting; Shao, Yun; Gong, Huaze; Li, Lin; Wang, Longfei; Department of Earth Sciences, School of Science
    Lop Nur, a playa lake located on the eastern margin of Tarim Basin in northwestern China, is famous for the “Ear” feature of its salt crust, which appears in remote-sensing images. In this study, partial least squares (PLS) regression was used to estimated Lop Nur playa salt-crust properties, including total salt, Ca2+, Mg2+, Na+, Si2+, and Fe2+ using laboratory hyperspectral data. PLS results for laboratory-measured spectra were compared with those for resampled laboratory spectra with the same spectral resolution as Hyperion using the coefficient of determination (R2) and the ratio of standard deviation of sample chemical concentration to root mean squared error (RPD). Based on R2 and RPD, the results suggest that PLS can predict Ca2+ using Hyperion reflectance spectra. The Ca2+ distribution was compared to the “Ear area” shown in a Landsat Thematic Mapper (TM) 5 image. The mean value of reflectance from visible bands for a 14 km transversal profile to the “Ear area” rings was extracted with the TM 5 image. The reflectance was used to build a correlation with Ca2+ content estimated with PLS using Hyperion. Results show that the correlation between Ca2+ content and reflectance is in accordance with the evolution of the salt lake. Ca2+ content variation was consistent with salt deposition. Some areas show a negative correlation between Ca2+ content and reflectance, indicating that there could have been a small-scale temporary runoff event under an arid environmental background. Further work is needed to determine whether these areas of small-scale runoff are due to natural (climate events) or human factors (upstream channel changes)
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    Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction
    (American Heart Association, 2020-06) Wang, Longfei; Halliday, Gunner; Huot, Joshua R.; Satoh, Taijyu; Baust, Jeff J.; Fisher, Amanda; Cook, Todd; Hu, Jian; Avolio, Theodore; Goncharov, Dmitry A.; Bai, Yang; Vanderpool, Rebecca R.; Considine, Robert V.; Bonetto, Andrea; Tan, Jiangning; Bachman, Timothy N.; Sebastiani, Andrea; Mora, Ana L.; Machado, Roberto F.; Goncharova, Elena A.; Gladwin, Mark T.; Lai, Yen-Chun; Surgery, School of Medicine
    Objective: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle. Conclusions: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.