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

An, Cheng; Sun, Fei; Liu, Can; Huang, Shaojun; Xu, Tao; Zhang, Chengxin; Ge, Shenglin

doi:10.1016/j.intimp.2023.110795

Cited by 14 publications

(5 citation statements)

References 46 publications

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“…Recent investigations have disclosed that cytoplasmic mtDNA, functioning as endogenous DNA, can activate the STING pathway, thereby precipitating an inflammatory response [ 20 ]. Concurrently, additional studies have highlighted the activation of the STING pathway within endothelial cells throughout atherogenesis [ 23 , 24 ]. In light of this, we evaluated the activation levels of the STING pathway in the aortas of both ApoE −/− and Gsdme −/− /ApoE −/− mice at 18 weeks of age following a WD regimen.…”

Section: Resultsmentioning

confidence: 99%

GSDME in Endothelial Cells: Inducing Vascular Inflammation and Atherosclerosis via Mitochondrial Damage and STING Pathway Activation

Xie,

Su,

Song

et al. 2023

Biomedicines

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The initiation of atherosclerotic plaque is characterized by endothelial cell inflammation. In light of gasdermin E’s (GSDME) role in pyroptosis and inflammation, this study elucidates its function in atherosclerosis onset. Employing Gsdme- and apolipoprotein E-deficient (Gsdme−/−/ApoE−/−) and ApoE−/− mice, an atherosclerosis model was created on a Western diet (WD). In vitro examinations with human umbilical vein endothelial cells (HUVECs) included oxidized low-density lipoprotein (ox-LDL) exposure. To explore the downstream mechanisms linked to GSDME, we utilized an agonist targeting the stimulator of the interferon genes (STING) pathway. The results showed significant GSDME activation in ApoE−/− mice arterial tissues, corresponding with atherogenesis. Gsdme−/−/ApoE−/− mice displayed fewer plaques and decreased vascular inflammation. Meanwhile, GSDME’s presence was confirmed in endothelial cells. GSDME inhibition reduced the endothelial inflammation induced by ox-LDL. GSDME was linked to mitochondrial damage in endothelial cells, leading to an increase in cytoplasmic double-stranded DNA (dsDNA). Notably, STING activation partially offset the effects of GSDME inhibition in both in vivo and in vitro settings. Our findings underscore the pivotal role of GSDME in endothelial cells during atherogenesis and vascular inflammation, highlighting its influence on mitochondrial damage and the STING pathway, suggesting a potential therapeutic target for vascular pathologies.

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Section: Resultsmentioning

confidence: 99%

GSDME in Endothelial Cells: Inducing Vascular Inflammation and Atherosclerosis via Mitochondrial Damage and STING Pathway Activation

Xie,

Su,

Song

et al. 2023

Biomedicines

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“…Recent reports have suggested that the cGAS-STING signaling pathway plays an important role in cardiovascular inflammation [ 91 ]. The PA-induced release of mtDNA from endothelial cells activates the cGAS-STING-IRF3 signaling pathway to promote increased levels of inflammatory cytokines IL-1β, IL-6, and NLRP3 inflammasome, leading to pyroptosis onset and affecting the formation of AS; using small interfering RNAs cGAS or STING inhibits this process [ 92 ]. Guo et al [ 56 ] found that iNOS deficiency inhibits mtDNA release to attenuate stress-induced aseptic cardiac inflammation; however, activated cGAS-STING attenuates its cardioprotective function, suggesting that preventing sterile inflammation is particularly critical for CVDs.…”

Section: Risk Factors For Activating Cgas-sting In Daily Lifementioning

confidence: 99%

“…Interestingly, a study linking neuroinflammation in the paraventricular nucleus of mice with hypertensive heart disease found that an intra-feeding perfusion of RU.521 blocked microglia autophagic fluxes to attenuate the hypertensive myocardial injury caused by neuroinflammation and sympathetic overactivation [ 113 ]. Meanwhile, RU.521 plays a critical role in attenuating sepsis-induced cardiac dysfunction [ 109 ], endothelial focal death-induced AS [ 92 ], ischemia–reperfusion-induced myocardial apoptosis, and cardiac dysfunction [ 114 ]. These findings provide a new phase in the clinical application of RU.521 for the treatment of CVDs.…”

