The Experts below are selected from a list of 6186 Experts worldwide ranked by ideXlab platform
Hao Zhou - One of the best experts on this subject based on the ideXlab platform.
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serca overexpression improves mitochondrial quality control and attenuates cardiac Microvascular Ischemia reperfusion injury
Molecular therapy. Nucleic acids, 2020Co-Authors: Ying Tan, Sam Toan, David Mui, Pingjun Zhu, Hao ZhouAbstract: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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mitochondrial quality control in cardiac Microvascular Ischemia reperfusion injury new insights into the mechanisms and therapeutic potentials
Pharmacological Research, 2020Co-Authors: Jin Wang, Sam Toan, Hao ZhouAbstract:Thrombolytic therapy and revascularization strategies create a complete recanalization of the occluded epicardial coronary artery in patients with myocardial infarction (MI). However, about 35 % of patients still experience an impaired myocardial reperfusion, which is termed a no-reflow phenomenon mainly caused by cardiac Microvascular Ischemia-reperfusion (I/R) injury. Mitochondria are essential for Microvascular endothelial cells' survival, both because of their roles as metabolic energy producers and as regulators of programmed cell death. Mitochondrial structure and function are regulated by a mitochondrial quality control (MQC) system, a series of processes including mitochondrial biogenesis, mitochondrial dynamics/mitophagy, mitochondrial proteostasis, and mitochondria-mediated cell death. Our review discusses the MQC mechanisms and how they are linked to cardiac Microvascular I/R injury. Additionally, we will summarize the molecular basis that results in defective MQC mechanisms and present potential therapeutic interventions for improving MQC in cardiac Microvascular I/R injury.
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new insights into the role of mitochondria in cardiac Microvascular Ischemia reperfusion injury
Angiogenesis, 2020Co-Authors: Jin Wang, Sam Toan, Hao ZhouAbstract:As reperfusion therapies have become more widely used in acute myocardial infarction patients, Ischemia-induced myocardial damage has been markedly reduced, but reperfusion-induced cardiac injury has become increasingly evident. The features of cardiac Ischemia–reperfusion (I/R) injury include Microvascular perfusion defects, platelet activation and sequential cardiomyocyte death due to additional ischemic events at the reperfusion stage. Microvascular obstruction, defined as a no-reflow phenomenon, determines the infarct zone, myocardial function and peri-operative mortality. Cardiac Microvascular endothelial cell injury may occur much earlier and with much greater severity than cardiomyocyte injury. Endothelial cells contain fewer mitochondria than other cardiac cells, and several of the pathological alterations during cardiac Microvascular I/R injury involve mitochondria, such as increased mitochondrial reactive oxygen species (mROS) levels and disturbed mitochondrial dynamics. Although mROS are necessary physiological second messengers, high mROS levels induce oxidative stress, endothelial senescence and apoptosis. Mitochondrial dynamics, including fission, fusion and mitophagy, determine the shape, distribution, size and function of mitochondria. These adaptive responses modify extracellular signals and orchestrate intracellular processes such as cell proliferation, migration, metabolism, angiogenesis, permeability transition, adhesive molecule expression, endothelial barrier function and anticoagulation. In this review, we discuss the involvement of mROS and mitochondrial morphofunction in cardiac Microvascular I/R injury.
