New and revisited approaches to preserving the reperfused myocardium

Kloner, Robert A.; Brown, David A.; Csete, Marie; Dai, Wangde; Downey, James M.; Gottlieb, Roberta A.; Hale, Sharon L.; Shi, Jianru

doi:10.1038/nrcardio.2017.102

Cited by 57 publications

(68 citation statements)

References 293 publications

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“…The mitochondria have a central role in reperfusion injury in general (Kloner et al, 2017). Moreover, in pressure-overloaded mice, DNase activity or ablation of TLR9 disrupts the deleterious inflammatory response to mtDNA and improves survival after transaortic constriction (Oka et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation

Mariero

Torp

Heiestad

et al. 2019

British J Pharmacology

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Background and purpose Cellular debris causes sterile inflammation after myocardial infarction. Mitochondria constitute about 30 percent of the human heart. Mitochondrial DNA (mtDNA) is a damage‐associated‐molecular‐pattern that induce injurious sterile inflammation. Little is known about mtDNA's inflammatory signalling pathways in cardiomyocytes and how mtDNA is internalized to associate with its putative receptor, toll‐like receptor 9 (TLR9). Experimental Approach We hypothesized that mtDNA can be internalized in cardiomyocytes and induce an inflammatory response. Adult mouse cardiomyocytes were exposed to hypoxia‐reoxygenation and extracellular DNA. Microscale thermophoresis was used to demonstrate binding between nucleolin and DNA. Key results Expression of the pro‐inflammatory cytokines IL‐1β and TNFα were upregulated by mtDNA, but not by nuclear DNA (nDNA), in cardiomyocytes exposed to hypoxia‐reoxygenation. Blocking the RNA/DNA binding protein nucleolin with midkine reduced expression of IL‐1β/TNFα and the nucleolin inhibitor AS1411 reduced interleukin‐6 release in adult mouse cardiomyocytes. mtDNA bound 10‐fold stronger than nDNA to nucleolin. In HEK293‐NF‐κB reporter cells, mtDNA induced NF‐κB activity in normoxia, while CpG‐DNA and hypoxia‐reoxygenation, synergistically induced TLR9‐dependent NF‐κB activity. Protein expression of nucleolin was found in the plasma membrane of cardiomyocytes and inhibition of nucleolin with midkine inhibited cellular uptake of CpG‐DNA. Inhibition of endocytosis did not reduce CpG‐DNA uptake in cardiomyocytes. Conclusion and implications mtDNA, but not nDNA, induce an inflammatory response in mouse cardiomyocytes during hypoxia‐reoxygenation. In cardiomyocytes, nucleolin is expressed on the membrane and blocking nucleolin reduce inflammation. Nucleolin might be a therapeutic target to prevent uptake of immunogenic DNA and reduce inflammation. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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Section: Introductionmentioning

confidence: 99%

Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation

Mariero

Torp

Heiestad

et al. 2019

British J Pharmacology

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“…Preserving the reperfused myocardium is an important task in clinical cardiology to reduce morbidity and mortality after myocardial infarction. It is of interest to researchers that new approaches include those that target mitochondrial function and energetic as well as prevention of no-reflow phenomenon [ 43 ]. Besides prevention of excessive ROS, one of the possible mechanisms by which RPO might confer cardiovascular protection during ischemia/reperfusion is via increased phosphorylation of Akt kinase [ 19 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Red Palm Oil on Myocardial Antioxidant Enzymes, Nitric Oxide Synthase and Heart Function in Spontaneously Hypertensive Rats

Katengua-Thamahane

Bacova

Bernátová

et al. 2017

IJMS

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The purpose of this study was to investigate the effect of antioxidants rich red palm oil (RPO) supplementation on cardiac oxidative stress known as crucial factor deteriorating heart function in hypertension. 3-month-old, male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) were fed standard rat chow without or with RPO (0.2 mL/day/5 weeks). General characteristic of rats were registered. Left ventricular tissue (LV) was used to determine expression of superoxide dismutases (SOD1, SOD2) and glutathione peroxidases (Gpx) as well as activity of nitric oxide synthase (NOS). Functional parameters of the heart were examined during basal conditions and at the early-phase of post-ischemic reperfusion using Langendorff-perfused system. RPO intake significantly reduced elevated blood pressure and total NOS activity as well as increased lowered expression of mitochondrial SOD2 in SHR hearts during basal condition. Moreover, RPO supplementation resulted in suppression of elevated heart rate, increase of reduced coronary flow and enhancement of systolic and diastolic heart function at the early-phase of post-ischemic reperfusion. It is concluded that SHR benefit from RPO intake due to decrease of blood pressure, amelioration of oxidative stress and protection of heart function that was deteriorated by post-ischemic reperfusion.

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“…Although contentious, the protein kinase C (PKC) family of isoenzymes has been involved in pre‐conditioning protection against ischaemia‐reperfusion injury . The KAI‐9803 peptide (delcasertib) inhibits δ‐PKC activity and prevents translocation of δ‐PKC to the mitochondria during prolonged ischaemia reperfusion.…”

Section: Mechanisms Underlying Attenuation Of Mitochondrial Dysfunctimentioning

confidence: 99%

“…Although contentious, 41 the protein kinase C (PKC) family of isoenzymes has been involved in pre-conditioning protection against ischaemia-reperfusion injury. 42 The KAI-9803 peptide (delcasertib) inhibits δ-PKC activity and prevents translocation of δ-PKC to the mitochondria during prolonged ischaemia reperfusion. Whereas administration of KAI-9803 may preserve mitochondrial function, it has no direct action on MPTP opening, but would rather prevent apoptosis by limiting the accumulation and dephosphorylation of the pro-apoptotic Bcl-2-associated death promoter.…”

Section: Kai-9803mentioning

confidence: 99%

Translational issues for mitoprotective agents as adjunct to reperfusion therapy in patients with ST‐segment elevation myocardial infarction

Bøtker

Cabrera-Fuentes

Ruiz‐Meana

et al. 2020

J Cellular Molecular Medi

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Pre‐clinical studies have indicated that mitoprotective drugs may add cardioprotection beyond rapid revascularization, antiplatelet therapy and risk modification. We review the clinical efficacy of mitoprotective drugs that have progressed to clinical testing comprising cyclosporine A, KAI‐9803, MTP131 and TRO 40303. Whereas cyclosporine may reduce infarct size in patients undergoing primary angioplasty as evaluated by release of myocardial ischaemic biomarkers and infarct size imaging, the other drugs were not capable of demonstrating this effect in the clinical setting. The absent effect leaves the role of the mitochondrial permeability transition pore for reperfusion injury in humans unanswered and indicates that targeting one single mechanism to provide mitoprotection may not be efficient. Moreover, the lack of effect may relate to favourable outcome with current optimal therapy, but conditions such as age, sex, diabetes, dyslipidaemia and concurrent medications may also alter mitochondrial function. However, as long as the molecular structure of the pore remains unknown and specific inhibitors of its opening are lacking, the mitochondrial permeability transition pore remains a target for alleviation of reperfusion injury. Nevertheless, taking conditions such as ageing, sex, comorbidities and co‐medication into account may be of paramount importance during the design of pre‐clinical and clinical studies testing mitoprotective drugs.

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New and revisited approaches to preserving the reperfused myocardium

Cited by 57 publications

References 293 publications

Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation

Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation

Effects of Red Palm Oil on Myocardial Antioxidant Enzymes, Nitric Oxide Synthase and Heart Function in Spontaneously Hypertensive Rats

Translational issues for mitoprotective agents as adjunct to reperfusion therapy in patients with ST‐segment elevation myocardial infarction

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