Effects of Rapamycin on Clinical Manifestations and Blood Lipid Parameters in Different Preeclampsia-like Mouse Models
- Author:
- No author available
- Journal Title:
- Chinese Medical Journal
- Issue:
- 9
- DOI:
- 10.4103/0366-6999.204924
- Key Word:
- Mouse;Preeclampsia;Rapamycin
Abstract： Background:The pathogenesis of some types of preeclampsia is related to fatty acid oxidation disorders.Rapamycin can regulate fatty acid metabolism.This study aimed to investigate the effects of rapamycin on the clinical manifestations and blood lipid parameters in different preeclampsia-like mouse models.Methods:Two preeclampsia-like mouse models and a control group were established:L-NA (injected with Nω-nitro-L-arginine methyl ester),LPS (injected with lipopolysaccharide),and the control group with normal saline (NS).The mouse models were established at preimplantation (PI),early-and late-pregnancy (EP,LP) according to the time of pregnancy.The administration of rapamycin (RA;L-NA+RA,LPS+RA,and NS+RA) or vehicle as controls (C;L-NA+C,LPS+C,NS+C) were followed on the 2nd day after the mouse models' establishment.Each subgroup consisted of eight pregnant mice.The mean arterial pressure (MAP),24-h urinary protein,blood lipid,fetus,and placental weight were measured.The histopathological changes and lipid deposition of the liver and placenta were observed.Student's t-test was used for comparing two groups.Repeated measures analysis of variance was used for blood pressure analysis.Qualitative data were compared by Chi-square test.Results:The MAP and 24-h urinary protein in the PI,EP,and LP subgroups of the L-NA+C and LPS+C groups were significantly higher compared with the respective variables in the NS+C group (P ＜ 0.05).The preeclampsia-like mouse models were established successfully.There was no significant difference in the MAP between the PI,EP,and LP subgroups of the L-NA+RA and L-NA+C groups and theLPS+RA and LPS+C groups.The 24-h urine protein levels in the PI and EP subgroups of the L-NA+RA group were significantly lower compared with the respective levels in the L-NA+C groups (1037 ± 63 vs.2127 ± 593 μg;976 ± 42 vs.1238 ± 72 μg;both P ＜ 0.05),also this effect appeared similar in the PI and EP subgroups of the LPS+RA and LPS+C groups (1022 ± 246 vs.2141 ± 432 μ g;951 ± 41 vs.1308 ± 30 μg;both P ＜ 0.05).The levels of serum-free fatty acid (FFA) in the PI and EP subgroups of the L-NA+RA groups were significantly lower compared with the respective levels in the L-NA+C group (2.49 ± 0.44 vs.3.30 ± 0.18 mEq/L;2.23 ± 0.29 vs.2.84 ± 0.14 mEq/L;both P ＜ 0.05).The levels of triglycerides (TG) and total cholesterol in the PI subgroup of the L-NA+RA group were significantly lower compared with the respective levels in the L-NA+C (1.51 ± 0.16 vs.2.41 ± 0.37 mmol/L;2.11 ± 0.17 vs.2.47 ± 0.26 mmol/L;both P ＜ 0.05),whereas high-density lipoprotein serum concentration was significantly higher (1.22 ± 0.19 vs.0.87 ± 0.15 mmol/L;P ＜ 0.05) and low-density lipoprotein serum concentration did not exhibit a significant difference.There were no significant differences in the FFA of the PI,EP,and LP subgroups between the LPS+RA and the LPS+C groups.The levels of TG in the PI subgroup of the LPS+RA group were significantly lower compared with the respective levels in the LPS+C group (0.97 ± 0.05 vs.1.22 ± 0.08 mmol/L;P ＜ 0.05).Conclusion:Rapamycin can improve clinical manifestations and blood lipid profile in part of the preeclampsia-like mouse models.
- [1]王伽略,杨孜,王荣,等.子痫前期患者血脂代谢调节的探讨[J].2006,(6).
- [2]MA Rui-Qiong,SUN Min-na,Yang Zi.Inhibition of nitric oxide synthase lowers fatty acid oxidation in preeclampsia-like mice at early gestational stage[J].2011,(19).
- [3]Yi-Wei Han,Zi YANG,Xiao-Yan DING,etc.Differences in Liver Injury and Trophoblastic Mitochondrial Damage in Different Preeclampsia-like Mouse Models[J].2015,(12).