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pathological roles of mitochondrial oxidative stress and mitochondrial dynamics in cardiac Microvascular Ischemia reperfusion injury
Biomolecules, 2020Co-Authors: Hao Zhou, Sam ToanAbstract:Mitochondria are key regulators of cell fate through controlling ATP generation and releasing pro-apoptotic factors. Cardiac Ischemia/reperfusion (I/R) injury to the coronary microcirculation has manifestations ranging in severity from reversible edema to interstitial hemorrhage. A number of mechanisms have been proposed to explain the cardiac Microvascular I/R injury including edema, impaired vasomotion, coronary microembolization, and capillary destruction. In contrast to their role in cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. It is clear that abnormal mitochondrial signatures, including mitochondrial oxidative stress, mitochondrial fission, mitochondrial fusion, and mitophagy, play a substantial role in endothelial cell function. While the pathogenic role of each of these mitochondrial alterations in the endothelial cells I/R injury remains complex, profiling of mitochondrial oxidative stress and mitochondrial dynamics in endothelial cell dysfunction may offer promising potential targets in the search for novel diagnostics and therapeutics in cardiac Microvascular I/R injury. The objective of this review is to discuss the role of mitochondrial oxidative stress on cardiac Microvascular endothelial cells dysfunction. Mitochondrial dynamics, including mitochondrial fission and fusion, are critically discussed to understand their roles in endothelial cell survival. Finally, mitophagy, as a degradative mechanism for damaged mitochondria, is summarized to figure out its contribution to the progression of Microvascular I/R injury.
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bi1 alleviates cardiac Microvascular Ischemia reperfusion injury via modifying mitochondrial fission and inhibiting xo ros f actin pathways
Journal of Cellular Physiology, 2019Co-Authors: Hao Zhou, Jin Wang, Hong Zhu, Sam Toanc, Jun RenAbstract:Pathogenesis of cardiac Microvascular Ischemia-reperfusion (IR) injury is associated with excessive mitochondrial fission. However, the upstream mediator of mitochondrial fission remains obscure. Bax inhibitor 1 (BI1) is linked to multiple mitochondrial functions, and there have been no studies investigating the contribution of BI1 on mitochondrial fission in the setting of cardiac Microvascular IR injury. This study was undertaken to establish the action of BI1 on the cardiac Microvascular reperfusion injury and figure out whether BI1 sustained endothelial viability via inhibiting mitochondrial fission. Our observation indicated that BI1 was downregulated in reperfused hearts and overexpression of BI1 attenuated Microvascular IR injury. Mechanistically, reperfusion injury elevated the levels of xanthine oxidase (XO), an effect that was followed by increased reactive oxygen species (ROS) production. Subsequently, oxidative stress mediated F-actin depolymerization and the latter promoted mitochondrial fission. Aberrant fission caused mitochondrial dysfunction and ultimately activated mitochondrial apoptosis in cardiac Microvascular endothelial cells. By comparison, BI1 overexpression repressed XO expression and thus neutralized ROS, interrupting F-actin-mediated mitochondrial fission. The inhibitory effect of BI1 on mitochondrial fission sustained endothelial viability, reversed endothelial barrier integrity, attenuated the Microvascular inflammation response, and maintained microcirculation patency. Altogether, we conclude that BI1 is essential in maintaining mitochondrial homeostasis and alleviating cardiac Microvascular IR injury. Deregulated BI1 via the XO/ROS/F-actin pathways plays a causative role in the development of cardiac Microvascular reperfusion injury.
Sam Toan - One of the best experts on this subject based on the ideXlab platform.
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serca overexpression improves mitochondrial quality control and attenuates cardiac Microvascular Ischemia reperfusion injury
Molecular therapy. Nucleic acids, 2020Co-Authors: Ying Tan, Sam Toan, David Mui, Pingjun Zhu, Hao ZhouAbstract: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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mitochondrial quality control in cardiac Microvascular Ischemia reperfusion injury new insights into the mechanisms and therapeutic potentials
Pharmacological Research, 2020Co-Authors: Jin Wang, Sam Toan, Hao ZhouAbstract:Thrombolytic therapy and revascularization strategies create a complete recanalization of the occluded epicardial coronary artery in patients with myocardial infarction (MI). However, about 35 % of patients still experience an impaired myocardial reperfusion, which is termed a no-reflow phenomenon mainly caused by cardiac Microvascular Ischemia-reperfusion (I/R) injury. Mitochondria are essential for Microvascular endothelial cells' survival, both because of their roles as metabolic energy producers and as regulators of programmed cell death. Mitochondrial structure and function are regulated by a mitochondrial quality control (MQC) system, a series of processes including mitochondrial biogenesis, mitochondrial dynamics/mitophagy, mitochondrial proteostasis, and mitochondria-mediated cell death. Our review discusses the MQC mechanisms and how they are linked to cardiac Microvascular I/R injury. Additionally, we will summarize the molecular basis that results in defective MQC mechanisms and present potential therapeutic interventions for improving MQC in cardiac Microvascular I/R injury.
