Proinflammatory Effect of Endothelial Microparticles Is Mitochondria Mediated and Modulated Through MAPKAPK2 (MAPK-Activated Protein Kinase 2) Leading to Attenuation of Cardiac Hypertrophy

Tripathi, Dipti; Biswas, Bharti; Manhas, Amit; Singh, Abhinav; Goyal, Dipika; Gaestel, Matthias; Jagavelu, Kumaravelu

doi:10.1161/atvbaha.119.312533

Cited by 28 publications

(15 citation statements)

References 32 publications

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“…In agreement with these findings, in vitro studies demonstrated increased ROS production and the increased phosphorylation of p38, a signaling protein involved in endothelial activation [60]. Other studies have also shown that EMPs induce ROS production in endothelial cells [18,60,61,62]. This increase is explained, at least in part, by the activation of the NADPH oxidase pathway [18].…”

Section: Internalization and Signaling Pathways Induced By Empsmentioning

confidence: 53%

Endothelial Microparticles in Uremia: Biomarkers and Potential Therapeutic Targets

Favretto

Cunha

Dalboni

et al. 2019

Toxins

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Endothelial microparticles (EMPs) are vesicles derived from cell membranes, which contain outsourced phosphatidylserine and express adhesion molecules, such as cadherin, intercellular cell adhesion molecule-1 (ICAM-1), E-selectin, and integrins. EMPs are expressed under physiological conditions and continue circulating in the plasma. However, in pathologic conditions their levels increase, and they assume a pro-inflammatory and pro-coagulant role via interactions with monocytes; these effects are related to the development of atherosclerosis. Chronic kidney dysfunction (CKD) characterizes this dysfunctional scenario through the accumulation of uremic solutes in the circulating plasma, whose toxicity is related to the development of cardiovascular diseases. Therefore, this review aims to discuss the formation of EMPs and their biological effects in the uremic environment. Data from previous research demonstrate that uremic toxins are closely associated with the activation of inflammatory biomarkers, cardiovascular dysfunction processes, and the release of EMPs. The impact of a decrease in circulating EMPs in clinical studies has not yet been evaluated. Thus, whether MPs are biochemical markers and/or therapeutic targets has yet to be established.

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Section: Internalization and Signaling Pathways Induced By Empsmentioning

confidence: 53%

Endothelial Microparticles in Uremia: Biomarkers and Potential Therapeutic Targets

Favretto

Cunha

Dalboni

et al. 2019

Toxins

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“…The activation of inflammasome was identified in cardiomyocytes in pathological conditions. Further, inflammatory response plays an important role in regulating myocardial hypertrophy and heart failure[20][21][22] . Our data therefore identified S-nitrosylated MLP as a key regulator, which together with TLR3 may serve as putative therapeutic targets in treating pathological myocardial hypertrophy and heart failure.…”

mentioning

confidence: 99%

SNO-MLP (S-Nitrosylation of Muscle LIM Protein) Facilitates Myocardial Hypertrophy Through TLR3 (Toll-Like Receptor 3)–Mediated RIP3 (Receptor-Interacting Protein Kinase 3) and NLRP3 (NOD-Like Receptor Pyrin Domain Containing 3) Inflammasome Activation

