Exploring cuproptosis as a mechanism and potential intervention target in cardiovascular diseases DOI Creative Commons
Yang Yang, Qi Feng, Ying Luan

et al.

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 11, 2023

Copper (Cu) is a vital trace element for maintaining human health. Current evidence suggests that genes responsible regulating copper influx and detoxification help preserve its homeostasis. Adequate Cu levels sustain normal cardiac blood vessel activity by mitochondrial function. Cuproptosis, unlike other forms of cell death, characterized alterations in enzymes. Therapeutics targeting cuproptosis cardiovascular diseases (CVDs) mainly include chelators, inhibitors chaperone proteins, ionophores. In this review, we expound on the primary mechanisms, critical signaling pathways involved cuproptosis, along with impact CVDs role it plays different types cells. Additionally, explored influence key regulatory proteins associated determined whether intervening metabolism can enhance outcomes CVDs. The insights from review provide fresh perspective pathogenesis new targets intervention these diseases.

Language: Английский

Mitochondrial DNA Release in Innate Immune Signaling DOI Creative Commons
Laura Newman, Gerald S. Shadel

Annual Review of Biochemistry, Journal Year: 2023, Volume and Issue: 92(1), P. 299 - 332

Published: March 31, 2023

According to the endosymbiotic theory, most of DNA original bacterial endosymbiont has been lost or transferred nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is present-day mitochondrial (mtDNA). The ability mtDNA escape mitochondria and integrate into nuclear genome was discovered budding yeast, along with genes regulate this process. Mitochondria have emerged as key regulators innate immunity, it now recognized released cytoplasm, outside cell, circulation activates multiple immune signaling pathways. Here, we first review mechanisms through which including several inducible pores defective mitophagy autophagy. Next, cover how different forms activate specific nucleic acid sensors inflammasomes. Finally, discuss intracellular extracellular release, circulating cell-free promotes systemic inflammation, are implicated human diseases, viral infections, senescence aging.

Language: Английский

Citations

105
CircRNA DICAR as a novel endogenous regulator for diabetic cardiomyopathy and diabetic pyroptosis of cardiomyocytes DOI Creative Commons
Qiong Yuan,

Yunwei Sun,

Fan Yang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 8, 2023

Abstract In this study, we identified that a conserved circular RNA (circRNA) DICAR, which was downregulated in diabetic mouse hearts. DICAR had an inhibitory effect on cardiomyopathy (DCM), as the spontaneous cardiac dysfunction, cell hypertrophy, and fibrosis occurred deficiency ( +/− ) mice, whereas DCM alleviated DICAR-overexpressed Tg mice. At cellular level, found overexpression of inhibited, but knockdown enhanced cardiomyocyte pyroptosis. molecular DICAR-VCP-Med12 degradation could be underlying mechanism DICAR-mediated effects. The synthesized junction part (DICAR-JP) exhibited similar to entire DICAR. addition, expression circulating blood cells plasma from patients lower than health controls, consistent with decreased DICAR-JP may drug candidates for DCM.

Language: Английский

Citations

63
cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation DOI Creative Commons
Jingwen Liu, Jing Zhou,

Yuling Luan

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 9, 2024

Abstract Background Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression organ degeneration, but the mechanism regulation of crosstalk network remain unclear. Main body abstract Cellular stress disrupts mitochondrial homeostasis, facilitates opening permeability transition pore leakage DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, subsequently induces activation onset pyroptosis. Meanwhile, inflammasome-associated protein caspase-1, Gasdermin D, CARD domain ASC potassium channel are involved in regulating pathway. Importantly, this has a cascade amplification effect that exacerbates immuno-inflammatory response, worsening pathological process autoimmune diseases. Given importance innate immunity, it is emerging new avenue explore mechanisms multiple disease pathogenesis. Therefore, efforts define strategies selectively modulate different settings have been or ongoing. In review, we will describe how mechanistic understanding driving possible therapeutics targeting network, focusing on interacting regulatory proteins, pathways, hub between inflammasomes, Short conclusion This review aims provide insight into roles pyroptosis, highlight some promising directions future research intervention.