- [4]Das,A.,Durrant,D.,Koka,S.,etc.Mammalian target of rapamycin (mTOR) inhibition with rapamycin improves cardiac function in type 2 diabetic mice: Potential role of attenuated oxidative stress and altered contractile protein expression[J].2014,289(7).
- [5]Alperovich G,Poveda R,Carrera M,etc.New immunosuppresor strategies in the treatment of murine lupus nephritis.[J].2007,16(1).
- [6]Stillman IE,Karumanchi SA.The glomerular injury of preeclampsia.[J].2007,18(8).
- [7]Rakheja D,Rogers BB,Foster BM,etc.Evidence for fatty acid oxidation in human placenta, and the relationship of fatty acid oxidation enzyme activities with gestational age.[J].2002,23(5).
- [8]Tian, Jihua,Wang, Yanhong,Guo, Haixiu,etc.The Akt/mTOR/p70S6K pathway is activated in IgA nephropathy and rapamycin may represent a viable treatment option[J].2015,99(3).
- [9]Ding, Xiaoyan,Yang, Zi,Han, Yiwei,etc.Fatty Acid Oxidation Changes and the Correlation with Oxidative Stress in Different Preeclampsia-Like Mouse Models.[J].2014,9(10).
- [10]Martin, Faehling,Vera, Wienhausen-Wilke,Sabine, Fallscheer,etc.Long-term stable lung function and second uncomplicated pregnancy on sirolimus in lymphangioleiomyomatosis (LAM).[J].2015,32(3).
- [11]E J, Brown,M W, Albers,T B, Shin,etc.A mammalian protein targeted by G1-arresting rapamycin-receptor complex.[J].1994,369(6483).
- [12]Anderl S,Freeland M,Kwiatkowski DJ,etc.Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex.[J].2011,20(23).
- [13]Nambi P,Adelman SJ,Basso MD.Effect of sirolimus on the cholesterol content of aortic arch in ApoE knockout mice.[J].2003,35(8).
- [14]Schiariti, Michele,Andrei, Catalina Liliana,Gaspard, Philippe,etc.Oral sirolimus: A possible treatment for refractory angina pectoris in the elderly[J].2016,222.
- [15]Bugatto,F.,Bartha,J.L.,Visiedo,F.,etc.Decreased mitochondrial fatty acid oxidation in placentas from women with preeclampsia[J].2012,33(2).
- [16]Brown NF,Sipula IJ,Stefanovic-Racic M,etc.The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes.[J].2007,56(11).
- [17]Cyganek A,Teisseyre M,Markiewicz M,etc.Absence of teratogenicity of sirolimus used during early pregnancy in a liver transplant recipient.[J].2004,36(10).
- [18]Hooman, Tabatabai-Mir,Kavithalakshmi, Sataranatarajan,Hak Joo, Lee,etc.Rapamycin selectively alters serum chemistry in diabetic mice.[J].2012,2.
- [19].Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients[J].2012,18(17).
- [20]Tao, Peng,Todd R, Golub,David M, Sabatini.The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation.[J].2002,22.
- [21]Ding, Xiaoyan,Yang, Zi,Han, Yiwei,etc.Correlation of long-chain fatty acid oxidation with oxidative stress and inflammation in pre-eclampsia-like mouse models[J].2015,36(12).
- [22]Joanna, Trelińska,Iwona, Dachowska,Katarzyna, Kotulska,etc.Everolimus treatment among patients with tuberous sclerosis affects serum lipid profile.[J].2016.
- [23]David Neal Franz,Jennifer Leonard,Cynthia Tudor,etc.Rapamycin causes regression of astrocytomas in tuberous sclerosis complex[J].2006,59(3).
- [24]Roos S,Jansson N,Palmberg I,etc.Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth.[J].2007,582(Pt.1).
- [25].Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan[J].2015,120(4).
- [26]Cha, J.,Daikoku, T.,Yoshie, M.,etc.Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice[J].2011,108(44).
- [27]Zhang, Ying,Zhang, Bo,Wei, Zhao-Lian,etc.Diagnostic Significance of Phosphoinositide 3-Kinase and Mammalian Target of Rapamycin Complex 1 in Preeclampsia[J].2017,24(2).