High Sensitivity of SIRT3 Deficient Hearts to Ischemia-Reperfusion Is Associated with Mitochondrial Abnormalities
| العنوان: | High Sensitivity of SIRT3 Deficient Hearts to Ischemia-Reperfusion Is Associated with Mitochondrial Abnormalities |
|---|---|
| المؤلفون: | Rebecca M. Parodi-Rullán, Xavier Chapa-Dubocq, Pedro J. Rullán, Sehwan Jang, Sabzali Javadov |
| المصدر: | Frontiers in Pharmacology Frontiers in Pharmacology, Vol 8 (2017) |
| بيانات النشر: | Frontiers Media SA, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | sanglifehrin A, 0301 basic medicine, Pharmacology, lcsh:RM1-950, protein acetylation, Correction, heart, ischemia-reperfusion, mitochondria, SIRT3, 03 medical and health sciences, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Pharmacology (medical), Original Research |
| الوصف: | Aim: Sirtuins are NAD+-dependent deacetylases that regulate cell metabolism through protein acetylation/deacetylation, and SIRT3 is the major deacetylase among mitochondrial isoforms. Here, we elucidated the possible role of acetylation of cyclophilin D, a key regulator of the mitochondrial permeability transition pore (mPTP), in mitochondria-mediated cardiac dysfunction induced by ischemia-reperfusion (IR) in wild type (WT) and SIRT3 knockout (SIRT3-/-) mice. Materials and Methods: Isolated and Langendorff-mode perfused hearts of WT and SIRT3-/- mice were subjected to 25-min global ischemia followed by 60-min of reperfusion in the presence or absence of the mPTP inhibitor, sanglifehrin A (SfA). Results: Analysis of mitochondrial sirtuins demonstrated that SIRT3 deficiency upregulated SIRT4 with no effect on SIRT5 expression. Hearts of SIRT3-/- mice exhibited significantly less recovery of cardiac function at the end of IR compared to WT mice. Intact (non-perfused) SIRT3-/- hearts exhibited an increased rate of Ca2+-induced swelling in mitochondria as an indicator of mPTP opening. However, there was no difference in mPTP opening and cyclophilin D acetylation between WT and SIRT3-/- hearts subjected to IR injury. Ca2+-stimulated H2O2 production was significantly higher in SIRT3-/- mitochondria that was prevented by SfA. Superoxide dismutase activity was lower in SIRT3-/- heart mitochondria subjected to IR which correlated with an increase in protein carbonylation. However, mitochondrial DNA integrity was not affected in SIRT3-/- hearts after IR. Conclusion: SIRT3 deficiency exacerbates cardiac dysfunction during post-ischemic recovery, and increases mPTP opening and ROS generation without oxidative damage to mitochondrial proteins and DNA. |
| تدمد: | 1663-9812 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1c25db2a4b536ce1d28881a5b9c76faTest https://doi.org/10.3389/fphar.2017.00275Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a1c25db2a4b536ce1d28881a5b9c76fa |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16639812 |
|---|