CN103417970A - Application of estrogen up-regulation endothelial system protection molecule sphingosine-1-phosphate - Google Patents
Application of estrogen up-regulation endothelial system protection molecule sphingosine-1-phosphate Download PDFInfo
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Abstract
The invention discloses application of an estrogen up-regulation endothelial system protection molecule, sphingosine-1-phosphate and discloses novel applications of estrogen, namely promoting synthesis and excretion of endothelial system sphingosine-1-phosphate (S1P). The endogenous form, estradiol stimulated endothelial cell (EA. Hy926), of the estrogen is used for a certain period of time; then, the level of S1P in the endothelial cell and culture medium is increased significantly. The specific activator to the endothelial cell sphingosine kinase 2 is found. The novel technical means of up-regulating the level of S1P in the cell or plasma is provided. The novel molecular mechanism for cardiovascular protection of the estrogen is provided. The fact that the estrogen can activate a signal channel of a S1P/S1P receptor (S1P/S1PR) is found, and the signal channel is proved to participate in various cardiovascular protections.
Description
Technical field
The present invention relates to the protection of ecs function that estrogen is new, specifically about estrogen, raise the application of endothelial system protection molecule sphingol 1-phosphoric acid level.
Background technology
Atherosclerotic cardiovascular disease is the highest chronic inflammation disease of M & M in global range, and the protection endothelial system is one of atherosclerotic Critical policies of control.Last century, the nineties people attempted to use estrogen replacement therapy containment women cardiovascular diseases, found not occur Expected Results after more than ten years.The estrogen atherosclerosis molecular mechanism that its reason may be found with people in experiment exists major defect relevant.Therefore, the estrogenic vascular protection mechanism of re-examine and molecular target likely provide new thinking for estrogen replacement therapy.
Sphingol 1-phosphoric acid (S1P) is that one of most important active sphingolipid molecule is found in research at present, and it can promote the various biological functions such as growth, propagation and anti-inflammatory of cell.The vascular protection effect is played in the effect that it can be in cell causes apoptosis molecule ceramide by inhibition; Can bring into play its molecular biology effect by activating S1P receptor (S1PR) in extracellular.S1P is by the isozyme of E.C. 2.7.1.91, and synthesize in cell E.C. 2.7.1.91 1 and 2.Be distributed with five kinds of S1PR on cell membrane, called after S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5, wherein S1PR1-3 is distributed widely in the blood vessel endothelium system.Existing research shows that the S1P/S1PR signal path playing the part of important role in the endothelial system function aspects.For example: the S1PR1 knock-out mice is because vascularization is obstructed, and retention of dead fetus, show that S1PR1 brings into play extremely important effect at cardiovascular system; In addition, S1PR2 and S1PR3 also have certain vascular protection function.
Epidemiological study shows estrogen, and particularly its endogenous main component estradiol, can effectively protect the women to avoid the puzzlement of angiopathy clinical complication; Yet this protective effect is lost after Women’s climacteric.Experimentation shows, estrogen can effectively protect blood vessel to escape injury, and can suppress the deterioration of the cardiovascular disease such as atherosclerosis; And long-term estrin treatment can promote cardiovascular endothelial function.
Although estrogen and S1P all are proved in the blood vessel endothelium system and play a role as important protection molecule, about the association between the two, know little about it.Within 2012, studies show that, estradiol can raise the synthetic of lung cancer cell line S1P and efflux, and its mechanism is transported sub-ABCC1 and ABCG2 for activating E.C. 2.7.1.91 1 and S1P.At cardiovascular system, contain multiple endogenous estrogen, particularly estradiol in blood; Endotheliocyte directly contacts with blood, and is distributed with estrogen receptor on endotheliocyte.Therefore, whether estrogen scalable endotheliocyte S1P synthetic and effluxing, and then bring into play its vascular protection effect and just become the focus that we pay close attention to.Suppose that estrogen can affect the synthetic of S1P, should there be male and female difference in the level of blood plasma S1P so.Therefore this studies the S1P tandem mass spectrum detection method that we adopt our unit to set up, and at first measures the S1P level in mice and human plasma sample; Inquire into again the molecular mechanism of Effect of estrogen S1P metabolism through the Human umbilical vein endothelial cells of In vitro culture, for adopting the metabolism of estrogen regulation activity lipid molecular S1P, in particular for the new mechanism by the estrin treatment cardiovascular disease, provide foundation.