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new insights into the role of mitochondria in cardiac Microvascular Ischemia reperfusion injury
Angiogenesis, 2020Co-Authors: Jin Wang, Sam Toan, Hao ZhouAbstract:As reperfusion therapies have become more widely used in acute myocardial infarction patients, Ischemia-induced myocardial damage has been markedly reduced, but reperfusion-induced cardiac injury has become increasingly evident. The features of cardiac Ischemia–reperfusion (I/R) injury include Microvascular perfusion defects, platelet activation and sequential cardiomyocyte death due to additional ischemic events at the reperfusion stage. Microvascular obstruction, defined as a no-reflow phenomenon, determines the infarct zone, myocardial function and peri-operative mortality. Cardiac Microvascular endothelial cell injury may occur much earlier and with much greater severity than cardiomyocyte injury. Endothelial cells contain fewer mitochondria than other cardiac cells, and several of the pathological alterations during cardiac Microvascular I/R injury involve mitochondria, such as increased mitochondrial reactive oxygen species (mROS) levels and disturbed mitochondrial dynamics. Although mROS are necessary physiological second messengers, high mROS levels induce oxidative stress, endothelial senescence and apoptosis. Mitochondrial dynamics, including fission, fusion and mitophagy, determine the shape, distribution, size and function of mitochondria. These adaptive responses modify extracellular signals and orchestrate intracellular processes such as cell proliferation, migration, metabolism, angiogenesis, permeability transition, adhesive molecule expression, endothelial barrier function and anticoagulation. In this review, we discuss the involvement of mROS and mitochondrial morphofunction in cardiac Microvascular I/R injury.
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pathological roles of mitochondrial oxidative stress and mitochondrial dynamics in cardiac Microvascular Ischemia reperfusion injury
Biomolecules, 2020Co-Authors: Hao Zhou, Sam ToanAbstract:Mitochondria are key regulators of cell fate through controlling ATP generation and releasing pro-apoptotic factors. Cardiac Ischemia/reperfusion (I/R) injury to the coronary microcirculation has manifestations ranging in severity from reversible edema to interstitial hemorrhage. A number of mechanisms have been proposed to explain the cardiac Microvascular I/R injury including edema, impaired vasomotion, coronary microembolization, and capillary destruction. In contrast to their role in cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. It is clear that abnormal mitochondrial signatures, including mitochondrial oxidative stress, mitochondrial fission, mitochondrial fusion, and mitophagy, play a substantial role in endothelial cell function. While the pathogenic role of each of these mitochondrial alterations in the endothelial cells I/R injury remains complex, profiling of mitochondrial oxidative stress and mitochondrial dynamics in endothelial cell dysfunction may offer promising potential targets in the search for novel diagnostics and therapeutics in cardiac Microvascular I/R injury. The objective of this review is to discuss the role of mitochondrial oxidative stress on cardiac Microvascular endothelial cells dysfunction. Mitochondrial dynamics, including mitochondrial fission and fusion, are critically discussed to understand their roles in endothelial cell survival. Finally, mitophagy, as a degradative mechanism for damaged mitochondria, is summarized to figure out its contribution to the progression of Microvascular I/R injury.
