Oxycodone protects cardiac microvascular endothelial cells against ischemia/reperfusion injury by binding to Sigma-1 Receptor

Ji, Meihua; Cheng, Jing; Zhang, Dai‐Min

doi:10.1080/21655979.2022.2057632

Cited by 11 publications

(3 citation statements)

References 50 publications

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“…Either pre or posttreatment with opioid have a clear myocardial protective effect (22). Oxycodone, as a potent opioid, was also proved to significantly improve myocardial ischemia-reperfusion, especially exerts a good inhibitory effect on apoptosis caused by ischemia-reperfusion injury(20) (23). Few reports are available for the effect of oxycodone in septic myocardial injury.…”

Section: Discussionmentioning

confidence: 99%

Oxycodone attenuates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidation and pyroptosis via Nrf2/HO-1 signaling pathway

Yu,

Wang,

Feng

et al. 2024

Preprint

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Myocardial injury and cardiovascular dysfunction are the most common complications in patients with sepsis, and effective therapeutic candidate is still lacking. This study aims to investigate the protective effect of oxycodone in the myocardial injury in lipopolysaccharide-induced sepsis and its related signaling pathways. Wildtype and Nrf2-knockout mice, as well as H9c2 cardiomyocytes culture treated with LPS were used as models of septic myocardial injury. In vitro model showed that oxycodone protected the cells from pyroptosis induced by LPS. In vivo model showed oxycodone pretreatment significantly attenuated myocardial pathological damage and improved cardiac function with increased ejection fraction (EF) and fractional shortening (FS) as well as decreased cardiac troponin I (cTnI), creatine kinase isoenzymes MB (CK-MB). Oxycodone also reduced the levels of inflammatory factors and oxidative stress damage induced by LPS, which involves pyroptosis-related proteins including the NLRP3, Caspase-1, ASC, and GSDMD. These changes were mediated by Nrf2 and HO-1 because Nrf2-knockout mice or Nrf2 knockdown in H9c2 cells significantly reversed the beneficial effect of oxycodone on oxidative stress, inflammatory responses and NLRP3-mediated pyroptosis. Our findings proved that oxycodone therapy reduces LPS -induced myocardial injury by suppressing NLRP3-mediated pyroptosis via the Nrf2/HO-1 signaling pathway in vivo and in vitro.

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Section: Discussionmentioning

confidence: 99%

Oxycodone attenuates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidation and pyroptosis via Nrf2/HO-1 signaling pathway

Yu,

Wang,

Feng

et al. 2024

Preprint

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“…Endothelial dysfunction is considered as the earliest stage in the development of cardiovascular disease, prior to the clinical manifestation of symptoms [ 22 ]. Apparently, endothelial dysfunction occurs in the microcirculation before affecting macrovascular structures [ 23 , 24 ], but most research in CKD-related CVD has been devoted to macrovascular complications [ 25 ]. CMECs, which account for one-third of the total number of heart cells, is the major cell type in the processes of cardiovascular angiogenesis and play a critical role in maintaining sufficient cardiac perfusion.…”

Section: Discussionmentioning

confidence: 99%

Association of circulating MtDNA with CVD in hemodialysis patients and in vitro effect of exogenous MtDNA on cardiac microvascular inflammation