Tang¹,

Pan²,

Zhao³

et al. 2020

Circulation

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Background: S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of SNO of MLP (muscle LIM protein) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload. Methods: Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. SNO sites were further identified through liquid chromatography–tandem mass spectrometry. Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry and confirmed by coimmunoprecipitation. Recruitment of TLR3 (Toll-like receptor 3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA–transfected neonatal rat cardiomyocytes and in a TLR3 knockout mouse model. Results: SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction. The level of SNO-MLP also increased in angiotensin II– or phenylephrine-treated neonatal rat cardiomyocytes. S-nitrosylated site of MLP at cysteine 79 was identified by liquid chromatography–tandem mass spectrometry and confirmed in neonatal rat cardiomyocytes. Mutation of cysteine 79 significantly reduced hypertrophic growth in angiotensin II– or phenylephrine-treated neonatal rat cardiomyocytes and transverse aortic constriction mice. Reducing SNO-MLP level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, SNO-MLP stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupted this interaction by downregulating TLR3-attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and RIP3 (receptor-interacting protein kinase 3). This interaction in turn induced NLRP3 (nucleotide-binding oligomerization domain–like receptor pyrin domain containing 3) inflammasome activation, thereby promoting the development of myocardial hypertrophy. Conclusions: Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a therapeutic target for myocardial hypertrophy and heart failure.

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“…It has been found that some cells can secrete EVs containing mitochondria or mitochondrial compositions, such as monocytes 9 , hepatocytes 74 , endothelial cells 75 , and MSCs 76,77 , and their effect on recipient cells is determined by the activated status of their source of cells. In the recipient cell, EVs will bind to the cell surface and initiate intracellular signaling pathways through receptor ligand binding.…”

Section: The Transfer Of Mitochondria Between Cellsmentioning

confidence: 99%

“…Moreover, the transfer of mitochondria via exosomes derived from proinflammatory myeloid-derived regulatory cells results in its co-localization with the mitochondrial network of the T cells to produce ROS 83 . Endothelial microparticles (EMPs) derived from lipopolysaccharide-treated endothelial cells contain dysfunctional mitochondria, which contributed to the EMPs-mediated inflammatory response 75 . Mitochondrial Lon induced the release of EVs-containing mtDNA, which enhances the M2 macrophages function through the TLR9-dependent pathway and inhibits CD8+ T cell activity, promoting tumor progression 84 .…”

Section: The Transfer Of Mitochondria Between Cellsmentioning

confidence: 99%

The effect of extracellular vesicles on the regulation of mitochondria under hypoxia

et al. 2021

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Mitochondria are indispensable organelles for maintaining cell energy metabolism, and also are necessary to retain cell biological function by transmitting information as signal organelles. Hypoxia, one of the important cellular stresses, can directly regulates mitochondrial metabolites and mitochondrial reactive oxygen species (mROS), which affects the nuclear gene expression through mitochondrial retrograde signal pathways, and also promotes the delivery of signal components into cytoplasm, causing cellular injury. In addition, mitochondria can also trigger adaptive mechanisms to maintain mitochondrial function in response to hypoxia. Extracellular vesicles (EVs), as a medium of information transmission between cells, can change the biological effects of receptor cells by the release of cargo, including nucleic acids, proteins, lipids, mitochondria, and their compositions. The secretion of EVs increases in cells under hypoxia, which indirectly changes the mitochondrial function through the uptake of contents by the receptor cells. In this review, we focus on the mitochondrial regulation indirectly through EVs under hypoxia, and the possible mechanisms that EVs cause the changes in mitochondrial function. Finally, we discuss the significance of this EV-mitochondria axis in hypoxic diseases.

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Proinflammatory Effect of Endothelial Microparticles Is Mitochondria Mediated and Modulated Through MAPKAPK2 (MAPK-Activated Protein Kinase 2) Leading to Attenuation of Cardiac Hypertrophy

Cited by 28 publications

References 32 publications

Endothelial Microparticles in Uremia: Biomarkers and Potential Therapeutic Targets

Endothelial Microparticles in Uremia: Biomarkers and Potential Therapeutic Targets

SNO-MLP (S-Nitrosylation of Muscle LIM Protein) Facilitates Myocardial Hypertrophy Through TLR3 (Toll-Like Receptor 3)–Mediated RIP3 (Receptor-Interacting Protein Kinase 3) and NLRP3 (NOD-Like Receptor Pyrin Domain Containing 3) Inflammasome Activation

The effect of extracellular vesicles on the regulation of mitochondria under hypoxia

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