Summary of the invention
The purpose of this invention is to provide new function and molecular mechanism that a kind of estrogen raises endothelial system protection molecule sphingol 1-phosphoric acid level, can make up prior art and theoretical deficiency.
Estrogen raises the application of endothelial system protection molecule sphingol 1-phosphoric acid level.
Above-mentioned estrogen refers to endogenous estrogen and exogenous estrogen.
Above-mentioned endogenous estrogen comprises: estrone, estradiol and estriol etc.
Above-mentioned exogenous estrogen comprises: nonsteroidal synthetic estrogen, diethylstilbestrol steroid synthetic estrogen, natural estrogen (as: isoflavone, soybean isoflavone, Radix Puerariae isoflavone, Oviductus Ranae, Deng), selectively acting is in estrogen (as: the different methylnorethindron of 7-of target tissue, Deng), estrogen synthesis derivant (ethinylestradiol, Deng), etc.
For realizing this purpose, the technical solution used in the present invention is: at first adopt the tandem mass spectrum detection method, measure sphingol 1-phosphoric acid (S1P) level in male and female mice and human plasma sample; Carry out again estrogen and raise application and the Mechanism Study that endotheliocyte S1P is synthetic and efflux.
The present invention finds that C57BL/6 mice plasma S1P level of the same age is female and is significantly higher than male reaching more than 30%; It is male that the adult also exists female blood plasma S1P level to be significantly higher than, and blood plasma S1P level 40% left and right that significantly descended before than climacteric after Women’s climacteric.Adopt estrogenic main endogenous existence form, estradiol, handler's huve cell (EA.hy926), and measure in cell and the level of S1P in culture medium with the liquid phase tandem mass spectrometry.Experimental result is found: the S1P level has raise respectively 9 times and 3 times in the EA.hy926 cell and in culture medium; The mRNA of E.C. 2.7.1.91 2 and protein level have also raise respectively 10 times and 3 times, and the mRNA of E.C. 2.7.1.91 1 and protein level are without significant change; The mrna expression that S1P transports sub-ABCG2 and Spns2 has raise respectively 2 times and 3 times; On the EA.hy926 cell membrane, the expression of S1PR1, S1PR2 and S1PR3 has been raised respectively 4 times, 3 times and 2 times, wherein with the mrna expression of the closely-related S1PR1 of cardiovascular protection function, raises the most remarkable.This research shows: estrogen can raise the synthetic of endotheliocyte S1P by activating E.C. 2.7.1.91 2, and S1P transports sub-ABCG2 and Spns2 promotes that S1P effluxes by activating.The above-mentioned estrogen protection endothelial system that is found to be provides new molecular mechanism and Research Thinking, for the estrin treatment neovascular disorders provides possible New Policy.
The invention has the advantages that:
1, the present invention has developed estrogenic new purposes, promotes the synthetic of endothelial system sphingol 1-phosphoric acid (S1P) and effluxes.After adopting estrogenic main endogenous form estradiol stimulating endothelial cell (EA.hy926) certain hour, in endotheliocyte and the S1P level in culture medium significantly promote.
2, the present invention has found the specific agonist of endotheliocyte E.C. 2.7.1.91 2.
3, the present invention provides new technological means for raising S1P level in cell or blood plasma.
4, the present invention provides new molecular mechanism for estrogenic cardiovascular protection effect.The present invention finds that estrogen can activate the S1P/S1PR signal path, and this path is proved the multiple cardiovascular protection effect that participates in.
The accompanying drawing explanation
The activity analysis of Fig. 1 .C57BL/6 mice plasma S1P level and phospholipid transport protein.(A) female mice blood plasma S1P level is significantly higher than male mice; (B) specific activity of mice plasma phospholipid transport protein is to the analysis showed that between male and female without significant difference; (C) activity analysis of male mice blood plasma phospholipid transport protein in 60 minutes; (D) activity analysis of male mice blood plasma phospholipid transport protein in 60 minutes.*p＜0.05。
Fig. 2. human plasma S1P level is in all ages and classes phase change.(A) male blood plasma S1P level; (B) women's blood plasma S1P level; (C) 19-55 year age group male wants women's blood plasma S1P level; (D) women's blood plasma S1P level significantly descends after climacteric.*p＜0.05，**p＜0.01。
Fig. 3. human plasma S1P level becomes positive correlation with HDL-C, with the age, becomes negative correlation.(A) linear relationship of blood plasma S1P and HDL-C; (B) linear relationship at blood plasma S1P and age.