Section: Therapeutic Targets Of the Cgas-sting Pathway In Cvdsmentioning

confidence: 99%

The cGAS-STING pathway in cardiovascular diseases: from basic research to clinical perspectives

An,

Li,

Chen

et al. 2024

Cell Biosci

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The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, an important component of the innate immune system, is involved in the development of several diseases. Ectopic DNA-induced inflammatory responses are involved in several pathological processes. Repeated damage to tissues and metabolic organelles releases a large number of damage-associated molecular patterns (mitochondrial DNA, nuclear DNA, and exogenous DNA). The DNA fragments released into the cytoplasm are sensed by the sensor cGAS to initiate immune responses through the bridging protein STING. Many recent studies have revealed a regulatory role of the cGAS-STING signaling pathway in cardiovascular diseases (CVDs) such as myocardial infarction, heart failure, atherosclerosis, and aortic dissection/aneurysm. Furthermore, increasing evidence suggests that inhibiting the cGAS-STING signaling pathway can significantly inhibit myocardial hypertrophy and inflammatory cell infiltration. Therefore, this review is intended to identify risk factors for activating the cGAS-STING pathway to reduce risks and to simultaneously further elucidate the biological function of this pathway in the cardiovascular field, as well as its potential as a therapeutic target.

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“…The activation of the cGAS-STING pathway was observed in dysfunctional endothelial cells with elevated cytosolic mtDNA and nuDNA, leading to an increase in the expression of IL-6 mRNA in AS ( 98 ). Moreover, research indicates that damaged endothelial cells within these plaques, due to mitochondrial dysfunction, exhibit significantly elevated mtDNA levels, inducing the activation of the cGAS-STING pathway, thereby exacerbating endothelial cell damage ( 99 ). The functionality of endothelial cells is largely contingent upon Ca 2+ concentrations.…”

Section: Role Of Cgas-sting Pathway In the Risk Factors Of Ischemic S...mentioning

confidence: 99%

Novel insight into cGAS-STING pathway in ischemic stroke: from pre- to post-disease

Ma,

Xin,

She

et al. 2023

Front. Immunol.

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Ischemic stroke, a primary cause of disability and the second leading cause of mortality, has emerged as an urgent public health issue. Growing evidence suggests that the Cyclic GMP-AMP synthase (cGAS)- Stimulator of interferon genes (STING) pathway, a component of innate immunity, is closely associated with microglia activation, neuroinflammation, and regulated cell death in ischemic stroke. However, the mechanisms underlying this pathway remain inadequately understood. This article comprehensively reviews the existing literature on the cGAS-STING pathway and its multifaceted relationship with ischemic stroke. Initially, it examines how various risk factors and pre-disease mechanisms such as metabolic dysfunction and senescence (e.g., hypertension, hyperglycemia, hyperlipidemia) affect the cGAS-STING pathway in relation to ischemic stroke. Subsequently, we explore in depth the potential pathophysiological relationship between this pathway and oxidative stress, endoplasmic reticulum stress, neuroinflammation as well as regulated cell death including ferroptosis and PANoptosis following cerebral ischemia injury. Finally, it suggests that intervention targeting the cGAS-STING pathway may serve as promising therapeutic strategies for addressing neuroinflammation associated with ischemic stroke. Taken together, this review concludes that targeting the microglia cGAS-STING pathway may shed light on the exploration of new therapeutic strategies against ischemic stroke.

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

Cited by 14 publications

References 46 publications

GSDME in Endothelial Cells: Inducing Vascular Inflammation and Atherosclerosis via Mitochondrial Damage and STING Pathway Activation

GSDME in Endothelial Cells: Inducing Vascular Inflammation and Atherosclerosis via Mitochondrial Damage and STING Pathway Activation

The cGAS-STING pathway in cardiovascular diseases: from basic research to clinical perspectives

Novel insight into cGAS-STING pathway in ischemic stroke: from pre- to post-disease

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