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inhibitory effect of melatonin on necroptosis via repressing the ripk3 pgam5 cypd mptp pathway attenuates cardiac Microvascular Ischemia reperfusion injury
Journal of Pineal Research, 2018Co-Authors: Hao Zhou, Sam Toan, Jin Wang, Yundai Chen, Pingjun Zhu, Yingmei ZhangAbstract:The molecular features of necroptosis in cardiac Ischemia-reperfusion (IR) injury have been extensively explored. However, there have been no studies investigating the physiological regulatory mechanisms of melatonin acting on necroptosis in cardiac IR injury. This study was designed to determine the role of necroptosis in Microvascular IR injury, and investigate the contribution of melatonin in repressing necroptosis and preventing IR-mediated endothelial system collapse. Our results demonstrated that Ripk3 was primarily activated by IR injury and consequently aggravated endothelial necroptosis, microvessel barrier dysfunction, capillary hyperpermeability, the inflammation response, microcirculatory vasospasms, and Microvascular perfusion defects. However, administration of melatonin prevented Ripk3 activation and provided a pro-survival advantage for the endothelial system in the context of cardiac IR injury, similar to the results obtained via genetic ablation of Ripk3. Functional investigations clearly illustrated that activated Ripk3 upregulated PGAM5 expression, and the latter increased CypD phosphorylation, which obligated endothelial cells to undergo necroptosis via augmenting mPTP (mitochondrial permeability transition pore) opening. Interestingly, melatonin supplementation suppressed mPTP opening and interrupted endothelial necroptosis via blocking the Ripk3-PGAM5-CypD signal pathways. Taken together, our studies identified the Ripk3-PGAM5-CypD-mPTP axis as a new pathway responsible for reperfusion-mediated Microvascular damage via initiating endothelial necroptosis. In contrast, melatonin treatment inhibited the Ripk3-PGAM5-CypD-mPTP cascade and thus reduced cellular necroptosis, conferring a protective advantage to the endothelial system in IR stress. These findings establish a new paradigm in Microvascular IR injury and update the concept for cell death management handled by melatonin under the burden of reperfusion attack.
Jin Wang - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial quality control in cardiac Microvascular Ischemia reperfusion injury new insights into the mechanisms and therapeutic potentials
Pharmacological Research, 2020Co-Authors: Jin Wang, Sam Toan, Hao ZhouAbstract:Thrombolytic therapy and revascularization strategies create a complete recanalization of the occluded epicardial coronary artery in patients with myocardial infarction (MI). However, about 35 % of patients still experience an impaired myocardial reperfusion, which is termed a no-reflow phenomenon mainly caused by cardiac Microvascular Ischemia-reperfusion (I/R) injury. Mitochondria are essential for Microvascular endothelial cells' survival, both because of their roles as metabolic energy producers and as regulators of programmed cell death. Mitochondrial structure and function are regulated by a mitochondrial quality control (MQC) system, a series of processes including mitochondrial biogenesis, mitochondrial dynamics/mitophagy, mitochondrial proteostasis, and mitochondria-mediated cell death. Our review discusses the MQC mechanisms and how they are linked to cardiac Microvascular I/R injury. Additionally, we will summarize the molecular basis that results in defective MQC mechanisms and present potential therapeutic interventions for improving MQC in cardiac Microvascular I/R injury.
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new insights into the role of mitochondria in cardiac Microvascular Ischemia reperfusion injury
Angiogenesis, 2020Co-Authors: Jin Wang, Sam Toan, Hao ZhouAbstract:As reperfusion therapies have become more widely used in acute myocardial infarction patients, Ischemia-induced myocardial damage has been markedly reduced, but reperfusion-induced cardiac injury has become increasingly evident. The features of cardiac Ischemia–reperfusion (I/R) injury include Microvascular perfusion defects, platelet activation and sequential cardiomyocyte death due to additional ischemic events at the reperfusion stage. Microvascular obstruction, defined as a no-reflow phenomenon, determines the infarct zone, myocardial function and peri-operative mortality. Cardiac Microvascular endothelial cell injury may occur much earlier and with much greater severity than cardiomyocyte injury. Endothelial cells contain fewer mitochondria than other cardiac cells, and several of the pathological alterations during cardiac Microvascular I/R injury involve mitochondria, such as increased mitochondrial reactive oxygen species (mROS) levels and disturbed mitochondrial dynamics. Although mROS are necessary physiological second messengers, high mROS levels induce oxidative stress, endothelial senescence and apoptosis. Mitochondrial dynamics, including fission, fusion and mitophagy, determine the shape, distribution, size and function of mitochondria. These adaptive responses modify extracellular signals and orchestrate intracellular processes such as cell proliferation, migration, metabolism, angiogenesis, permeability transition, adhesive molecule expression, endothelial barrier function and anticoagulation. In this review, we discuss the involvement of mROS and mitochondrial morphofunction in cardiac Microvascular I/R injury.
