Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles

Lassen, Thomas Ravn; Just, Jesper; Hjortbak, Marie Vognstoft; Jespersen, Nichlas Riise; Stenz, Katrine Tang; Gu, Tingting; Yan, Yan; Su, Junjing; Hansen, Jakob; Bæk, Rikke; Jørgensen, Maléne Møller; Nyengaard, Jens Randel; Kristiansen, Steen Buus; Drasbek, Kim Ryun; Kjems, Jørgen; Bøtker, Hans Erik

doi:10.1007/s00395-021-00856-w

Cited by 31 publications

(23 citation statements)

References 87 publications

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“…When an acute myocardial injury, such as myocardial infarction, occurs, cardiomyocytes are in a state of stress and their mitochondria are extremely vulnerable to damage ( Ji et al, 2016 ; Alakoski et al, 2019 ; Lassen et al, 2021 ), so autophagy is crucial to eliminate damaged mitochondria and avoid further oxidative stress and apoptosis ( Kubli et al, 2015 ). PINK1/Parkin-induced mitophagy was found to be significantly upregulated during myocardial stress in response to ischemia and hypoxia ( Steffen et al, 2020 ; Yang et al, 2021b ).…”

Section: Receptor-dependent and Receptor-independent Pathwaysmentioning

confidence: 99%

RETRACTED: Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets

Kimberlee

et al. 2021

Front. Physiol.

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A variety of complex risk factors and pathological mechanisms contribute to myocardial stress, which ultimately promotes the development of cardiovascular diseases, including acute cardiac insufficiency, myocardial ischemia, myocardial infarction, high-glycemic myocardial injury, and acute alcoholic cardiotoxicity. Myocardial stress is characterized by abnormal metabolism, excessive reactive oxygen species production, an insufficient energy supply, endoplasmic reticulum stress, mitochondrial damage, and apoptosis. Mitochondria, the main organelles contributing to the energy supply of cardiomyocytes, are key determinants of cell survival and death. Mitophagy is important for cardiomyocyte function and metabolism because it removes damaged and aged mitochondria in a timely manner, thereby maintaining the proper number of normal mitochondria. In this review, we first introduce the general characteristics and regulatory mechanisms of mitophagy. We then describe the three classic mitophagy regulatory pathways and their involvement in myocardial stress. Finally, we discuss the two completely opposite effects of mitophagy on the fate of cardiomyocytes. Our summary of the molecular pathways underlying mitophagy in myocardial stress may provide therapeutic targets for myocardial protection interventions.

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Section: Receptor-dependent and Receptor-independent Pathwaysmentioning

confidence: 99%

RETRACTED: Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets

Kimberlee

et al. 2021

Front. Physiol.

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“…For example, Lassen et al demonstrated that beneficial effects of RIC are delivered through EVs and their miRNA content. The transferability of EV-mediated RIC cardioprotection from the RIC-treated patients to in vitro cultured murine myoblasts was also demonstrated ( 184 ). In this study, the three miRNAs were most upregulated in association with cardioprotection after the RIC treatment were miR-144-3p, miR-451a, and miR-16-5p.…”

Section: Role Of Micrornas In Transferring the Ric Protective Signalsmentioning

confidence: 99%

“…Similarly, whether RIC cardioprotection is transferable from the RIC-treated subject's plasma to naïve untreated subjects, and if this is mediated by circulating EVs, has been examined in both rodents and humans ( 184 – 186 ). Notably, these studies suggest RIC increased the release of EVs from the heart, RIC-induced protective signal is conveyed in part to the target organ via EVs, and this protection is transferable intra and across species.…”

Section: Ric: Role Of Evs In Transferring the Protective Signalmentioning

confidence: 99%

“…Aside from the regulatory role of miRNAs in the underlying mechanisms of conditioning-induced neuroprotection, miRNAs have also shown to be involved in the cardioprotective effects of conditioning ( 184 ). For example, Lassen et al demonstrated that beneficial effects of RIC are delivered through EVs and their miRNA content.…”

Section: Role Of Micrornas In Transferring the Ric Protective Signalsmentioning

confidence: 99%

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Immune Modulation as a Key Mechanism for the Protective Effects of Remote Ischemic Conditioning After Stroke

2021

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Remote ischemic conditioning (RIC), which involves a series of short cycles of ischemia in an organ remote to the brain (typically the limbs), has been shown to protect the ischemic penumbra after stroke and reduce ischemia/reperfusion (IR) injury. Although the exact mechanism by which this protective signal is transferred from the remote site to the brain remains unclear, preclinical studies suggest that the mechanisms of RIC involve a combination of circulating humoral factors and neuronal signals. An improved understanding of these mechanisms will facilitate translation to more effective treatment strategies in clinical settings. In this review, we will discuss potential protective mechanisms in the brain and cerebral vasculature associated with RIC. We will discuss a putative role of the immune system and circulating mediators of inflammation in these protective processes, including the expression of pro-and anti-inflammatory genes in peripheral immune cells that may influence the outcome. We will also review the potential role of extracellular vesicles (EVs), biological vectors capable of delivering cell-specific cargo such as proteins and miRNAs to cells, in modulating the protective effects of RIC in the brain and vasculature.

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“…In addition, RIC-derived EVs from human plasma transferred cardioprotection and reduced infarct size when EVs were perfused in rat hearts subjected to I/R injury ex vivo. These benefits were associated with the upregulation of miRNAs that target the mTOR pathway, including miR-16-5p, miR-144-3p and miR-451a [299]. Additionally, RIC-derived EVs from serum of patients under isoflurane anesthesia protected H9c2 cardiomyoblasts against hypoxiaevoked apoptosis [300].…”

Section: Remote Conditioning and Evs In Cardiac Protectionmentioning

confidence: 99%

Mitochondrial Quality Control in Cardiac-Conditioning Strategies against Ischemia-Reperfusion Injury

García-Niño

Zazueta

Buelna‐Chontal

et al. 2021

Life

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Mitochondria are the central target of ischemic preconditioning and postconditioning cardioprotective strategies, which consist of either the application of brief intermittent ischemia/reperfusion (I/R) cycles or the administration of pharmacological agents. Such strategies reduce cardiac I/R injury by activating protective signaling pathways that prevent the exacerbated production of reactive oxygen/nitrogen species, inhibit opening of mitochondrial permeability transition pore and reduce apoptosis, maintaining normal mitochondrial function. Cardioprotection also involves the activation of mitochondrial quality control (MQC) processes, which replace defective mitochondria or eliminate mitochondrial debris, preserving the structure and function of the network of these organelles, and consequently ensuring homeostasis and survival of cardiomyocytes. Such processes include mitochondrial biogenesis, fission, fusion, mitophagy and mitochondrial-controlled cell death. This review updates recent advances in MQC mechanisms that are activated in the protection conferred by different cardiac conditioning interventions. Furthermore, the role of extracellular vesicles in mitochondrial protection and turnover of these organelles will be discussed. It is concluded that modulation of MQC mechanisms and recognition of mitochondrial targets could provide a potential and selective therapeutic approach for I/R-induced mitochondrial dysfunction.

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Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles

Cited by 31 publications

References 87 publications

RETRACTED: Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets

RETRACTED: Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets

Immune Modulation as a Key Mechanism for the Protective Effects of Remote Ischemic Conditioning After Stroke

Mitochondrial Quality Control in Cardiac-Conditioning Strategies against Ischemia-Reperfusion Injury

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