GSNO或诱生型NOS激活糖酵解通路及HIF-1α相关机制研究
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摘要
第一部分GSNO致内皮细胞HIF-1αS-亚硝基化激活糖酵解通路
目的：
探索S-亚硝基谷胱甘肽(S-nitrosoglutathione, GSNO)致内皮细胞线粒体异常时,以醛缩酶(aldolase, ALD)家族为核心的糖酵解因子表征,及HIF-1α蛋白激活对其调控作用；进一步探讨S-亚硝基化修饰及PI3K/Akt通路对HIF-la调控,论证GSNO引起糖酵解流量调控的可能分子机制。
方法：
1.采用外源性GSNO处理内皮细胞,致细胞线粒体功能异常。MTT法检测内皮细胞1h,3h,6h,12h细胞活力,NO试剂盒检测细胞培养液GSNO释放NO水平,JC-1染色法检测线粒体膜电位(mitochondrial membrane potential,△Ψm)变化,电镜考察GSNO处理内皮细胞后线粒体形态学变化。2.RT-PCR法考察GSNO处理内皮细胞后糖酵解酶系和葡萄糖转运体1mRNA表达情况。3. RT-PCR法和免疫细胞化学方法考察ALD家族在内皮细胞中主要亚型。Western blot法考察ALD蛋白表达情况,ALD酶活性试剂盒检测ALD催化活性。乳酸测定试剂盒检测上清液乳酸释放水平。4.为进一步探讨GSNO引起内皮细胞糖代谢因子变化,考察HIF-1α转录和蛋白翻译水平变化,免疫荧光法考察HIF-1α;是否入核被激活；siHIF-1α进一步确认HIF-1α是否介导GSNO引起内皮细胞糖酵解通路变化。5.Modified Biotin Switch法检测GSNO对内皮细胞S-亚硝基化水平影响,通过加入二硫键还原剂二硫苏糖醇(1,4-dithiothreitol, DTT)或P13K抑制剂LY294002,分别评价S-亚硝基化修饰和PI3K/Akt信号通路是否参与GSNO引起糖酵解因子变化机制。
结果：
1. GSNO作用于内皮细胞1h,3h,6h,12h, NO水平呈时间依赖性上调；过量NO致内皮细胞△Ψm下降以及线粒体结构异常；而对内皮细胞存活率并无显著影响；提示GSNO作用于内皮细胞损伤细胞线粒体功能,而对内皮细胞存活率无明显影响。2.通过对糖酵解酶系mRNA水平考察,GSNO可引起GLUT1、 ALD A、 LDHA以及PDK1上调；GSNO上调ALD A, GLUT1蛋白表达及增加乳酸释放；结果提示GSNO可上调糖酵解因子转录和翻译水平进而激活糖酵解通路。3.GSNO上调HIF-1α转录水平,维持HIF-1α蛋白稳定表达,促HIF-1α入核激活低氧信号通路。siHIF-1α可减弱由GSNO引起的ALD A、 GLUT1蛋白上调,提示HIF-1α蛋白稳定表达是GSNO引起糖酵解因子ALDA、 GLUT1上调的关键因素。4. Modified Biotin Switch法结果显示GSNO可易化内皮细胞S-亚硝基化修饰水平；加入DTT后,GSNO引起的S-亚硝基化修饰被明显抑制,提示DTT可作为S-亚硝基化修饰的抑制剂。DTT可阻滞由GSNO引起的HIF-1α蛋白积聚及下游因子ALD A、 GLUT1蛋白上调,提示GSNO经由S-亚硝基化修饰维持HIF-1α蛋白稳定表达影响糖酵解。5. GSNO可上调Akt磷酸化水平,LY294002可部分抑制HIF-1α蛋白积聚及下游因子ALDA、 GLUT1上调,提示PI3K/Akt通路也可能参与调控HIF-1α表达。
结论：
1.过量GSNO可上调内皮细胞ALD A表达和酶活性,上调GLUT1, ALD A, LDHA, PDK1转录,激活糖酵解通路；该作用与乳酸释放上调相平行,提示GSNO可促进糖酵解流量。
2.过量GSNO可上调内皮细胞HIF-1α转录、维持HIF-1α蛋白快速稳定表达,该过程受PI3K/Akt信号通路调控。siHIF-1α阻止GSNO上调ALD A和GLUT1蛋白表达,提示HIF-1α稳定表达是GSNO激活糖酵解过程关键因素。
3.过量GSNO可经由S-亚硝基化修饰维持HIF-1α蛋白稳定,持续激活糖酵解通路。