Fig. 4. estradiol promotes S1P synthetic at Human umbilical vein endothelial cells EA.hy926 by activating E.C. 2.7.1.91 2.(A) estradiol significantly increases S1P level in cell; (B) estradiol does not make significant difference to mRNA and the protein level of E.C. 2.7.1.91 1; (C) estradiol significantly strengthens mRNA and the protein level of E.C. 2.7.1.91 2; (D) estradiol time dependence ground promotes S1P level in cell; (E) at all time points of measuring, estradiol does not make significant difference to mRNA and the protein level of E.C. 2.7.1.91 1; (F) estradiol time dependence ground improves mRNA and the protein level of E.C. 2.7.1.91 2.* p<0.01, compare with blank group.
Fig. 5. estradiol significantly promotes S1P to be effluxed by Human umbilical vein endothelial cells EA.hy926.(A) estradiol significantly promotes S1P level in culture medium; (B) estradiol does not make significant difference to the mrna expression of transporting sub-ABCC1; (C) estradiol does not make significant difference to the mrna expression of transporting sub-ABCC2; (D) estradiol significantly promotes to transport the mrna expression of sub-ABCG2; (E) estradiol significantly promotes to transport the mrna expression of sub-Spns2; (F) estradiol time dependence ground impels S1P to efflux; (G) estradiol time dependence ground promotes the mrna expression of the sub-ABCG2 of transhipment; (H) estradiol time dependence ground promotes the mrna expression of the sub-Spns2 of transhipment.* p<0.05, * * p<0.01, compare with the blank group.
Fig. 6. the impact of estradiol on the upper S1P expression of receptor of Human umbilical vein endothelial cells EA.hy926.(A) estradiol time dependence ground raises the mrna expression of S1P receptor 1; (B) estradiol time dependence ground raises the mrna expression of S1P receptor 2; (C) estradiol time dependence ground raises the mrna expression of S1P receptor 3; (D) estradiol is significantly higher than the mrna expression to S1P receptor 2 or 3 to the mrna expression rise degree of S1P receptor 1.* p<0.05, * * p<0.01, compare with the blank group; + p<0.05, ++ p<0.01, with the mrna expression of S1P receptor 3, compare; #p<0.05, compare with the mrna expression of S1P receptor 1.
Fig. 7. estrogen raises the molecular mechanism of S1P level.Estrogen, by acting on estrogen receptor, activates the synthetic S1P in E.C. 2.7.1.91 2 (SphK2), and activates two sub-Spns2 of main transhipment of S1P and ABCG2, next activates the S1P receptor 1-3 of endothelial system.The S1P discharged by endothelial system can be transported to lipoprotein by transhipment, thereby brings into play its cardiovascular protection function.
The specific embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.
22 week age, the C57BL/6 mice was 10, male and female half and half.After fasting 4 hours, adopt the eye socket venous plexus to get blood, through 3000 rpms centrifugal 10 minutes, obtain blood plasma.
