The contribution of chymase-dependent formation of ANG II to cardiac dysfunction in metabolic syndrome of young rats: roles of fructose and EETs
| Autor: | Zan Weng, Dong Sun, Ghezal Froogh, Roopa Duvvi, Yicong Le, Sharath Kandhi, Norah Alruwaili, Jonathan O Ashe, An Huang |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Physiology 030204 cardiovascular system & hematology medicine.disease_cause Antioxidants Rats Sprague-Dawley chemistry.chemical_compound 8 11 14-Eicosatrienoic Acid 0302 clinical medicine Piperidines Heart Rate Hyperinsulinemia Cardiac Output Enzyme Inhibitors Cells Cultured Epoxide Hydrolases Metabolic Syndrome NADPH oxidase biology Angiotensin II Heart cardiovascular system Cardiology and Cardiovascular Medicine hormones hormone substitutes and hormone antagonists Research Article Epoxide hydrolase 2 medicine.medical_specialty Heart Diseases Normal diet Fructose Nitric oxide 03 medical and health sciences Chymases Physiology (medical) Internal medicine medicine Animals Myocardium Phenylurea Compounds Chymase medicine.disease Rats Oxidative Stress 030104 developmental biology Endocrinology chemistry biology.protein Oxidative stress |
| Zdroj: | Am J Physiol Heart Circ Physiol |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.00633.2019 |
| Popis: | The roles of ACE-independent ANG II production via chymase and therapeutic potential of epoxyeicosatrienoic acids (EETs) in fructose-induced metabolic syndrome (MetS) in the adolescent population remain elusive. Thus we tested the hypothesis that a high-fructose diet (HFD) in young rats elicits chymase-dependent increases in ANG II production and oxidative stress, responses that are reversible by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), an inhibitor of soluble epoxide hydrolase (sEH) that metabolizes EETs. Three groups of weanling rats (21-day-old) were fed a normal diet, 60% HFD, and HFD with TPPU, respectively, for 30 days. HFD rats developed MetS, characterized by hyperglycemia, hyperinsulinemia, and hypertension and associated with decreases in cardiac output and stroke volume and loss of nitric oxide (NO) modulation of myocardial oxygen consumption; all impairments were normalized by TPPU that significantly elevated circulating 11,12-EET, a major cardiac EET isoform. In the presence of comparable cardiac angiotensin-converting enzyme (ACE) expression/activity among the three groups, HFD rats exhibited significantly greater chymase-dependent ANG II formation in hearts, as indicated by an augmented cardiac chymase content as a function of enhanced mast cell degranulation. The enhanced chymase-dependent ANG II production was paralleled with increases in ANG II type 1 receptor (AT(1)R) expression and NADPH oxidase (Nox)-induced superoxide, alterations that were significantly reversed by TPPU. Conversely, HFD-induced downregulation of cardiac ACE2, followed by a lower Ang-(1–7) level displayed in an TPPU-irreversible manner. In conclusion, HFD-driven adverse chymase/ANG II/Nox/superoxide signaling in young rats was prevented by inhibition of sEH via, at least in part, an EET-mediated stabilization of mast cells, highlighting chymase and sEH as therapeutic targets during treatment of MetS. NEW & NOTEWORTHY As the highest fructose consumers, the adolescent population is highly susceptible to the metabolic syndrome, where increases in mast cell chymase-dependent formation of ANG II, ensued by cardiometabolic dysfunction, are reversible in response to inhibition of soluble epoxide hydrolase (sEH). This study highlights chymase and sEH as therapeutic targets and unravels novel avenues for the development of optimal strategies for young patients with fructose-induced metabolic syndrome. Listen to this article’s corresponding podcast at: https://ajpheart.podbean.com/e/tppu-reversible-alterations-of-renin-angiotensin-system/. |
| Databáze: | OpenAIRE |
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