第二部分LPS致大鼠内毒素血症激活糖酵解通路伴HIF-1α上调
目的：
LPS致大鼠内毒素血症中,大量生成NO可诱发若干蛋白发生体内S-亚硝基化修饰。本部分进一步探讨LPS致大鼠内毒血症早期,以ALD家族为核心的糖酵解因子在其脑、肝脏和骨骼肌组织等表达特征,并论证其表达变化的可能机制,为揭示糖酵解因子在内毒素血症早期表达特征和生物学意义提供实验依据。
方法：
1.SD大鼠12只,250g-300g,雌雄各半。分为两组,每组6只。阴性组腹腔注射生理盐水,给药组腹腔注射LPS (2mg/kg)制备内毒素血症模型。给药6h后,断颈椎处死。取新鲜大鼠脑、肝、骨骼肌等3个组织备用。2. RT-PCR测定各组织GLUT家族,HK家族,PFK1, ALD家族,ENO1, PGK1, PDK1和LDH家族mRNA表达。3. Western blot法考察ALD家族及低氧效应因子HIF-1α表达。4.取新鲜骨骼肌组织与GSNO共孵育,用醛缩酶KIT检测骨骼肌中ALD A酶活性变化,检测ALD A是否被GSNO翻译后修饰。
结果：
1.LPS腹腔注射给药6h,糖酵解因子基因转录层面表达特征：在脑组织中,GLUT1、 ALDC、 ENO1、 PGK1、 PDK1以及LDHA mRNA水平上调,提示此时脑组织糖酵解通路转录层面激活相关。在骨骼肌组织中,GLUT1和ALD A mRNA表达上调,提示此时可影响骨骼肌中糖酵解因子。在肝组织未发现有糖酵解相关因子mRNA表达上调,可能与肝组织尚具备糖异生作用相关。上述结果提示LPS致大鼠内毒素血症早期,糖酵解变化顺序依次为脑组织>骨骼肌组织>肝脏组织。
2.LPS腹腔注射给药后6h,ALD家族及HIF1α蛋白表达特征：骨骼肌中ALD A表达上调,脑组织中ALDC表达上调,而肝脏组织中ALDB表达无明显变化。检测脑、肝、骨骼肌三个组织中低氧诱导因子HIF-1α蛋白表达情况,发现脑、骨骼肌组织中HIF-1α蛋白积聚与ALD家族表达相平行,提示其可能是ALD家族表达上调关联的促发低氧信号通路的分子事件。
3. GSNO在200-1000μmol/L浓度范围内,作用于新鲜骨骼肌组织1h后,对骨骼肌中ALDA催化活性有明显抑制,且呈浓度依赖性抑制。结合课题组前期研究,GSNO可S-亚硝基化修饰纯ALDA蛋白抑制其催化活性,提示骨骼肌ALDA也可能受GSNO介导的S-亚硝基化修饰活性位点,从而影响了酶催化活性。
结论：
1.大鼠腹腔注射LPS6h,可上调脑组织、骨骼肌组织器官糖酵解因子,糖酵解因子变化幅度依次为脑组织>骨骼肌组织>肝脏组织。提示在LPS致内毒素模型早期机体具备自我调控糖酵解通路的特性。
2.大鼠腹腔注射LPS6h,脑与骨骼肌组织中ALD家族蛋白上调与HIF-1α表达相平行,提示糖酵解因子表达变化可能受HIF-1α调控。
3.外源性高浓度GSNO可能通过S-亚硝基化修饰骨骼肌ALDA蛋白游离巯基而抑制其催化活性。该结果对探讨骨骼肌ALDA催化酶活性调控机制具有重要意义。
Part I S-Nitrosoglutathione activated glycolysis pathway via HIF-1α accumulation by S-nitrosylation in human endothelial cells Objective
Present study attempted to elucidate the role of glycolysis factors in S-Nitrosoglutathione (GSNO) induced mitochondria function loss on human endothelial cells, as well as to explore the regulatory mechanisms by S-nitrosylation and PI3K/Akt activation involved in this process, so as to clarify the energy metabolism regulation from a new perspective.
