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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Main Authors: Ying Tan, David Mui, Sam Toan, Pingjun Zhu, Ruibing Li, Hao Zhou
Format: Article
Language:English
Published: Elsevier 2020-12-01
Series:Molecular Therapy: Nucleic Acids
Subjects:
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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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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AT samtoan sercaoverexpressionimprovesmitochondrialqualitycontrolandattenuatescardiacmicrovascularischemiareperfusioninjury
AT pingjunzhu sercaoverexpressionimprovesmitochondrialqualitycontrolandattenuatescardiacmicrovascularischemiareperfusioninjury
AT ruibingli sercaoverexpressionimprovesmitochondrialqualitycontrolandattenuatescardiacmicrovascularischemiareperfusioninjury
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