Academic Journal
Impact of statins on cellular respiration and de‐differentiation of myofibroblasts in human failing hearts
| العنوان: | Impact of statins on cellular respiration and de‐differentiation of myofibroblasts in human failing hearts |
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| المؤلفون: | Emelyanova, Larisa, Sra, Amar, Schmuck, Eric G., Raval, Amish N., Downey, Francis X., Jahangir, Arshad, Rizvi, Farhan, Ross, Gracious R. |
| المساهمون: | Aurora Health Care, Cardiovascular Surgical Research Award |
| المصدر: | ESC Heart Failure ; volume 6, issue 5, page 1027-1040 ; ISSN 2055-5822 2055-5822 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2019 |
| المجموعة: | Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: | Aims Fibroblast to myofibroblast trans‐differentiation with altered bioenergetics precedes cardiac fibrosis (CF). Either prevention of differentiation or promotion of de‐differentiation could mitigate CF‐related pathologies. We determined whether 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A (HMG‐CoA) reductase inhibitors—statins, commonly prescribed to patients at risk of heart failure (HF)—can de‐differentiate myofibroblasts, alter cellular bioenergetics, and impact the human ventricular fibroblasts (hVFs) in HF patients. Methods and results Either in vitro statin treatment of differentiated myofibroblasts ( n = 3–6) or hVFs, isolated from human HF patients under statin therapy (HF + statin) vs. without statins (HF) were randomly used ( n = 4–12). In vitro , hVFs were differentiated by transforming growth factor‐β1 (TGF‐β1) for 72 h (TGF‐72 h). Differentiation status and cellular oxygen consumption rate (OCR) were determined by α‐smooth muscle actin (α‐SMA) expression and Seahorse assay, respectively. Data are mean ± SEM except Seahorse (mean ± SD); P < 0.05, considered significant. In vitro , statins concentration‐dependently de‐differentiated the myofibroblasts. The respective half‐maximal effective concentrations were 729 ± 13 nmol/L (atorvastatin), 3.6 ± 1 μmol/L (rosuvastatin), and 185 ± 13 nmol/L (simvastatin). Mevalonic acid (300 μmol/L), the reduced product of HMG‐CoA, prevented the statin‐induced de‐differentiation (α‐SMA expression: 31.4 ± 10% vs. 58.6 ± 12%). Geranylgeranyl pyrophosphate (GGPP, 20 μmol/L), a cholesterol synthesis‐independent HMG‐CoA reductase pathway intermediate, completely prevented the statin‐induced de‐differentiation (α‐SMA/GAPDH ratios: 0.89 ± 0.05 [TGF‐72 h + 72 h], 0.63 ± 0.02 [TGF‐72 h + simvastatin], and 1.2 ± 0.08 [TGF‐72 h + simvastatin + GGPP]). Cellular metabolism involvement was observed when co‐incubation of simvastatin (200 nmol/L) with glibenclamide (10 μmol/L), a K ATP channel inhibitor, attenuated the simvastatin‐induced de‐differentiation (0.84 ± 0.05). ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1002/ehf2.12509 |
| الاتاحة: | http://dx.doi.org/10.1002/ehf2.12509 https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fehf2.12509 https://onlinelibrary.wiley.com/doi/pdf/10.1002/ehf2.12509 https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ehf2.12509 |
| Rights: | http://creativecommons.org/licenses/by-nc/4.0/ |
| رقم الانضمام: | edsbas.EF98729A |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/ehf2.12509 |
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