Objective:To investigate the regulatory effect of Qiliqiangxin Capsule on mitochondrial Ca^(2+)related genes in rats with myocardial infarction(MI).Methods:The rat model of MI was established by ligation of the left a...Objective:To investigate the regulatory effect of Qiliqiangxin Capsule on mitochondrial Ca^(2+)related genes in rats with myocardial infarction(MI).Methods:The rat model of MI was established by ligation of the left anterior descending coronary artery.After operation,the rats were randomly assigned to the model group,the Qiliqiangxin group and the captopril group;a sham-operated group was also available as a control.After four weeks of treatment,the extent of infarction in rats was observed by gross cardiac structure and the morphological changes of myocardial histopathology were observed by HE staining.Detection of mitochondrial Ca^(2+)transport-related genes such as inositol-1,4,5-trisphosphate receptor 2(IP3R2),glucose regulated protein 75(GRP75),voltage-dependent anion channel 1(VDAC1),and mitofusion 2(Mfn2)and mitochondrial apoptosis-related genes such as B-cell lymphoma-2(Bcl-2)and Bcl-2 related X protein(Bax)mRNA expression changes was measured by RT-PCR in the infarct margins of the heart;Western blot was used to detect changes in Bcl-2,Bax protein expression in myocardial tissue.The rate of apoptosis in cardiac myocardial tissue was detected by TUNEL staining.Results:Compared with the sham group,the anterior left ventricular wall of the model group showed a large area of infarction,and the structure of myocardial tissue was disordered.The mRNA expression level of mitochondrial Ca^(2+)transport-related genes such as IP3R2,GRP75,VDAC1,and Mfn2 were significantly increased(P<0.05,P<0.01);The mRNA and protein expression of Bcl-2,a molecule related to mitochondrial apoptosis,were significantly decreased(P<0.01),while the mRNA and protein expression of Bax were significantly increased(P<0.01);and apoptosis rate was significantly increased(P<0.01).Compared with the model group,the infarct size of cardiac gross specimens in the Qiliqiangxin group and the captopril group was reduced and myocardial fibers were relatively well ordered;The mRNA expression of mitochondrial Ca^(2+)transport-related genes such as IP3R2,GRP75,VDAC1,and Mfn2 were significantly reduced(P<0.01);the mRNA and protein expression of Bcl-2,a molecule related to mitochondrial apoptosis,were increased(P<0.05,P<0.01),and the mRNA and protein expression of Bax were significantly decreased(P<0.05,P<0.01).and apoptosis rate was significantly decreased(P<0.01).Conclusion:Qiliqiangxin Capsule can improve the morphological structure of the heart of rats with MI,and its mechanism is related to regulation of the gene expression of mitochondrial Ca^(2+)transport complex IP3R2/GRP75/VDAC1,thereby inhibiting apoptosis.展开更多
The stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs) play pivotal roles in the modulation of Ca^(2+)-regulated pathways from ...The stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs) play pivotal roles in the modulation of Ca^(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes.Increasing evidence has implicated the dysregulation of STIM-ORAI and IP_3Rs in tumorigenesis and tumor progression.By controlling the activities,structure,and/or expression levels of these Ca^(2+)-transporting proteins,malignant cancer cells can hijack them to drive essential biological functions for tumor development.However,the molecular mechanisms underlying the participation of STIM-ORAI and IP_3Rs in the biological behavior of cancer remain elusive.In this review,we summarize recent advances regarding STIM-ORAI and IP_3Rs and discuss how they promote cell proliferation,apoptosis evasion,and cell migration through temporal and spatial rearrangements in certain types of malignant cells.An understanding of the essential roles of STIM-ORAI and IP_3Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.展开更多
Ca2＋ signals participate in various cellular processes with spatial and temporal dynamics, among which, inositol 1,4,5-trisphosphate receptors （IP3Rs）-mediated Ca2＋ signals are essential for early development. How...Ca2＋ signals participate in various cellular processes with spatial and temporal dynamics, among which, inositol 1,4,5-trisphosphate receptors （IP3Rs）-mediated Ca2＋ signals are essential for early development. However, the underlying mechanisms of IP3R- regulated cell fate decision remain largely unknown. Here we report that IP3Rs are required for the hematopoietic and cardiac fate divergence of mouse embryonic stem cells （mESCs）. Deletion of IP3Rs （IP3R-tKO） reduced FIkl＋/PDGFRα- hematopoietic mesoderm, c-Kit＋/CD41＋ hematopoietic progenitor ceil population, and the colony-forming unit activity, but increased cardiac progenitor markers as well as cardiomyocytes. Concomitantly, the expression of a key regulator of hematopoiesis, Ely2, was reduced in IP3R-tKO cells, which could be rescued by the activation of Ca2＋ signals and calcineurin or overexpression of constitutively active form of NFATc3. Furthermore, IP3R-tKO impaired specific targeting of Ely2 by NFATc3 via its evolutionarily conserved cis-element in differentiating ESCs. Importantly, the activation of Ca2＋-calcineurin-NFAT pathway reversed the phenotype of IP3R-tKO cells. These findings reveal an unrecognized governing role of IP3Rs in hematopoietic and cardiac fate commitment via IP3Rs-Ca2＋-calcineurin-NFATc3- Etv2 pathway.展开更多