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bi1 alleviates cardiac Microvascular Ischemia reperfusion injury via modifying mitochondrial fission and inhibiting xo ros f actin pathways
Journal of Cellular Physiology, 2019Co-Authors: Hao Zhou, Jin Wang, Hong Zhu, Sam Toanc, Jun RenAbstract:Pathogenesis of cardiac Microvascular Ischemia-reperfusion (IR) injury is associated with excessive mitochondrial fission. However, the upstream mediator of mitochondrial fission remains obscure. Bax inhibitor 1 (BI1) is linked to multiple mitochondrial functions, and there have been no studies investigating the contribution of BI1 on mitochondrial fission in the setting of cardiac Microvascular IR injury. This study was undertaken to establish the action of BI1 on the cardiac Microvascular reperfusion injury and figure out whether BI1 sustained endothelial viability via inhibiting mitochondrial fission. Our observation indicated that BI1 was downregulated in reperfused hearts and overexpression of BI1 attenuated Microvascular IR injury. Mechanistically, reperfusion injury elevated the levels of xanthine oxidase (XO), an effect that was followed by increased reactive oxygen species (ROS) production. Subsequently, oxidative stress mediated F-actin depolymerization and the latter promoted mitochondrial fission. Aberrant fission caused mitochondrial dysfunction and ultimately activated mitochondrial apoptosis in cardiac Microvascular endothelial cells. By comparison, BI1 overexpression repressed XO expression and thus neutralized ROS, interrupting F-actin-mediated mitochondrial fission. The inhibitory effect of BI1 on mitochondrial fission sustained endothelial viability, reversed endothelial barrier integrity, attenuated the Microvascular inflammation response, and maintained microcirculation patency. Altogether, we conclude that BI1 is essential in maintaining mitochondrial homeostasis and alleviating cardiac Microvascular IR injury. Deregulated BI1 via the XO/ROS/F-actin pathways plays a causative role in the development of cardiac Microvascular reperfusion injury.
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inhibitory effect of melatonin on necroptosis via repressing the ripk3 pgam5 cypd mptp pathway attenuates cardiac Microvascular Ischemia reperfusion injury
Journal of Pineal Research, 2018Co-Authors: Hao Zhou, Sam Toan, Jin Wang, Yundai Chen, Pingjun Zhu, Yingmei ZhangAbstract:The molecular features of necroptosis in cardiac Ischemia-reperfusion (IR) injury have been extensively explored. However, there have been no studies investigating the physiological regulatory mechanisms of melatonin acting on necroptosis in cardiac IR injury. This study was designed to determine the role of necroptosis in Microvascular IR injury, and investigate the contribution of melatonin in repressing necroptosis and preventing IR-mediated endothelial system collapse. Our results demonstrated that Ripk3 was primarily activated by IR injury and consequently aggravated endothelial necroptosis, microvessel barrier dysfunction, capillary hyperpermeability, the inflammation response, microcirculatory vasospasms, and Microvascular perfusion defects. However, administration of melatonin prevented Ripk3 activation and provided a pro-survival advantage for the endothelial system in the context of cardiac IR injury, similar to the results obtained via genetic ablation of Ripk3. Functional investigations clearly illustrated that activated Ripk3 upregulated PGAM5 expression, and the latter increased CypD phosphorylation, which obligated endothelial cells to undergo necroptosis via augmenting mPTP (mitochondrial permeability transition pore) opening. Interestingly, melatonin supplementation suppressed mPTP opening and interrupted endothelial necroptosis via blocking the Ripk3-PGAM5-CypD signal pathways. Taken together, our studies identified the Ripk3-PGAM5-CypD-mPTP axis as a new pathway responsible for reperfusion-mediated Microvascular damage via initiating endothelial necroptosis. In contrast, melatonin treatment inhibited the Ripk3-PGAM5-CypD-mPTP cascade and thus reduced cellular necroptosis, conferring a protective advantage to the endothelial system in IR stress. These findings establish a new paradigm in Microvascular IR injury and update the concept for cell death management handled by melatonin under the burden of reperfusion attack.