Methods
1. Cell viability was observed by MTT assay with GSNO treatment for1h,3h,6h,12h. NO release was detected by NO KIT. JC-1staining was performed to determine mitochondrial membrane potential. The structure of mitochondrial was obversed by transmission electron microscope.2. RT-PCR assay was established to evaluate glycolysis factors-HK family, PFK1, ALD family, PGK1, ENO1, LDHA, LDHB, PDK1, GLUT family mRNA levels.3. ALD family location on human endothelial cells was detected by immunochemistry staining. When endothelial cells were treated with GSNO, ALD family expression was determined by RT-PCR or Western blot, respectively. ALD A activity was detected by ALDOLASE KIT. And lactate release was evaluated by Lactic acid KIT.4. To further elucidate the mechanism of GSNO induced glycolysis factors changes, HIF-1α expression and activation were evaluated. Suppression of HIF-1a with siRNA against HIF-1a to endothelial cells was used to confirm the role of HIF-1a in GSNO-induced glycolysis factors.To further evaluate the details mechanism of GSNO-induced HIF-1a accumulation, modified biotin switch method was established to detect whether GSNO enhanced S-nitrosylation on endothelial cells. Disulfide bonds inhibitor dithiothreitol (DTT) was used to confirm GSNO-induced HIF-1a accumulation through S-nitrosylation.5. Akt phosphorylation was detected with GSNO treatment. After adding the PI3K inhibitor LY294002, expression of HIF-1a and GLUT1, ALD A proteins was examined.
Results
1. GSNO evoked a sharp NO release in a time-dependent manner. GSNO triggered△Ψm decrease and impacted inner cristae integrity. Cell viability had no changes after GSNO treatment within12h.2. GSNO induced an enhancement in the gene expression of glycolytic enzyme ALD A as well as GLUT, LDHA, PDK1. As a consequence of GSNO treatment, an enhanced total ALD A activity and lactate release by endothelial cells, indicated glycolysis enhancement under NO-induced mitochondria dysfunction.3. HIF-1a represented possible regulator of glycolysis enhancement due to the protein stability by GSNO-induced S-nitrosylation as well as ALD A and GLUT1upregulation on endothelial cells, which were prevented by downregulating HIF-1α using a free thiol agent DTT. SiHIF-1a inhibited glycolysis factors which activated by GSNO without HIF-1α accumulation.4. GSNO increased Akt phosphorylation. The PI3K inhibitor LY294002reversed GSNO induced the ratio of p-Akt/Akt. LY294002also reduced HIF-1α accumulationblocked HIF-1α downstream factor ALD A and GLUT1. It indicated that PI3K/Akt participated into GSNO induced HIF-1α upregulation.
Conclusion
1. GSNO upregulated ALD A expression and activity, as well as glycolysis related factors mRNA levels, suggesting to be related to influence glycolysis, which was indicated to be related to the increased lactic acid release.
2. GSNO increased HIF-1α mRNA and protein stability to enhance glycolysis flux, which was regulated by PI3K/Akt signaling pathway. si-HIF-1a reduced GSNO-induced ALD A and GLUT1upregulation, indicating that HIF-1a protein stability might play an important role in GSNO effects on glycolysis factors.
3. GSNO induced HIF-1a accumulation to activate glycolysis via S-nitrosylation.
Part II Glycolysis pathway was activated in LPS-induced endotoxemic rats with HIF-1α upregulation
Objective
Characterization of glycolysis factors in LPS-induced endotoxemic rats was investigated, and this information helps to understand potential roles of glycolysis factors in endotoxemic rats.