Blood plasma S1P adopts the alcohol deposition method preparation, adds the methanol of 4 times of amounts of blood plasma or ethanol ultrasonic extraction 20 minutes, and 12,000 * g removes insoluble granule in centrifugal 10 minutes, carries out the liquid phase Tandem Mass Spectrometry Analysis; Lipids extraction step in culture medium is as follows: to the sodium hydroxide that adds chloroform, methanol, 3mol/L in culture medium, volume ratio is 1: 1: 1: 0.1 (pH=12) mixes centrifugal 10 minutes of 3000 * g.The upper water phase transfer, to new pipe, adds the hydrochloric acid (pH=3) of chloroform and 6mol/L, centrifugal 10 minutes of 3000 * g, lower floor's organic facies dries up through nitrogen, heavily is dissolved in methanol 12,000 * g removes insoluble granule in centrifugal 10 minutes, carries out the liquid phase Tandem Mass Spectrometry Analysis; In cell, the extraction of S1P is carried out with reference to the extracting method of S1P in culture medium.Liquid-phase chromatographic column adopts reverse C18 chromatographic column, and mobile phase is 90% methanol that contains 0.1% formic acid and 2mM ammonium formate.Mass spectrum adopts many reaction detection pattern (MRM), and S1P's quantitatively usings C17-S1P as interior mark.Experimental result shows (as Fig. 1): C57BL/6 mice plasma S1P level, female mice blood plasma S1P level is significantly higher than male mice (female 182.3 ± 21.1ng/mL, male 142.4 ± 10.8ng/mL, p<0.05).The phospholipid transport protein is the functional protein of balance phospholipid in vivo, and we show there was no significant difference between male and female (as Fig. 1) to the research of male and female mice plasma phospholipoprotein activity; That is to say, the S1P level difference between the male and female mice and phospholipoprotein are without significant dependency.Epidemiological study shows estrogen, can effectively protect the women to avoid the puzzlement of angiopathy clinical complication; Simultaneously, S1P is found to have the cardiovascular protection function in recent years.Above-mentioned experimental result prompting, estrogen may be brought into play its Endothelium Protective effect by raising S1P.
108 participants, the age is between 3-90 year (47 women, 61 male).Be divided into three groups, 3-15 year, 18-55 year and 56-90 year according to the age.In fasting, plasma sample gathers the next day after 12 hours, through 3000 rpms centrifugal 10 minutes, obtain blood plasma.Blood plasma adopts standby sphingol 1-phosphoric acid (S1P) extracting solution of methanol extraction legal system, and extracting solution carries out the liquid phase Tandem Mass Spectrometry Analysis through 12000 * g after centrifugal 10 minutes.Experimental result is as shown in Figures 2 and 3: the S1P level descends with age growth.In 3-15 year group, men and women's mean age is respectively 8.2 ± 3.4 and 8.2 ± 3.6 years old, and men and women's blood plasma S1P level is respectively: 146.5 ± 28.3 and 150.4 ± 35.6ng/mL; In 19-55 year group, men and women's mean age is respectively 37.5 ± 13.2 and 37.8 ± 11.1 years old, men and women's blood plasma S1P level be respectively 110.9 ± 20.4 and 130.1 ± 30.8ng/mL women be significantly higher than the male; In 19-55 year group, the men and women is respectively 63.5 ± 7.4 and 67.2 ± 8.8 years old the mean age, and blood plasma S1P content is respectively 79.6 ± 17.0 and 85.8 ± 19.5ng/mL.Be worth special concern: the S1P content 80.5 ± 14.6ng/mL after Women’s climacteric is significantly lower than 132.9 ± 25.4ng/mL before climacteric (p<0.01).Difference between male and female mainly comes from hormone, and women's estrogen level is significantly higher than the male; And the estrogen level of women after climacteric is significantly lower than before climacteric.Above-mentioned estrogenic variation tendency is consistent with the variation tendency of human plasma S1P level.Further prove: the difference of blood plasma S1P level mainly comes from estrogen, and furtherly, estrogen probably has the effect of raising blood plasma S1P level.