Language: Английский

Citations

30
mtDNA-cGAS-STING axis-dependent NLRP3 inflammasome activation contributes to postoperative cognitive dysfunction induced by sevoflurane in mice DOI Creative Commons

Nan‐Shi‐Yu Yang,

Wenjing Zhong,

Han-Xi Sha

et al.

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(5), P. 1927 - 1946

Published: Jan. 1, 2024

The activation of NLRP3 inflammasome in microglia is critical for neuroinflammation during postoperative cognitive dysfunction (POCD) induced by sevoflurane.However, the molecular mechanism which sevoflurane activates remains unclear.The cGAS-STING pathway an evolutionarily conserved inflammatory defense mechanism.The role sevoflurane-induced inflammasome-dependent and underlying mechanisms require further investigation.We found that prolonged anesthesia with triggered characterized vivo.Interestingly, was activated hippocampus mice receiving sevoflurane.While blockade cGAS RU.521 attenuated mice.In vitro, we treatment significantly microglia, while pre-treatment robustly inhibited activation.Mechanistically, mitochondrial fission released DNA (mtDNA) into cytoplasm, could be abolished Mdivi-1.Blocking mtDNA release via mPTP-VDAC channel inhibitor cytosolic escape reduced finally inhibiting activation.Therefore, regulating targeting may provide a novel therapeutic target POCD.

Language: Английский

Citations

20
Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases DOI Open Access
Yu Liu,

Yuejia Huang,

Chong Xu

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(24), P. 16053 - 16053

Published: Dec. 16, 2022

High mortality rates due to cardiovascular diseases (CVDs) have attracted worldwide attention. It has been reported that mitochondrial dysfunction is one of the most important mechanisms affecting pathogenesis CVDs. Mitochondrial DNA (mtDNA) mutations may result in impaired oxidative phosphorylation (OXPHOS), abnormal respiratory chains, and ATP production. In dysfunctional mitochondria, electron transport chain (ETC) uncoupled energy supply reduced, while reactive oxygen species (ROS) production increased. Here, we discussed analyzed relationship between mtDNA mutations, mitophagy, decreased OXPHOS, elevated ROS, CVDs from perspective dysfunction. Furthermore, explored current potential therapeutic strategies for by eliminating (e.g., editing replacement), enhancing improving OXPHOS capacity supplement with NAD+, nicotinamide riboside (NR), mononucleotide (NMN), nano-drug delivery), reducing ROS Coenzyme Q10 other antioxidants), dissected their respective advantages limitations. fact, some are still a long way achieving safe effective clinical treatment. Although establishing remains challenging, starting holds bright prospects.

Language: Английский

Citations

65
PGAM5-Mediated PHB2 Dephosphorylation Contributes to Diabetic Cardiomyopathy by Disrupting Mitochondrial Quality Surveillance DOI Creative Commons
Rongjun Zou, Jun Tao, Jie He

et al.

Research, Journal Year: 2022, Volume and Issue: 2022

Published: Jan. 1, 2022

Disruption of the mitochondrial quality surveillance (MQS) system contributes to dysfunction in diabetic cardiomyopathy (DCM). In this study, we observed that cardiac expression phosphoglycerate mutase 5 (PGAM5), a Ser/Thr protein phosphatase, is upregulated mice with streptozotocin-induced DCM. Notably, DCM-related structural and functional deficits were negated cardiomyocyte-specific

Language: Английский

Citations

53
Gasdermin D-mediated pyroptosis in myocardial ischemia and reperfusion injury: Cumulative evidence for future cardioprotective strategies DOI Creative Commons
Panat Yanpiset, Chayodom Maneechote,

Sirawit Sriwichaiin

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2022, Volume and Issue: 13(1), P. 29 - 53