Methods
1. SD rats were treated with a single dose injection (i.p.) of LPS (2mg/kg), and rats in control group were given equal amount of NaCl (0.9%)(n=6). After6h, brain, liver and skeletal muscle tissues were abtained from the rats.2. The mRNA expression of GLUT family, HK family, PFK1, ALD family, ENO1, PGK1, PDK1and LDH family were assayed by RT-PCR.3. The proteins expression of ALD family and hypoxia-related factors were determined by Western blot.4. Rat skeletal muscle was treated with50μmol/L,200μmol/L,500μmol/L,1000μmol/L GSNO, and ALD activity was detected by ALDOLASE KIT.
Results
1. Glycolysis related factors mRNA levels were detected in brain, liver and skeletal muscles after LPS challenged. In brain tissue, LPS increased GLUT1, ALD C, ENO1, PGK1, PDK1and LDHA mRNA levels, it indicated that LPS might impact glycolysis flux in the brain tissue. LPS had no effects on liver tissue. However, ALD A and GLUT1mRNA up regulated in skeletal muscle with LPS treatment. As showed above, LPS targeted to glycolysis in brain and skeletal muscle rather than liver.2. LPS increased ALD A and ALD C expression in skeletal muscle or brain respectively after LPS challenged. But LPS had no effects on ALD B in liver tissue. To further determine the hypoxia related signaling role in LPS challenged rats, HIF-1α protein was detected. It showed that HIF-la accumulated in brain and skeletal muscle. It indicated that hypoxia related signaling might involve in LPS induced endotoxemic rats.3. Functionally, GSNO (200,500,1000μmol/L) inhibited ALD activity in a dose-dependent manner. It indicated that ALD activity site was blocked thought a post-transcriptional manner.
Conclusions
1. The characterization of glycolysis factors was organ-specific in LPS-induced endotoxemic rats, which suggested their multifaceted roles in glycolysis and organs functions. LPS targeted to brain and muscles rather that liver, indicating certain rats organs played the roles in glycolysis regulation.
2. The upregulation of ALD family was matched to HIF-1a accumulation in brain and skeletal muscle, indicating HIF-1αaccumulation might be important in regulation glycolysis in LPS-challenged rats.
3. Skeletal muscle ALD A activity could be inhibited by exogenous GSNO. It might be related with S-nitrosylation. This data contributed to the regulatory mechanisms of enzyme activity.
目的：
