Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

Redox Biology, Год журнала: 2021, Номер 45, С. 102049 - 102049

Опубликована: Июнь 17, 2021

Mitochondrial dysfunction is a fundamental challenge in septic cardiomyopathy. Mitophagy and the mitochondrial unfolded protein response (UPRmt) are predominant stress-responsive protective mechanisms involved repairing damaged mitochondria. Although homeostasis requires coordinated actions of mitophagy UPRmt, their molecular basis interactive poorly understood sepsis-induced myocardial injury. Our investigations showed that lipopolysaccharide (LPS)-induced sepsis contributed to cardiac damage. both UPRmt were slightly activated by LPS cardiomyocytes, endogenous activation failed prevent sepsis-mediated However, administration urolithin A, an inducer mitophagy, obviously reduced depression normalizing function. Interestingly, this beneficial action was undetectable cardiomyocyte-specific FUNDC1 knockout (FUNDC1CKO) mice. Notably, supplementation with had no impact on whereas genetic ablation significantly upregulated expression genes related LPS-treated hearts. In contrast, enhancement through oligomycin injury dysfunction; cardioprotective effect imperceptible FUNDC1CKO Lastly, once inhibited, mitophagy-mediated protection mitochondria cardiomyocytes partly blunted. Taken together, it plausible stress they work together sustain performance Endogenous downstream signal played compensatory role maintaining case inhibition. negative inhibition compromised partial mitophagy. This study shows how modulates attenuate inflammation-related suggests potential application targeting treatment stress.

Язык: Английский

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Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

Redox Biology, Год журнала: 2022, Номер 52, С. 102288 - 102288

Опубликована: Март 18, 2022

Mitophagy preserves microvascular structure and function during myocardial ischemia/reperfusion (I/R) injury. Empagliflozin, an anti-diabetes drug, may also protect mitochondria. We explored whether empagliflozin could reduce cardiac I/R injury by enhancing mitophagy. In mice, induced luminal stenosis, microvessel wall damage, erythrocyte accumulation perfusion defects in the microcirculation. Additionally, triggered endothelial hyperpermeability neutrophil infiltration, which upregulated adhesive factors endothelin-1 but downregulated vascular cadherin nitric oxide synthase heart tissue. vitro, impaired barrier integrity of cells (CMECs), while preserved CMEC homeostasis thus maintained function. activated mitochondrial fission, oxidative stress apoptotic signaling CMECs, whereas normalized fission fusion, neutralized supraphysiologic reactive oxygen species concentrations suppressed apoptosis. Empagliflozin exerted these protective effects activating FUNDC1-dependent mitophagy through AMPKα1/ULK1 pathway. Both vitro vivo, genetic ablation AMPKα1 or FUNDC1 abolished beneficial on microvasculature CMECs. Taken together, preservation activation AMPKα1/ULK1/FUNDC1/mitophagy pathway is working mechanism attenuating

Язык: Английский

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Cellular Crosstalk between Endothelial and Smooth Muscle Cells in Vascular Wall Remodeling

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(14), С. 7284 - 7284

Опубликована: Июль 6, 2021

Pathological vascular wall remodeling refers to the structural and functional changes of vessel that occur in response injury eventually leads cardiovascular disease (CVD). Vessel are composed two major primary cells types, endothelial (EC) smooth muscle (VSMCs). The physiological communications between these cell types (EC–VSMCs) crucial development vasculature homeostasis mature vessels. Moreover, aberrant EC–VSMCs communication has been associated promotor various states including remodeling. Paracrine regulations by bioactive molecules, via direct contact (junctions) or information transfer extracellular vesicles matrix main crosstalk mechanisms. Identification nature this may offer strategies develop new insights for prevention treatment curse with Here, we will review molecular mechanisms underlying interplay EC VSMCs. Additionally, highlight potential applicable methodologies co-culture systems identify cellular involved pathological remodeling, opening questions about future research directions.

Язык: Английский

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The lncRNA Malat1 regulates microvascular function after myocardial infarction in mice via miR-26b-5p/Mfn1 axis-mediated mitochondrial dynamics

Redox Biology, Год журнала: 2021, Номер 41, С. 101910 - 101910

Опубликована: Фев. 23, 2021

Myocardial infarction (MI) is a leading cause of cardiovascular mortality globally. The improvement microvascular function critical for cardiac repair after MI. Evidence now points to long non-coding RNAs (lncRNAs) as key regulators remodelling processes. lncRNA Malat1 involved in the development and progression multiple diseases. Studies have shown that closely related regulation endothelial cell regeneration. However, potential molecular mechanisms repairing dysfunction MI remain unreported.The present study found upregulated border zone mouse hearts, well isolated cells (CMECs). Targeted knockdown exacerbated oxidative stress, attenuated angiogenesis perfusion, result decreased mice. Further studies showed silencing obviously inhibited CMEC proliferation, migration tube formation, which was at least part attributed disturbed mitochondrial dynamics activation apoptosis pathway. Moreover, bioinformatic analyses, luciferase assays pull-down indicated acted competing endogenous RNA (ceRNA) miR-26b-5p formed signalling axis with Mfn1 regulate functions. Overexpression markedly reversed injuries were aggravated by via inhibition excessive fragments mitochondria-dependent apoptosis.The elucidated functions microcirculation underlying effects could be its blocking on miR-26b-5p/Mfn1 pathway-mediated apoptosis.