Published: Aug. 14, 2022

Cardiomyocyte death is one of the major mechanisms contributing to development myocardial infarction (MI) and ischemia/reperfusion (MI/R) injury. Due limited regenerative ability cardiomyocytes, understanding cardiomyocyte necessary. Pyroptosis, regulated programmed cell pathways, has recently been shown play important roles in MI MI/R Pyroptosis activated by damage-associated molecular patterns (DAMPs) that are released from damaged cells activate formation an apoptosis-associated speck-like protein containing a CARD (ASC) interacting with NACHT, LRR, PYD domains-containing 3 (NLRP3), resulting caspase-1 cleavage which promotes activation Gasdermin D (GSDMD). This pathway known as canonical pathway. GSDMD also be non-canonical during injury via caspase-4/5/11. Suppression provide cardioprotection against Although effects or on pyroptosis have previously discussed, knowledge concerning these settings remains limited. In this review, evidence vitro, vivo, clinical studies focusing cardiac comprehensively summarized discussed. Implications review will help pave way for new therapeutic target ischemic heart disease.

Language: Английский

Citations

45
IQGAP1 promotes mitochondrial damage and activation of the mtDNA sensor cGAS-STING pathway to induce endothelial cell pyroptosis leading to atherosclerosis DOI Open Access

Cheng An,

Fei Sun, Can Liu

et al.

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 123, P. 110795 - 110795

Published: Aug. 17, 2023

Language: Английский

Citations

34
Nrf2 signaling in diabetic nephropathy, cardiomyopathy and neuropathy: Therapeutic targeting, challenges and future prospective DOI Creative Commons
Mehrdad Hashemi, Mohammad Arad Zandieh,

Setayesh Ziaolhagh

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2023, Volume and Issue: 1869(5), P. 166714 - 166714

Published: April 5, 2023

Language: Английский

Citations

32
STING mediates microglial pyroptosis via interaction with NLRP3 in cerebral ischaemic stroke DOI Creative Commons
Wenyu Li, Nan Shen,

Lingqi Kong

et al.

Stroke and Vascular Neurology, Journal Year: 2023, Volume and Issue: 9(2), P. 153 - 164

Published: July 3, 2023

Background Ischaemia-evoked neuroinflammation is a critical pathogenic event following ischaemic stroke. Gasdermin D (GSDMD)-associated pyroptosis represents type of inflammation-associated programmed cell death, which can exacerbate neuroinflammatory responses and brain damage. Stimulator interferon genes (STING) was recently described as vital innate immune adaptor protein associated with neuroinflammation. Nevertheless, the regulatory effects STING on microglial post-stroke have not been well elaborated. Methods STING-knockout wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAO). small interfering RNA (siRNA) transfected into BV2 cells before oxygen-glucose deprivation/reoxygenation (OGD/R). STING-overexpressing adeno-associated virus (AAV) NOD-like receptor family pyrin domain containing 3 (NLRP3) siRNA administered by stereotaxic injection. 2,3,5-Triphenyl tetrazolium chloride (TTC) staining, TdT-mediated dUTP nick end labeling (TUNEL) Fluoro-Jade C (FJC) neurobehavioural tests, immunohistochemistry, cytokine antibody array assay, transmission electron microscopy, immunoblot, Enzyme-linked immunosorbent assay (ELISA) quantitative real-time polymerase chain reaction (qRT-PCR) carried out. Co-immunoprecipitation assays used investigate interplay between NLRP3. Results expression increased after MCAO mainly detected microglia. deletion alleviated infarction, neuronal damage impairment in MCAO. knockout suppressed activation secretion inflammatory chemokines, accompanied mitigation pyroptosis. Specific upregulation AAV-F4/80-STING aggravated injury Mechanistically, co-immunoprecipitation showed that bound NLRP3 Supplementation reversed AAV-F4/80-STING-induced deterioration Conclusions The current findings indicate modulates NLRP3-mediated may serve therapeutic target induced ischaemic/reperfusion (I/R) injury.

Language: Английский

Citations

30