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nr4a1 aggravates the cardiac Microvascular Ischemia reperfusion injury through suppressing fundc1 mediated mitophagy and promoting mff required mitochondrial fission by ck2α
Basic Research in Cardiology, 2018Co-Authors: Hao Zhou, Sam Toan, Shunying Hu, Jin Wang, Yundai ChenAbstract:Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac Microvascular Ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac Microvascular IR injury, and its level was positively correlated with Microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute Microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked Microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac Microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.
Michael D Menger - One of the best experts on this subject based on the ideXlab platform.
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Microvascular in vivo assessment of reperfusion injury significance of prostaglandin e1 and i2 in postischemic no reflow and reflow paradox
Journal of Surgical Research, 2004Co-Authors: Stefan Tauber, Michael D Menger, Hansanton LehrAbstract:Abstract Background Microvascular Ischemia-reperfusion (I/R) injury is characterized by failure of capillary perfusion (“no-reflow”) and reoxygenation-associated phenomena (“reflow-paradox”), including activation of leukocyte-endothelium interaction with cytotoxic mediator-induced loss of endothelial integrity. The objectives of this study were to elucidate the impact of both prostaglandins E 1 (PGE 1 ) and I 2 (PGI 2 ) in Microvascular reperfusion injury, with special focus on the distinct pathophysiology of no-reflow- and reflow-paradox phenomena. Materials and methods By use of the hamster dorsal skinfold preparation and in vivo fluorescence microscopy, the microcirculation of a striated skin muscle was assessed before 4 h of pressure-induced Ischemia and 0.5, 2, and 24 h after onset of reperfusion. Results I/R was characterized by enhanced leukocyte-endothelium interaction in postcapillary venules, increase of macromolecular leakage, and reduction of functional capillary perfusion ( P 1 , starting with onset of reperfusion, reduced leukocyte adhesion and macromolecular leakage in postcapillary venules during early reperfusion ( P 2 infusion also attenuated postischemic leukocyte adhesion, which was significant by a 6-h prolonged administration ( P Conclusions Both prostaglandins did not significantly influence postischemic no-reflow phenomena, but appeared as potent inhibitors of reflow-paradox under the experimental circumstances of this study.
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Microvascular Ischemia reperfusion injury in striated muscle significance of no reflow
American Journal of Physiology-heart and Circulatory Physiology, 1992Co-Authors: Michael D Menger, D Steiner, K MessmerAbstract:“No reflow” has been implicated as prominent phenomenon in Microvascular injury associated with Ischemia-reperfusion (I/R). The objectives of this study were 1) to elucidate the significance of no ...
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Microvascular Ischemia reperfusion injury in striated muscle significance of reflow paradox
American Journal of Physiology-heart and Circulatory Physiology, 1992Co-Authors: Michael D Menger, S Pelikan, D Steiner, K MessmerAbstract:Ischemia-reperfusion (I/R)-induced Microvascular injury is characterized by capillary “no-reflow” and reflow-associated events, termed “reflow paradox,” including leukocyte-endothelium interaction ...
