SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury
Despite significant advances in the treatment of myocardial ischemia-reperfusion (I/R) injury, coronary circulation is a so far neglected target of cardioprotection. In this study, we investigated the molecular mechanisms underlying I/R injury to cardiac microcirculation. Using gene delivery, we ana...
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Elsevier
2020-12-01
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Series: | Molecular Therapy: Nucleic Acids |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253120302845 |
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author | Ying Tan David Mui Sam Toan Pingjun Zhu Ruibing Li Hao Zhou |
author_facet | Ying Tan David Mui Sam Toan Pingjun Zhu Ruibing Li Hao Zhou |
author_sort | Ying Tan |
collection | DOAJ |
description | Despite significant advances in the treatment of myocardial ischemia-reperfusion (I/R) injury, coronary circulation is a so far neglected target of cardioprotection. In this study, we investigated the molecular mechanisms underlying I/R injury to cardiac microcirculation. Using gene delivery, we analyzed microvascular protective effects of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) on the reperfused heart and examined the role of SERCA in regulating mitochondrial quality control in cardiac microvascular endothelial cells (CMECs). Our data showed that SERCA overexpression attenuates lumen stenosis, inhibits microthrombus formation, reduces inflammation response, and improves endothelium-dependent vascular relaxation. In vitro experiments demonstrated that SERCA overexpression improves endothelial viability, barrier integrity, and cytoskeleton assembly in CMECs. Mitochondrial quality control, including mitochondrial fusion, mitophagy, bioenergetics, and biogenesis, were disrupted by I/R injury but were restored by SERCA overexpression. SERCA overexpression also restored mitochondrial quality control by inhibiting calcium overload, inactivating xanthine oxidase (XO), and reducing intracellular/mitochondrial reactive oxygen species (ROS). Administration of exogenous XO or a calcium channel agonist abolished the protective effects of SERCA overexpression on mitochondrial quality control and offset the beneficial effects of SERCA overexpression after cardiac microvascular I/R injury. These findings indicate that SERCA overexpression may be an effective approach to targeting cardiac microvascular I/R injury by regulating calcium/XO/ROS signaling and preserving mitochondrial quality control. |
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language | English |
last_indexed | 2024-12-14T19:20:53Z |
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series | Molecular Therapy: Nucleic Acids |
spelling | doaj.art-820c99bae7ff411ba4a412dc7906ea0b2022-12-21T22:50:20ZengElsevierMolecular Therapy: Nucleic Acids2162-25312020-12-0122696707SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion InjuryYing Tan0David Mui1Sam Toan2Pingjun Zhu3Ruibing Li4Hao Zhou5Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, ChinaPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Chemical Engineering, University of Minnesota-Duluth, Duluth, MN 55812, USAChinese PLA Medical School, Chinese PLA General Hospital, Beijing 100853, ChinaChinese PLA Medical School, Chinese PLA General Hospital, Beijing 100853, ChinaChinese PLA Medical School, Chinese PLA General Hospital, Beijing 100853, China; Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China; Corresponding author: Hao Zhou, Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.Despite significant advances in the treatment of myocardial ischemia-reperfusion (I/R) injury, coronary circulation is a so far neglected target of cardioprotection. In this study, we investigated the molecular mechanisms underlying I/R injury to cardiac microcirculation. Using gene delivery, we analyzed microvascular protective effects of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) on the reperfused heart and examined the role of SERCA in regulating mitochondrial quality control in cardiac microvascular endothelial cells (CMECs). Our data showed that SERCA overexpression attenuates lumen stenosis, inhibits microthrombus formation, reduces inflammation response, and improves endothelium-dependent vascular relaxation. In vitro experiments demonstrated that SERCA overexpression improves endothelial viability, barrier integrity, and cytoskeleton assembly in CMECs. Mitochondrial quality control, including mitochondrial fusion, mitophagy, bioenergetics, and biogenesis, were disrupted by I/R injury but were restored by SERCA overexpression. SERCA overexpression also restored mitochondrial quality control by inhibiting calcium overload, inactivating xanthine oxidase (XO), and reducing intracellular/mitochondrial reactive oxygen species (ROS). Administration of exogenous XO or a calcium channel agonist abolished the protective effects of SERCA overexpression on mitochondrial quality control and offset the beneficial effects of SERCA overexpression after cardiac microvascular I/R injury. These findings indicate that SERCA overexpression may be an effective approach to targeting cardiac microvascular I/R injury by regulating calcium/XO/ROS signaling and preserving mitochondrial quality control.http://www.sciencedirect.com/science/article/pii/S2162253120302845cardiac microvascular I/R injuryXOROSSERCAmitochondrial quality control |
spellingShingle | Ying Tan David Mui Sam Toan Pingjun Zhu Ruibing Li Hao Zhou SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury Molecular Therapy: Nucleic Acids cardiac microvascular I/R injury XO ROS SERCA mitochondrial quality control |
title | SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury |
title_full | SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury |
title_fullStr | SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury |
title_full_unstemmed | SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury |
title_short | SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury |
title_sort | serca overexpression improves mitochondrial quality control and attenuates cardiac microvascular ischemia reperfusion injury |
topic | cardiac microvascular I/R injury XO ROS SERCA mitochondrial quality control |
url | http://www.sciencedirect.com/science/article/pii/S2162253120302845 |
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