Background Preeclampsia is a serious disorder of pregnancy characterized by h ypertension, proteinuria, edema, and coagulation and vascular abnormalities. At the cellular level, abnormalities include increased calcium...Background Preeclampsia is a serious disorder of pregnancy characterized by h ypertension, proteinuria, edema, and coagulation and vascular abnormalities. At the cellular level, abnormalities include increased calcium concentration in pla telets, lymphocytes, and erythrocytes. Recent studies have shown that antibodies directed against angiotensin II type I (AT1) receptors are also highly associat ed with preeclampsia. Methods and Results We tested the hypothesis that AT1 rec eptor agonistic antibodies(AT1 AAs) could activate AT1 receptors, leading to a n increased intracellular concentration of free calcium and to downstream activa tion of Ca2+signaling pathways. Sera of 30 pregnant patients, 16 diagnosed with severe preeclampsia and 14 normotensive, were examined for the presence of IgG capable of stimulating intracellular Ca2+mobilization. IgG from all preeclampti c patients activated AT1 receptors and increased intracellular free calcium. In contrast, none of the normotensive individuals had IgG capable of activating AT1 receptors. The specific mobilization of intracellular Ca2+by AT1 AAs was bloc ked by losartan, an AT1 receptor antagonist, and by a 7 amino acid peptide tha t corresponds to a portion of the second extracellular loop of the AT1 receptor. In addition, we have shown that AT1 AA stimulated mobilization of intracellul ar Ca2+results in the activation of the transcription factor, nuclear factor of activated T cells. Conclusions These results suggest that maternal antibodies capable of activating AT1 receptors are likely to account for increased intracel lular free Ca2+concentrations and changes in gene expression associated with pr eeclampsia.展开更多
目的肿瘤细胞受到由细胞增殖所引起的压力作用。细胞内各类钙离子通道可将机械信号转导为钙信号,调节细胞行为。本研究希望探究压力是否通过调节钙瞬态影响肿瘤细胞增殖、迁移,并阐明其潜在的分子机制。方法构建体外肿瘤细胞压力加载体...目的肿瘤细胞受到由细胞增殖所引起的压力作用。细胞内各类钙离子通道可将机械信号转导为钙信号,调节细胞行为。本研究希望探究压力是否通过调节钙瞬态影响肿瘤细胞增殖、迁移,并阐明其潜在的分子机制。方法构建体外肿瘤细胞压力加载体系,分析细胞增殖和迁移行为变化情况。利用钙探针,分析细胞钙水平变化与钙振荡频率变化。使用抑制剂与基因沉默探讨各类钙通道在压力应答中的作用,并进一步探究潜在的调控机制。结果对MDA-MB-231和HELA细胞施加0~100 k Pa的气压,发现压力对肿瘤细胞增殖和迁移等行为的调节具有剂量效应,低压(40 k Pa)有促进作用,高压(60、100 k Pa)则会抑制。利用钙荧光探针标记胞内游离钙离子,在加压条件下对胞内钙离子进行时序分析,发现加压后钙信号水平均显著升高,钙振荡频率增加、振幅增大、振荡细胞占比增加。抑制PIEZO1会阻碍加压引起的钙信号变化,且钙振荡仅表现为实验起始的单次;抑制IP3R,钙信号与抑制PIEZO1类似且更强烈,并能完全消除钙振荡。结论压力可激活肿瘤细胞PIEZO1和IP3R钙通道,调节胞质钙离子浓度,影响细胞钙信号动态,进而调控肿瘤细胞增殖和迁移行为。本研究阐明了压力通过钙信号转导途径影响肿瘤细胞行为的分子机制,为相关靶点药物开发提供新视角。展开更多
文摘Background Preeclampsia is a serious disorder of pregnancy characterized by h ypertension, proteinuria, edema, and coagulation and vascular abnormalities. At the cellular level, abnormalities include increased calcium concentration in pla telets, lymphocytes, and erythrocytes. Recent studies have shown that antibodies directed against angiotensin II type I (AT1) receptors are also highly associat ed with preeclampsia. Methods and Results We tested the hypothesis that AT1 rec eptor agonistic antibodies(AT1 AAs) could activate AT1 receptors, leading to a n increased intracellular concentration of free calcium and to downstream activa tion of Ca2+signaling pathways. Sera of 30 pregnant patients, 16 diagnosed with severe preeclampsia and 14 normotensive, were examined for the presence of IgG capable of stimulating intracellular Ca2+mobilization. IgG from all preeclampti c patients activated AT1 receptors and increased intracellular free calcium. In contrast, none of the normotensive individuals had IgG capable of activating AT1 receptors. The specific mobilization of intracellular Ca2+by AT1 AAs was bloc ked by losartan, an AT1 receptor antagonist, and by a 7 amino acid peptide tha t corresponds to a portion of the second extracellular loop of the AT1 receptor. In addition, we have shown that AT1 AA stimulated mobilization of intracellul ar Ca2+results in the activation of the transcription factor, nuclear factor of activated T cells. Conclusions These results suggest that maternal antibodies capable of activating AT1 receptors are likely to account for increased intracel lular free Ca2+concentrations and changes in gene expression associated with pr eeclampsia.
文摘目的肿瘤细胞受到由细胞增殖所引起的压力作用。细胞内各类钙离子通道可将机械信号转导为钙信号,调节细胞行为。本研究希望探究压力是否通过调节钙瞬态影响肿瘤细胞增殖、迁移,并阐明其潜在的分子机制。方法构建体外肿瘤细胞压力加载体系,分析细胞增殖和迁移行为变化情况。利用钙探针,分析细胞钙水平变化与钙振荡频率变化。使用抑制剂与基因沉默探讨各类钙通道在压力应答中的作用,并进一步探究潜在的调控机制。结果对MDA-MB-231和HELA细胞施加0~100 k Pa的气压,发现压力对肿瘤细胞增殖和迁移等行为的调节具有剂量效应,低压(40 k Pa)有促进作用,高压(60、100 k Pa)则会抑制。利用钙荧光探针标记胞内游离钙离子,在加压条件下对胞内钙离子进行时序分析,发现加压后钙信号水平均显著升高,钙振荡频率增加、振幅增大、振荡细胞占比增加。抑制PIEZO1会阻碍加压引起的钙信号变化,且钙振荡仅表现为实验起始的单次;抑制IP3R,钙信号与抑制PIEZO1类似且更强烈,并能完全消除钙振荡。结论压力可激活肿瘤细胞PIEZO1和IP3R钙通道,调节胞质钙离子浓度,影响细胞钙信号动态,进而调控肿瘤细胞增殖和迁移行为。本研究阐明了压力通过钙信号转导途径影响肿瘤细胞行为的分子机制,为相关靶点药物开发提供新视角。