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distribution pattern of capillary and venular red blood cell velocity following Ischemia reperfusion in striated muscle
Advances in Experimental Medicine and Biology, 1992Co-Authors: Michael D Menger, Gernot Feifel, Konrad MessmerAbstract:Microvascular red blood cell (RBC) velocity in striated muscle fluctuates with time and varies from capillary to capillary (Ellis et al., 1990). The heterogeneity of Microvascular RBC-velocity is known to be enhanced in pathologic conditions, such as Ischemia-reperfusion (Tyml and Budreau, 1988; Menger et al., 1988). Previous studies have shown that Microvascular Ischemia-reperfusion injury is located primarily in nutritive capillaries and postcapillary venules (Menger et al., 1989; Lehr et al., 1991; Granger et al., 1989). The aim of the present study was to analyze the distribution pattern of capillary and venular RBC-velocity following Ischemia-reperfusion to striated muscle. Using the hamster dorsal skinfold preparation intravital fluorescence microscopy provides a direct access to the striated muscle microcirculation, allowing repeated observations over a prolonged period of time in the awake animal, including quantitative analysis of different microhemodynamic parameters (Endrich et al., 1980).
Yundai Chen - One of the best experts on this subject based on the ideXlab platform.
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inhibitory effect of melatonin on necroptosis via repressing the ripk3 pgam5 cypd mptp pathway attenuates cardiac Microvascular Ischemia reperfusion injury
Journal of Pineal Research, 2018Co-Authors: Hao Zhou, Sam Toan, Jin Wang, Yundai Chen, Pingjun Zhu, Yingmei ZhangAbstract:The molecular features of necroptosis in cardiac Ischemia-reperfusion (IR) injury have been extensively explored. However, there have been no studies investigating the physiological regulatory mechanisms of melatonin acting on necroptosis in cardiac IR injury. This study was designed to determine the role of necroptosis in Microvascular IR injury, and investigate the contribution of melatonin in repressing necroptosis and preventing IR-mediated endothelial system collapse. Our results demonstrated that Ripk3 was primarily activated by IR injury and consequently aggravated endothelial necroptosis, microvessel barrier dysfunction, capillary hyperpermeability, the inflammation response, microcirculatory vasospasms, and Microvascular perfusion defects. However, administration of melatonin prevented Ripk3 activation and provided a pro-survival advantage for the endothelial system in the context of cardiac IR injury, similar to the results obtained via genetic ablation of Ripk3. Functional investigations clearly illustrated that activated Ripk3 upregulated PGAM5 expression, and the latter increased CypD phosphorylation, which obligated endothelial cells to undergo necroptosis via augmenting mPTP (mitochondrial permeability transition pore) opening. Interestingly, melatonin supplementation suppressed mPTP opening and interrupted endothelial necroptosis via blocking the Ripk3-PGAM5-CypD signal pathways. Taken together, our studies identified the Ripk3-PGAM5-CypD-mPTP axis as a new pathway responsible for reperfusion-mediated Microvascular damage via initiating endothelial necroptosis. In contrast, melatonin treatment inhibited the Ripk3-PGAM5-CypD-mPTP cascade and thus reduced cellular necroptosis, conferring a protective advantage to the endothelial system in IR stress. These findings establish a new paradigm in Microvascular IR injury and update the concept for cell death management handled by melatonin under the burden of reperfusion attack.
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nr4a1 aggravates the cardiac Microvascular Ischemia reperfusion injury through suppressing fundc1 mediated mitophagy and promoting mff required mitochondrial fission by ck2α
Basic Research in Cardiology, 2018Co-Authors: Hao Zhou, Sam Toan, Shunying Hu, Jin Wang, Yundai ChenAbstract:Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac Microvascular Ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac Microvascular IR injury, and its level was positively correlated with Microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute Microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked Microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac Microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.