Fan

Feng

Zang

et al. 2023

BMC Cardiovasc Disord

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Background Chronic kidney disease (CKD) patients sustain a fairly high prevalence of cardiovascular disease (CVD). Microvascular inflammation is an early manifestation of CVD, and the released mitochondrial DNA (MtDNA) has been proposed to be a crucial integrator of inflammatory signals. Herein, the aim of this study was to determine the relationship between CVD, microvessel, and circulating MtDNA in the settings of uremia. Methods Forty-two maintenance hemodialysis (MHD) patients and 36 health controls were enrolled in this study. Plasma cell-free MtDNA was detected by TaqMan-based qPCR assay. CVD risk markers including high-sensitive C-reactive protein (Hs-CRP), monocyte chemoattractant protein-1 (MCP-1), fibrinogen, and erythrocyte sedimentation rate (ESR) were measured by standard assays. Ten-year CVD risk was calculated from the Framingham risk score (FRS) model. In vitro study, human cardiac microvascular endothelial cells (HCMECs) were incubated with normal or uremic serum, with or without exogenous MtDNA. Intracellular toll-like receptor 9 (TLR9), adhesion molecule 1 (ICAM-1), MCP-1 and tumor necrosis factor-α (TNF-α) and cytosolic MtDNA were detected by qPCR. Results Plasma MtDNA in MHD patients was significantly higher than healthy controls (4.74 vs. 2.41 × 105 copies/mL; p = 0.000). Subsequently, the MHD patients were classified into two groups based on the MtDNA median (4.34 × 105 copies/mL). In stratified analyses, the levels of Hs-CRP (5.02 vs. 3.73 mg/L; p = 0.042) and MCP-l (99.97 vs. 64.72 pg/mL; p = 0.008) and FRS (21.80 vs. 16.52; p = 0.016) in the high plasma MtDNA group were higher than those in the low plasma MtDNA group. In vitro study, we found that exogenous MtDNA aggravated uremic serum-induced microvascular inflammation (ICAM-1 and TNF-α) in HCMECs (all p < 0.05). Besides, the addition of MtDNA to the medium resulted in a further increase in cytosolic MtDNA and TLR9 levels in uremic serum-treated cells (all p < 0.05). In patients with MHD, MtDNA levels in plasma were significantly reduced after a single routine hemodialysis (pre 4.47 vs. post 3.45 × 105 copies/mL; p = 0.001) or hemodiafiltration (pre 4.85 vs. post 4.09 × 105 copies/mL; p = 0.001). These two approaches seem similar in terms of MtDNA clearance rate (21.26% vs. 11.94%; p = 0.172). Conclusions Overall, the present study suggests that MtDNA released into the circulation under the uremic toxin environment may adversely affect the cardiovascular system by exacerbating microvascular inflammation, and that reducing circulating MtDNA might be a future therapeutic strategy for the prevention of MHD-related CVD.

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“…These studies also demonstrated Sigmar1’s involvement in mitochondrial bioenergetics regulation in vascular and lymphatic endothelial cells. A recent study showed that the opioid receptor agonist, oxycodone, preserves cardiac microvascular endothelial cell integrity and myocardial function after ischemia-reperfusion injury by binding to Sigmar1 ( Ji et al, 2022 ). Pharmacologic inhibition of Sigmar1 using its antagonist, such as haloperidol metabolite-II valproate ester [(±)-MRJF22] exhibited an antiangiogenic effect, significantly reducing cell viability, migration, and tube formation in human retinal endothelial cells stimulated with vascular endothelial growth factor A ( Olivieri et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Deletion of Sigmar1 leads to increased arterial stiffness and altered mitochondrial respiration resulting in vascular dysfunction

Remex,

Abdullah,

Aishwarya

et al. 2024

Front. Physiol.

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Sigmar1 is a ubiquitously expressed, multifunctional protein known for its cardioprotective roles in cardiovascular diseases. While accumulating evidence indicate a critical role of Sigmar1 in cardiac biology, its physiological function in the vasculature remains unknown. In this study, we characterized the expression of Sigmar1 in the vascular wall and assessed its physiological function in the vascular system using global Sigmar1 knockout (Sigmar1−/−) mice. We determined the expression of Sigmar1 in the vascular tissue using immunostaining and biochemical experiments in both human and mouse blood vessels. Deletion of Sigmar1 globally in mice (Sigmar1−/−) led to blood vessel wall reorganizations characterized by nuclei disarray of vascular smooth muscle cells, altered organizations of elastic lamina, and higher collagen fibers deposition in and around the arteries compared to wildtype littermate controls (Wt). Vascular function was assessed in mice using non-invasive time-transit method of aortic stiffness measurement and flow-mediated dilation (FMD) of the left femoral artery. Sigmar1−/− mice showed a notable increase in arterial stiffness in the abdominal aorta and failed to increase the vessel diameter in response to reactive-hyperemia compared to Wt. This was consistent with reduced plasma and tissue nitric-oxide bioavailability (NOx) and decreased phosphorylation of endothelial nitric oxide synthase (eNOS) in the aorta of Sigmar1−/− mice. Ultrastructural analysis by transmission electron microscopy (TEM) of aorta sections showed accumulation of elongated shaped mitochondria in both vascular smooth muscle and endothelial cells of Sigmar1−/− mice. In accordance, decreased mitochondrial respirometry parameters were found in ex-vivo aortic rings from Sigmar1 deficient mice compared to Wt controls. These data indicate a potential role of Sigmar1 in maintaining vascular homeostasis.

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Oxycodone protects cardiac microvascular endothelial cells against ischemia/reperfusion injury by binding to Sigma-1 Receptor

Cited by 11 publications

References 50 publications

Oxycodone attenuates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidation and pyroptosis via Nrf2/HO-1 signaling pathway

Oxycodone attenuates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidation and pyroptosis via Nrf2/HO-1 signaling pathway

Association of circulating MtDNA with CVD in hemodialysis patients and in vitro effect of exogenous MtDNA on cardiac microvascular inflammation

Deletion of Sigmar1 leads to increased arterial stiffness and altered mitochondrial respiration resulting in vascular dysfunction

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