基金This study was supported by Beijing University of Traditional Chinese Medicine Dongzhimen Hospital 2022 Science and Technology Innovation Special Project(DZMKJCX-2022-008)。
文摘Objective:To investigate the regulatory effect of Qiliqiangxin Capsule on mitochondrial Ca^(2+)related genes in rats with myocardial infarction(MI).Methods:The rat model of MI was established by ligation of the left anterior descending coronary artery.After operation,the rats were randomly assigned to the model group,the Qiliqiangxin group and the captopril group;a sham-operated group was also available as a control.After four weeks of treatment,the extent of infarction in rats was observed by gross cardiac structure and the morphological changes of myocardial histopathology were observed by HE staining.Detection of mitochondrial Ca^(2+)transport-related genes such as inositol-1,4,5-trisphosphate receptor 2(IP3R2),glucose regulated protein 75(GRP75),voltage-dependent anion channel 1(VDAC1),and mitofusion 2(Mfn2)and mitochondrial apoptosis-related genes such as B-cell lymphoma-2(Bcl-2)and Bcl-2 related X protein(Bax)mRNA expression changes was measured by RT-PCR in the infarct margins of the heart;Western blot was used to detect changes in Bcl-2,Bax protein expression in myocardial tissue.The rate of apoptosis in cardiac myocardial tissue was detected by TUNEL staining.Results:Compared with the sham group,the anterior left ventricular wall of the model group showed a large area of infarction,and the structure of myocardial tissue was disordered.The mRNA expression level of mitochondrial Ca^(2+)transport-related genes such as IP3R2,GRP75,VDAC1,and Mfn2 were significantly increased(P<0.05,P<0.01);The mRNA and protein expression of Bcl-2,a molecule related to mitochondrial apoptosis,were significantly decreased(P<0.01),while the mRNA and protein expression of Bax were significantly increased(P<0.01);and apoptosis rate was significantly increased(P<0.01).Compared with the model group,the infarct size of cardiac gross specimens in the Qiliqiangxin group and the captopril group was reduced and myocardial fibers were relatively well ordered;The mRNA expression of mitochondrial Ca^(2+)transport-related genes such as IP3R2,GRP75,VDAC1,and Mfn2 were significantly reduced(P<0.01);the mRNA and protein expression of Bcl-2,a molecule related to mitochondrial apoptosis,were increased(P<0.05,P<0.01),and the mRNA and protein expression of Bax were significantly decreased(P<0.05,P<0.01).and apoptosis rate was significantly decreased(P<0.01).Conclusion:Qiliqiangxin Capsule can improve the morphological structure of the heart of rats with MI,and its mechanism is related to regulation of the gene expression of mitochondrial Ca^(2+)transport complex IP3R2/GRP75/VDAC1,thereby inhibiting apoptosis.
文摘The stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs) play pivotal roles in the modulation of Ca^(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes.Increasing evidence has implicated the dysregulation of STIM-ORAI and IP_3Rs in tumorigenesis and tumor progression.By controlling the activities,structure,and/or expression levels of these Ca^(2+)-transporting proteins,malignant cancer cells can hijack them to drive essential biological functions for tumor development.However,the molecular mechanisms underlying the participation of STIM-ORAI and IP_3Rs in the biological behavior of cancer remain elusive.In this review,we summarize recent advances regarding STIM-ORAI and IP_3Rs and discuss how they promote cell proliferation,apoptosis evasion,and cell migration through temporal and spatial rearrangements in certain types of malignant cells.An understanding of the essential roles of STIM-ORAI and IP_3Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.
基金This study was supported by grants from the National Natural Science Foundation of China （31030050, 81520108004, and 81470422 to H.-T.Y.）, the Strategic Priority Research Program of Chinese Academy of Sciences （XDA01020204 to H.-T.Y.）, the National Basic Research Program of China （2014CB965100 to H.-T.Y.）, the National Science and Technology Major Project （2012ZX09501001 to H.-T.Y.）, and the Shenzhen Science, Technology and Innovation Committee OCYI 20160428154108239 to K.O.）.
文摘Ca2＋ signals participate in various cellular processes with spatial and temporal dynamics, among which, inositol 1,4,5-trisphosphate receptors （IP3Rs）-mediated Ca2＋ signals are essential for early development. However, the underlying mechanisms of IP3R- regulated cell fate decision remain largely unknown. Here we report that IP3Rs are required for the hematopoietic and cardiac fate divergence of mouse embryonic stem cells （mESCs）. Deletion of IP3Rs （IP3R-tKO） reduced FIkl＋/PDGFRα- hematopoietic mesoderm, c-Kit＋/CD41＋ hematopoietic progenitor ceil population, and the colony-forming unit activity, but increased cardiac progenitor markers as well as cardiomyocytes. Concomitantly, the expression of a key regulator of hematopoiesis, Ely2, was reduced in IP3R-tKO cells, which could be rescued by the activation of Ca2＋ signals and calcineurin or overexpression of constitutively active form of NFATc3. Furthermore, IP3R-tKO impaired specific targeting of Ely2 by NFATc3 via its evolutionarily conserved cis-element in differentiating ESCs. Importantly, the activation of Ca2＋-calcineurin-NFAT pathway reversed the phenotype of IP3R-tKO cells. These findings reveal an unrecognized governing role of IP3Rs in hematopoietic and cardiac fate commitment via IP3Rs-Ca2＋-calcineurin-NFATc3- Etv2 pathway.