Язык: Английский

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Mitochondrial quality control mechanisms as molecular targets in diabetic heart

Metabolism, Год журнала: 2022, Номер 137, С. 155313 - 155313

Опубликована: Сен. 17, 2022

Язык: Английский

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Molecular mechanisms of coronary microvascular endothelial dysfunction in diabetes mellitus: focus on mitochondrial quality surveillance

Angiogenesis, Год журнала: 2022, Номер 25(3), С. 307 - 329

Опубликована: Март 18, 2022

Язык: Английский

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Empagliflozin attenuates cardiac microvascular ischemia/reperfusion injury through improving mitochondrial homeostasis

Cardiovascular Diabetology, Год журнала: 2022, Номер 21(1)

Опубликована: Июнь 15, 2022

Abstract Background Empagliflozin has been reported to protect endothelial cell function, regardless of diabetes status. However, the role empagliflozin in microvascular protection during myocardial ischemia reperfusion injury (I/R) not fully understood. Methods Electron microscopy, western blots, immunofluorescence, qPCR, mutant plasmid transfection, co-immunoprecipitation were employed explore whether could alleviate damage and cardiac I/R injury. Results In mice, attenuated injury-induced occlusion microthrombus formation. human coronary artery cells, led adhesive factor upregulation, nitric oxide synthase inactivation, focal adhesion kinase downregulation, barrier dysfunction, cytoskeletal degradation cellular apoptosis; however, treatment diminished these effects. improved mitochondrial oxidative stress, respiration adenosine triphosphate metabolism I/R-treated cells by preventing phosphorylation dynamin-related protein 1 (Drp1) fission (Fis1), thus repressing fission. The protective effects on homeostasis function abrogated re-introduction phosphorylated Fis1, but Drp1, suggesting that Fis1 dephosphorylation is predominant mechanism whereby inhibits Besides, induced primarily activating DNA-dependent catalytic subunit (DNA-PKcs) pathway, while inactivated this pathway exerting anti-oxidative Conclusions These results demonstrated can microvasculature inhibiting DNA-PKcs/Fis1/mitochondrial

Язык: Английский

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Myocardial ischemia-reperfusion injury; Molecular mechanisms and prevention

Microvascular Research, Год журнала: 2023, Номер 149, С. 104565 - 104565

Опубликована: Июнь 10, 2023

Язык: Английский

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Intravenous Transplantation of an Ischemic-specific Peptide-TPP-mitochondrial Compound Alleviates Myocardial Ischemic Reperfusion Injury

ACS Nano, Год журнала: 2023, Номер 17(2), С. 896 - 909

Опубликована: Янв. 10, 2023

It is known that mitochondrial dysfunction a critical factor involved in myocardial ischemia–reperfusion injury. Mitochondrial transplantation has been suggested as an effective therapeutic strategy to protect against However, its clinical translation remains limited because it requires the local injection of mitochondria into myocardium. Here, polypeptide, CSTSMLKAC (PEP), bound triphenylphosphonium cations (TPP+) effectively binds form PEP–TPP–mitochondrial compound. Further investigation this compound revealed ischemia-sensing properties PEP promote translocation ischemic Additionally, targeting peptide, PEP, readily dissociates from compound, allowing for transplanted be efficiently internalized by cardiomyocytes or transferred endothelial cells. promotes cardiomyocyte energetics and mechanical contraction, subsequently reducing cellular apoptosis, macrophage infiltration, pro-inflammatory response, all which lead attenuation Thus, study provides promising evidence intravenous myocardium ameliorates

Язык: Английский

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New insights into the role of mitochondrial metabolic dysregulation and immune infiltration in septic cardiomyopathy by integrated bioinformatics analysis and experimental validation

Cellular & Molecular Biology Letters, Год журнала: 2024, Номер 29(1)

Опубликована: Янв. 30, 2024

Abstract Background Septic cardiomyopathy (SCM), a common cardiovascular comorbidity of sepsis, has emerged among the leading causes death in patients with sepsis. SCM’s pathogenesis is strongly affected by mitochondrial metabolic dysregulation and immune infiltration disorder. However, specific mechanisms their intricate interactions SCM remain unclear. This study employed bioinformatics analysis drug discovery approaches to identify regulatory molecules, distinct functions, underlying metabolism microenvironment, along potential interventional strategies SCM. Methods GSE79962, GSE171546, GSE167363 datasets were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) module identified using Limma Weighted Correlation Network Analysis (WGCNA), followed functional enrichment analysis. Machine learning algorithms, including support vector machine–recursive feature elimination (SVM–RFE), least absolute shrinkage selection operator (LASSO) regression, random forest, used screen mitochondria-related hub for early diagnosis Subsequently, nomogram was developed based on six genes. The immunological landscape evaluated single-sample gene set (ssGSEA). We also explored expression pattern distribution mitochondria/inflammation-related pathways UMAP plots single-cell dataset. Potential drugs Drug Signatures Database (DSigDB). In vivo vitro experiments performed validate pathogenetic mechanism therapeutic efficacy candidate drugs. Results Six DEGs [MitoDEGs; translocase inner membrane domain-containing 1 (TIMMDC1), ribosomal protein S31 (MRPS31), F-box only 7 (FBXO7), phosphatidylglycerophosphate synthase (PGS1), LYR motif containing (LYRM7), chaperone BCS1 (BCS1L)] identified. diagnostic model demonstrated high reliability validity both training validation sets. microenvironment differed between control groups. Spearman correlation revealed that MitoDEGs significantly associated cells. Upregulated showed remarkably naive/memory B cell, CD14 + monocyte, plasma cell subgroup, evidenced plot. varied across subgroups individuals. Metformin predicted be most promising highest combined score. Its restoring function suppressing inflammatory responses been validated. Conclusions presents comprehensive SCM, providing novel direction medical intervention

Язык: Английский

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