探索S-亚硝基谷胱甘肽(S-nitrosoglutathione, GSNO)致内皮细胞线粒体异常时,以醛缩酶(aldolase, ALD)家族为核心的糖酵解因子表征,及HIF-1α蛋白激活对其调控作用；进一步探讨S-亚硝基化修饰及PI3K/Akt通路对HIF-la调控,论证GSNO引起糖酵解流量调控的可能分子机制。
方法：
1.采用外源性GSNO处理内皮细胞,致细胞线粒体功能异常。MTT法检测内皮细胞1h,3h,6h,12h细胞活力,NO试剂盒检测细胞培养液GSNO释放NO水平,JC-1染色法检测线粒体膜电位(mitochondrial membrane potential,△Ψm)变化,电镜考察GSNO处理内皮细胞后线粒体形态学变化。2.RT-PCR法考察GSNO处理内皮细胞后糖酵解酶系和葡萄糖转运体1mRNA表达情况。3. RT-PCR法和免疫细胞化学方法考察ALD家族在内皮细胞中主要亚型。Western blot法考察ALD蛋白表达情况,ALD酶活性试剂盒检测ALD催化活性。乳酸测定试剂盒检测上清液乳酸释放水平。4.为进一步探讨GSNO引起内皮细胞糖代谢因子变化,考察HIF-1α转录和蛋白翻译水平变化,免疫荧光法考察HIF-1α;是否入核被激活；siHIF-1α进一步确认HIF-1α是否介导GSNO引起内皮细胞糖酵解通路变化。5.Modified Biotin Switch法检测GSNO对内皮细胞S-亚硝基化水平影响,通过加入二硫键还原剂二硫苏糖醇(1,4-dithiothreitol, DTT)或P13K抑制剂LY294002,分别评价S-亚硝基化修饰和PI3K/Akt信号通路是否参与GSNO引起糖酵解因子变化机制。
结果：
1. GSNO作用于内皮细胞1h,3h,6h,12h, NO水平呈时间依赖性上调；过量NO致内皮细胞△Ψm下降以及线粒体结构异常；而对内皮细胞存活率并无显著影响；提示GSNO作用于内皮细胞损伤细胞线粒体功能,而对内皮细胞存活率无明显影响。2.通过对糖酵解酶系mRNA水平考察,GSNO可引起GLUT1、 ALD A、 LDHA以及PDK1上调；GSNO上调ALD A, GLUT1蛋白表达及增加乳酸释放；结果提示GSNO可上调糖酵解因子转录和翻译水平进而激活糖酵解通路。3.GSNO上调HIF-1α转录水平,维持HIF-1α蛋白稳定表达,促HIF-1α入核激活低氧信号通路。siHIF-1α可减弱由GSNO引起的ALD A、 GLUT1蛋白上调,提示HIF-1α蛋白稳定表达是GSNO引起糖酵解因子ALDA、 GLUT1上调的关键因素。4. Modified Biotin Switch法结果显示GSNO可易化内皮细胞S-亚硝基化修饰水平；加入DTT后,GSNO引起的S-亚硝基化修饰被明显抑制,提示DTT可作为S-亚硝基化修饰的抑制剂。DTT可阻滞由GSNO引起的HIF-1α蛋白积聚及下游因子ALD A、 GLUT1蛋白上调,提示GSNO经由S-亚硝基化修饰维持HIF-1α蛋白稳定表达影响糖酵解。5. GSNO可上调Akt磷酸化水平,LY294002可部分抑制HIF-1α蛋白积聚及下游因子ALDA、 GLUT1上调,提示PI3K/Akt通路也可能参与调控HIF-1α表达。
结论：
1.过量GSNO可上调内皮细胞ALD A表达和酶活性,上调GLUT1, ALD A, LDHA, PDK1转录,激活糖酵解通路；该作用与乳酸释放上调相平行,提示GSNO可促进糖酵解流量。
2.过量GSNO可上调内皮细胞HIF-1α转录、维持HIF-1α蛋白快速稳定表达,该过程受PI3K/Akt信号通路调控。siHIF-1α阻止GSNO上调ALD A和GLUT1蛋白表达,提示HIF-1α稳定表达是GSNO激活糖酵解过程关键因素。
3.过量GSNO可经由S-亚硝基化修饰维持HIF-1α蛋白稳定,持续激活糖酵解通路。
第二部分LPS致大鼠内毒素血症激活糖酵解通路伴HIF-1α上调
目的：
LPS致大鼠内毒素血症中,大量生成NO可诱发若干蛋白发生体内S-亚硝基化修饰。本部分进一步探讨LPS致大鼠内毒血症早期,以ALD家族为核心的糖酵解因子在其脑、肝脏和骨骼肌组织等表达特征,并论证其表达变化的可能机制,为揭示糖酵解因子在内毒素血症早期表达特征和生物学意义提供实验依据。
方法：
1.SD大鼠12只,250g-300g,雌雄各半。分为两组,每组6只。阴性组腹腔注射生理盐水,给药组腹腔注射LPS (2mg/kg)制备内毒素血症模型。给药6h后,断颈椎处死。取新鲜大鼠脑、肝、骨骼肌等3个组织备用。2. RT-PCR测定各组织GLUT家族,HK家族,PFK1, ALD家族,ENO1, PGK1, PDK1和LDH家族mRNA表达。3. Western blot法考察ALD家族及低氧效应因子HIF-1α表达。4.取新鲜骨骼肌组织与GSNO共孵育,用醛缩酶KIT检测骨骼肌中ALD A酶活性变化,检测ALD A是否被GSNO翻译后修饰。
结果：
1.LPS腹腔注射给药6h,糖酵解因子基因转录层面表达特征：在脑组织中,GLUT1、 ALDC、 ENO1、 PGK1、 PDK1以及LDHA mRNA水平上调,提示此时脑组织糖酵解通路转录层面激活相关。在骨骼肌组织中,GLUT1和ALD A mRNA表达上调,提示此时可影响骨骼肌中糖酵解因子。在肝组织未发现有糖酵解相关因子mRNA表达上调,可能与肝组织尚具备糖异生作用相关。上述结果提示LPS致大鼠内毒素血症早期,糖酵解变化顺序依次为脑组织>骨骼肌组织>肝脏组织。
2.LPS腹腔注射给药后6h,ALD家族及HIF1α蛋白表达特征：骨骼肌中ALD A表达上调,脑组织中ALDC表达上调,而肝脏组织中ALDB表达无明显变化。检测脑、肝、骨骼肌三个组织中低氧诱导因子HIF-1α蛋白表达情况,发现脑、骨骼肌组织中HIF-1α蛋白积聚与ALD家族表达相平行,提示其可能是ALD家族表达上调关联的促发低氧信号通路的分子事件。