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bi1 is associated with Microvascular protection in cardiac Ischemia reperfusion injury via repressing syk nox2 drp1 mitochondrial fission pathways
Angiogenesis, 2018Co-Authors: Hao Zhou, Shunying Hu, Yundai ChenAbstract:Mitochondrial fission has been identified as the pathogenesis underlying the development of cardiac Microvascular Ischemia reperfusion (IR) injury, although the regulatory signaling upstream from fission is far from clear. Bax inhibitor is a novel anti-apoptotic factor, and, however, its role of cardiac Microvascular IR injury and mitochondrial homeostasis remains unclear. The cardiac Microvascular IR injury was performed in WT mice and BI1 transgenic (BITG) mice. The alterations of Microvascular structure and function were detected via electron microscope, immunohistochemistry and immunofluorescence in vivo. Cardiac Microvascular endothelial cells were isolated form WT and BITG mice and underwent hypoxia/reoxygenation injury in vitro. Cellular viability and apoptosis were analyzed via MTT assay and caspase-3 activity. Mitochondrial function, morphology and apoptosis were detected. Signaling pathways were analyzed via inhibitor, siRNA and mutant plasmid. Herein, we demonstrated that Bax inhibitor 1 (BI1) was downregulated following cardiac Microvascular IR injury, and its expression correlated negatively with Microvascular collapse, endothelial cell apoptosis and mitochondrial damage. However, compared to wild-type mice, BI1 transgenic mice were actually protected from the acute Microvascular injury and mitochondrial dysfunction. Functional studies illustrated that reintroduced BI1 directly interacted with and inhibited the Syk pathway, leading to the inactivation of Nox2. Subsequently, less Nox2 was associated with ROS downregulation, inhibiting Drp1 phosphorylated activation. Through repression of the Syk–Nox2–Drp1 signaling axis, BI1 strongly disrupted mitochondrial fission, abolishing mitochondrial apoptosis and thus sustaining endothelial cell viability. In summary, our report illustrates that BI1 functions as a novel Microvascular guardian in cardiac IR injury that operates via inhibition of the Syk–Nox2–Drp1-mitochondrial fission signaling axis. Thus, novel therapeutic strategies to regulate the balance between BI1 and mitochondrial fission could provide a survival advantage to microvasculature following IR stress.
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melatonin protects cardiac microvasculature against Ischemia reperfusion injury via suppression of mitochondrial fission vdac1 hk2 mptp mitophagy axis
Journal of Pineal Research, 2017Co-Authors: Hao Zhou, Shunying Hu, Ying Zhang, Feng Tian, Yundai ChenAbstract:: The cardiac Microvascular system, which is primarily composed of monolayer endothelial cells, is the site of blood supply and nutrient exchange to cardiomyocytes. However, Microvascular Ischemia/reperfusion injury (IRI) following percutaneous coronary intervention is a woefully neglected topic, and few strategies are available to reverse such pathologies. Here, we studied the effects of melatonin on microcirculation IRI and elucidated the underlying mechanism. Melatonin markedly reduced infarcted area, improved cardiac function, restored blood flow, and lower microcirculation perfusion defects. Histological analysis showed that cardiac microcirculation endothelial cells (CMEC) in melatonin-treated mice had an unbroken endothelial barrier, increased endothelial nitric oxide synthase expression, unobstructed lumen, reduced inflammatory cell infiltration, and less endothelial damage. In contrast, AMP-activated protein kinase α (AMPKα) deficiency abolished the beneficial effects of melatonin on microvasculature. In vitro, IRI activated dynamin-related protein 1 (Drp1)-dependent mitochondrial fission, which subsequently induced voltage-dependent anion channel 1 (VDAC1) oligomerization, hexokinase 2 (HK2) liberation, mitochondrial permeability transition pore (mPTP) opening, PINK1/Parkin upregulation, and ultimately mitophagy-mediated CMEC death. However, melatonin strengthened CMEC survival via activation of AMPKα, followed by p-Drp1S616 downregulation and p-Drp1S37 upregulation, which blunted Drp1-dependent mitochondrial fission. Suppression of mitochondrial fission by melatonin recovered VDAC1-HK2 interaction that prevented mPTP opening and PINK1/Parkin activation, eventually blocking mitophagy-mediated cellular death. In summary, this study confirmed that melatonin protects cardiac microvasculature against IRI. The underlying mechanism may be attributed to the inhibitory effects of melatonin on mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis via activation of AMPKα.