Vincristine (VCR), an alkaloid isolated from vinca, is a commonly used chemotherapeutic drug. However, treatment with VCR can lead to dose-dependent peripheral neurotoxicity, mainly manifesting as neuropathic pain, which is one of the dominant reasons for limiting its utility. Experimentally, we discovered that VCR-induced neuropathic pain was accompanied by astrocyte activation; the upregulation of p-CaMKII, Cav3.2, and Cx43 expression; and the production and release of in ammatory cytokines and chemokines in the spinal cord. Similar situations were also observed in astrocyte cultures.Interestingly, these alterations were all reversed by intrathecal injection of KN-93 (a CaMKII inhibitor) or L -Ascorbic acid (a Cav3.2 antagonist). In addition, KN-93 and L -Ascorbic acid inhibited the increase in [Ca 2+ ] i associated with astrocyte activation. We also veri ed that inhibiting and knocking down Cx43 levels via intrathecal injection of Gap27 and Cx43 siRNA relieved pain hypersensitivity and reduced the release of in ammatory factors; however, they did not affect astrocyte activation or p-CaMKII and Cav3.2 expression. The overexpression of Cx43 through the transfection of the Cx43 plasmid did not affect p-CaMKII or Cav3.2 expression in vitro. Therefore, CaMKII and Cav3.2 may activate astrocytes by increasing [Ca 2+ ] i , thereby mediating Cx43-dependent in ammation in VCR-induced neuropathic pain. Moreover, we demonstrated that the CaMKII signalling pathway was involved in VCR-induced in ammation, apoptosis, and mitochondrial damage. In summary, our ndings show a novel mechanism by which CaMKII and Cav3.2 mediate Cx43-dependent in ammation by activating astrocytes in neuropathic pain induced by VCR.
Leptin resistance in endothelial cells leads to vascular endothelial dysfunction, which is the beginning and crucial link of atherosclerosis. However, the mechanism of leptin resistance remains obscure. Acid sphingomyelinase (ASM) catalyzes the hydrolysis of sphingomyelin to produce ceramide, which plays an important role in the progression of metabolic and cardiovascular diseases. In this study, we investigated whether ASM could regulate leptin resistance in vascular endothelial cells. We induced endothelial leptin resistance in rat aortic endothelial cells through treatment with palmitic acid (0.3 mM) or knockdown of leptin receptor (Ob-Rb), which resulted in the increase of suppressor of cytokine signaling 3 expression, the decrease of Ob-Rb expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation at Tyr705. We found that these indicators of leptin resistance were reversed by knockdown of ASM or by the selective ASM inhibitors amitriptyline (AMI) and imipramine (IMI). Supplementation of ceramide inhibited Ob-Rb expression and STAT3 phosphorylation by inhibiting extracellular signal-regulated kinase 1/2 activation. Furthermore, we found that knockdown of ASM enhanced endothelial nitric oxide (NO) synthase activity and NO production, as well as the Akt phosphorylation at ser473, which was regulated by STAT3. High-fat diet (HFD) feeding-induced leptin resistance in rats in vivo; administration of AMI and IMI (10 mg· kg −1 per day, intraperitoneally, for 2 weeks) increased the release of endothelial NO to relieve the vasodilatory response and improved the endothelial leptin resistance in the aorta of HFD-fed rats. These results suggest that ASM downregulation reverses endothelial leptin resistance, and consequently improves vascular endothelial dysfunction. This study highlighted ASM as a potential therapeutic target for endothelial leptin resistance.
Vincristine (VCR), an alkaloid isolated from vinca, is a commonly used chemotherapeutic drug. However, treatment with VCR can lead to dose-dependent peripheral neurotoxicity, mainly manifesting as neuropathic pain, which is one of the dominant reasons for limiting its utility. Experimentally, we discovered that VCR-induced neuropathic pain was accompanied by astrocyte activation; the upregulation of p-CaMKII, Cav3.2, and Cx43 expression; and the production and release of inflammatory cytokines and chemokines in the spinal cord. Similar situations were also observed in astrocyte cultures. Interestingly, these alterations were all reversed by intrathecal injection of KN-93 (a CaMKII inhibitor) or L-Ascorbic acid (a Cav3.2 antagonist). In addition, KN-93 and L-Ascorbic acid inhibited the increase in [Ca2+]i associated with astrocyte activation. We also verified that inhibiting and knocking down Cx43 levels via intrathecal injection of Gap27 and Cx43 siRNA relieved pain hypersensitivity and reduced the release of inflammatory factors; however, they did not affect astrocyte activation or p-CaMKII and Cav3.2 expression. The overexpression of Cx43 through the transfection of the Cx43 plasmid did not affect p-CaMKII or Cav3.2 expression in vitro. Therefore, CaMKII and Cav3.2 may activate astrocytes by increasing [Ca2+]i, thereby mediating Cx43-dependent inflammation in VCR-induced neuropathic pain. Moreover, we demonstrated that the CaMKII signalling pathway was involved in VCR-induced inflammation, apoptosis, and mitochondrial damage. In summary, our findings show a novel mechanism by which CaMKII and Cav3.2 mediate Cx43-dependent inflammation by activating astrocytes in neuropathic pain induced by VCR.
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