3. GSNO在200-1000μmol/L浓度范围内,作用于新鲜骨骼肌组织1h后,对骨骼肌中ALDA催化活性有明显抑制,且呈浓度依赖性抑制。结合课题组前期研究,GSNO可S-亚硝基化修饰纯ALDA蛋白抑制其催化活性,提示骨骼肌ALDA也可能受GSNO介导的S-亚硝基化修饰活性位点,从而影响了酶催化活性。
结论：
1.大鼠腹腔注射LPS6h,可上调脑组织、骨骼肌组织器官糖酵解因子,糖酵解因子变化幅度依次为脑组织>骨骼肌组织>肝脏组织。提示在LPS致内毒素模型早期机体具备自我调控糖酵解通路的特性。
2.大鼠腹腔注射LPS6h,脑与骨骼肌组织中ALD家族蛋白上调与HIF-1α表达相平行,提示糖酵解因子表达变化可能受HIF-1α调控。
3.外源性高浓度GSNO可能通过S-亚硝基化修饰骨骼肌ALDA蛋白游离巯基而抑制其催化活性。该结果对探讨骨骼肌ALDA催化酶活性调控机制具有重要意义。
Part I S-Nitrosoglutathione activated glycolysis pathway via HIF-1α accumulation by S-nitrosylation in human endothelial cells Objective
Present study attempted to elucidate the role of glycolysis factors in S-Nitrosoglutathione (GSNO) induced mitochondria function loss on human endothelial cells, as well as to explore the regulatory mechanisms by S-nitrosylation and PI3K/Akt activation involved in this process, so as to clarify the energy metabolism regulation from a new perspective.
Methods
1. Cell viability was observed by MTT assay with GSNO treatment for1h,3h,6h,12h. NO release was detected by NO KIT. JC-1staining was performed to determine mitochondrial membrane potential. The structure of mitochondrial was obversed by transmission electron microscope.2. RT-PCR assay was established to evaluate glycolysis factors-HK family, PFK1, ALD family, PGK1, ENO1, LDHA, LDHB, PDK1, GLUT family mRNA levels.3. ALD family location on human endothelial cells was detected by immunochemistry staining. When endothelial cells were treated with GSNO, ALD family expression was determined by RT-PCR or Western blot, respectively. ALD A activity was detected by ALDOLASE KIT. And lactate release was evaluated by Lactic acid KIT.4. To further elucidate the mechanism of GSNO induced glycolysis factors changes, HIF-1α expression and activation were evaluated. Suppression of HIF-1a with siRNA against HIF-1a to endothelial cells was used to confirm the role of HIF-1a in GSNO-induced glycolysis factors.To further evaluate the details mechanism of GSNO-induced HIF-1a accumulation, modified biotin switch method was established to detect whether GSNO enhanced S-nitrosylation on endothelial cells. Disulfide bonds inhibitor dithiothreitol (DTT) was used to confirm GSNO-induced HIF-1a accumulation through S-nitrosylation.5. Akt phosphorylation was detected with GSNO treatment. After adding the PI3K inhibitor LY294002, expression of HIF-1a and GLUT1, ALD A proteins was examined.