After Human umbilical vein endothelial cells (EA.hy926) recovery, be inoculated in 6 orifice plates, adopt the DMEM culture medium culturing.37 ℃ of incubator temperature, gas concentration lwevel 5%.Adopt respectively PBS after cell attachment, sphingol or sphingol associating estradiol are processed (being 1uMol/L), continuation is hatched in 37 ℃ of incubators, and with the 0th minute, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 120 minutes and 180 minutes collecting cells for the mrna expression analysis; The 0th hour, 0.5 hour, 1 hour, 2 hours and 3 hours collecting cells and culture medium, for S1P level determination and protein level analysis.In culture medium, the extraction step of sphingol 1-phosphoric acid is as follows: to the sodium hydroxide that adds chloroform, methanol, 3mol/L in culture medium, volume ratio is 1: 1: 1: 0.1 (pH=12) mixes centrifugal 10 minutes of 3000 * g.The upper water phase transfer, to new pipe, adds the hydrochloric acid (pH=3) of chloroform and 6mol/L, centrifugal 10 minutes of 3000 * g, lower floor's organic facies dries up through nitrogen, heavily is dissolved in methanol 12,000 * g removes insoluble granule in centrifugal 10 minutes, carries out the liquid phase Tandem Mass Spectrometry Analysis; In cell, the extraction of S1P is carried out with reference to the extracting method of S1P in culture medium.Experimental result shows (as Fig. 4-6): the sphingol individual processing can not affect the synthetic of S1P and efflux, and after adding estrogenic main endogenous form estradiol, the endotheliocyte content of S1P and the content of culture medium have risen respectively 10 times and 3 times; MRNA and protein expression analysis to E.C. 2.7.1.91 show, estradiol can not affect E.C. 2.7.1.91 1 (SphK1) and be mainly to play a role by acting on E.C. 2.7.1.91 2 (SphK2); S1P is mainly transported to sub experiment and show, estrogen mainly activates Spns2 and ABCG2 and S1P synthetic in cell is transported to extracellular; Adopt the experiment of Real-time PCR Analysis S1P expression of receptor to show, on endotheliocyte, the receptor 1,2 and 3 of S1P has risen respectively 4 times, 3 times and 2 times, and estrogen can activate the S1P receptor 1,2 and 3 on endotheliocyte, but Main Function is in S1P receptor 1.Be summarized as follows (as Fig. 7): estrogen, by acting on estrogen receptor, activates the synthetic S1P in E.C. 2.7.1.91 2 (SphK2), and activates two sub-Spns2 of main transhipment of S1P and ABCG2, next activates the S1P receptor 1-3 of endothelial system; The result of above process is, estrogen promotes S1P the synthetic of endothelial system and efflux, and finally is shown as female blood plasma S1P level and is significantly higher than malely, and the activation of S1P receptor 1 can be played the effect of protection endothelial system.
Should be understood that, for those of ordinary skills, can be improved according to the above description or convert, and all these improvement and conversion all should belong to the protection domain of claims of the present invention.
Claims (5)
1. estrogen raises the application of endothelial system protection molecule sphingol 1-phosphoric acid level.
2. estrogen claimed in claim 1 refers to endogenous estrogen and exogenous estrogen.
3. endogenous estrogen claimed in claim 2 comprises: estrone or estradiol or estriol.
4. the described exogenous estrogen of claim 2 comprises: nonsteroidal synthetic estrogen, diethylstilbestrol steroid synthetic estrogen, natural estrogen, selectively acting are in estrogen, the estrogen synthesis derivant of target tissue.
5. application claimed in claim 1 also comprises that estrogen is used as the specific agonist of E.C. 2.7.1.91 2.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111103382A (en) * | 2019-12-25 | 2020-05-05 | 南京希麦迪医药科技有限公司 | Method for determining concentration of endogenous sphingosine-1-phosphate in human plasma by liquid chromatography-mass spectrometry |
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| WO2007097887A2 (en) * | 2006-02-15 | 2007-08-30 | Advanced Cardiovascular Systems, Inc. | Coatings for implantable medical devices containing attractants for endothelial cells |
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| CN1652757A (en) * | 2002-05-16 | 2005-08-10 | 诺瓦提斯公司 | Use of EDG receptor binding agents in cancer |
| WO2007097887A2 (en) * | 2006-02-15 | 2007-08-30 | Advanced Cardiovascular Systems, Inc. | Coatings for implantable medical devices containing attractants for endothelial cells |
Non-Patent Citations (2)
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| KAZUAKI TAKABE, ET AL: "Estradiol Induces Export of Sphingosine 1-Phosphate from Breast Cancer Cells via ABCC1 and ABCG2", 《J. BIOL. CHEM.》, vol. 285, no. 14, 28 January 2010 (2010-01-28) * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111103382A (en) * | 2019-12-25 | 2020-05-05 | 南京希麦迪医药科技有限公司 | Method for determining concentration of endogenous sphingosine-1-phosphate in human plasma by liquid chromatography-mass spectrometry |
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Application publication date: 20131204 |