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
| Autor: | Scott A. Hahn, Ying Tang, Mark T. Gladwin, Taijyu Satoh, Charles F. McTiernan, Kentaro Noda, Cynthia St. Hilaire, Bing Wang, Adam C. Straub, Samuel K. Wyman, Cristina Espinosa-Diez, Georgios Triantafyllou, Jeffrey J. Baust, Sruti Shiva, Matthew R Dent, Longfei Wang, Yijen L. Wu, Elena A. Goncharova, Dmitry A. Goncharov, Mike Reynolds, Yen Chun Lai, Andrea R. Levine, Elizabeth R. Rochon, Delphine Gomez, Stephen Y. Chan |
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| Rok vydání: | 2021 |
| Předmět: |
Ventricular Dysfunction
Right MIRN193 microRNA Cardiorespiratory Medicine and Haematology 030204 cardiovascular system & hematology Cardiovascular Mitochondria Heart Animals Genetically Modified chemistry.chemical_compound Soluble Guanylyl Cyclase 0302 clinical medicine Smooth Muscle pulmonary hypertension Ventricular Dysfunction 2.1 Biological and endogenous factors nuclear factor Y Aetiology Metabolic Syndrome 0303 health sciences Diabetes Heart Pulmonary Mitochondria Right Heart Disease Phenotype 5.1 Pharmaceuticals Hypertension Public Health and Health Services Disease Susceptibility Development of treatments and therapeutic interventions Cardiology and Cardiovascular Medicine Signal Transduction Guanylate cyclase medicine.medical_specialty Physiological Hypertension Pulmonary Clinical Sciences Myocytes Smooth Muscle Genetically Modified Stress Article Nitric oxide 03 medical and health sciences Downregulation and upregulation nitric oxide Stress Physiological Physiology (medical) Internal medicine medicine Animals Humans human Obesity Exercise Nutrition 030304 developmental biology Heart Failure Myocytes Mir 193b Animal business.industry Stroke Volume medicine.disease Pulmonary hypertension Rats Disease Models Animal MicroRNAs Endocrinology Cardiovascular System & Hematology CCAAT-Binding Factor Gene Expression Regulation chemistry Disease Models Metabolic syndrome Reactive Oxygen Species Heart failure with preserved ejection fraction business Biomarkers |
| Zdroj: | Circulation Circulation, vol 144, iss 8 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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