Results
1. GSNO evoked a sharp NO release in a time-dependent manner. GSNO triggered△Ψm decrease and impacted inner cristae integrity. Cell viability had no changes after GSNO treatment within12h.2. GSNO induced an enhancement in the gene expression of glycolytic enzyme ALD A as well as GLUT, LDHA, PDK1. As a consequence of GSNO treatment, an enhanced total ALD A activity and lactate release by endothelial cells, indicated glycolysis enhancement under NO-induced mitochondria dysfunction.3. HIF-1a represented possible regulator of glycolysis enhancement due to the protein stability by GSNO-induced S-nitrosylation as well as ALD A and GLUT1upregulation on endothelial cells, which were prevented by downregulating HIF-1α using a free thiol agent DTT. SiHIF-1a inhibited glycolysis factors which activated by GSNO without HIF-1α accumulation.4. GSNO increased Akt phosphorylation. The PI3K inhibitor LY294002reversed GSNO induced the ratio of p-Akt/Akt. LY294002also reduced HIF-1α accumulationblocked HIF-1α downstream factor ALD A and GLUT1. It indicated that PI3K/Akt participated into GSNO induced HIF-1α upregulation.
Conclusion
1. GSNO upregulated ALD A expression and activity, as well as glycolysis related factors mRNA levels, suggesting to be related to influence glycolysis, which was indicated to be related to the increased lactic acid release.
2. GSNO increased HIF-1α mRNA and protein stability to enhance glycolysis flux, which was regulated by PI3K/Akt signaling pathway. si-HIF-1a reduced GSNO-induced ALD A and GLUT1upregulation, indicating that HIF-1a protein stability might play an important role in GSNO effects on glycolysis factors.
3. GSNO induced HIF-1a accumulation to activate glycolysis via S-nitrosylation.
Part II Glycolysis pathway was activated in LPS-induced endotoxemic rats with HIF-1α upregulation
Objective
Characterization of glycolysis factors in LPS-induced endotoxemic rats was investigated, and this information helps to understand potential roles of glycolysis factors in endotoxemic rats.
Methods
1. SD rats were treated with a single dose injection (i.p.) of LPS (2mg/kg), and rats in control group were given equal amount of NaCl (0.9%)(n=6). After6h, brain, liver and skeletal muscle tissues were abtained from the rats.2. The mRNA expression of GLUT family, HK family, PFK1, ALD family, ENO1, PGK1, PDK1and LDH family were assayed by RT-PCR.3. The proteins expression of ALD family and hypoxia-related factors were determined by Western blot.4. Rat skeletal muscle was treated with50μmol/L,200μmol/L,500μmol/L,1000μmol/L GSNO, and ALD activity was detected by ALDOLASE KIT.
Results
1. Glycolysis related factors mRNA levels were detected in brain, liver and skeletal muscles after LPS challenged. In brain tissue, LPS increased GLUT1, ALD C, ENO1, PGK1, PDK1and LDHA mRNA levels, it indicated that LPS might impact glycolysis flux in the brain tissue. LPS had no effects on liver tissue. However, ALD A and GLUT1mRNA up regulated in skeletal muscle with LPS treatment. As showed above, LPS targeted to glycolysis in brain and skeletal muscle rather than liver.2. LPS increased ALD A and ALD C expression in skeletal muscle or brain respectively after LPS challenged. But LPS had no effects on ALD B in liver tissue. To further determine the hypoxia related signaling role in LPS challenged rats, HIF-1α protein was detected. It showed that HIF-la accumulated in brain and skeletal muscle. It indicated that hypoxia related signaling might involve in LPS induced endotoxemic rats.3. Functionally, GSNO (200,500,1000μmol/L) inhibited ALD activity in a dose-dependent manner. It indicated that ALD activity site was blocked thought a post-transcriptional manner.
Conclusions
1. The characterization of glycolysis factors was organ-specific in LPS-induced endotoxemic rats, which suggested their multifaceted roles in glycolysis and organs functions. LPS targeted to brain and muscles rather that liver, indicating certain rats organs played the roles in glycolysis regulation.
2. The upregulation of ALD family was matched to HIF-1a accumulation in brain and skeletal muscle, indicating HIF-1αaccumulation might be important in regulation glycolysis in LPS-challenged rats.
3. Skeletal muscle ALD A activity could be inhibited by exogenous GSNO. It might be related with S-nitrosylation. This data contributed to the regulatory mechanisms of enzyme activity.
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