The Inhibitory Effects of PSS-Loaded Nanoparticles on the Dysfunction of Cardiac Microvascular Endothelia in Rats with Diabetic Cardiomyopathy
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摘要
Propylene glycol alginate sodium sulfate-loaded nanoparticles(PSS-NP) has been shown potential to prevent the microvascular endothelial injuries caused by diabetic cardiomyopathy(DCM). In this study, we aimed to investigate the effects of PSS-NP on the dysfunction of cardiac microvascular endothelia in streptozotocin(STZ)-induced DCM rat model. Echocardiographic measurements showed a significant improvement of cardiac function in the PSS-NP-treated group. Our results revealed that the abnormalities of cardiac systolic and diastolic functions were suppressed by the treatments of prostaglandin E1(PGE1), low molecular weight heparin(LMWH), PSS and PSS-NP. Our comparison analysis indicated that PSS-NP showed the strongest inhibitory effects on microvascular endothelial injuries. Transmission electron microscopy analysis demonstrated that PSS-NP protected the cardiac microvascular endothelium and further improved endothelium dysfunction in DCM rats. ELISA and Western blot assays further showed a high efficiency of improving cardiac microvascular endothelial dysfunction with PSS-NP. Our results demonstrated that PSS-NP increased the protein expression of phosphatidylinositol 3-kinase(PI3K)-p85 and vascular endothelial growth factor(VEGF)-A, and the phosphorylation of protein kinase B(Akt) and endothelial nitric oxide synthase(eNOS), which were involved in the amelioration of cardiac microvascular endothelial dysfunction. These data suggest that PSS-NP may be a novel approach to the treatment the coronary microcirculation disorder diseases such as DCM.
Propylene glycol alginate sodium sulfate-loaded nanoparticles(PSS-NP) has been shown potential to prevent the microvascular endothelial injuries caused by diabetic cardiomyopathy(DCM). In this study, we aimed to investigate the effects of PSS-NP on the dysfunction of cardiac microvascular endothelia in streptozotocin(STZ)-induced DCM rat model. Echocardiographic measurements showed a significant improvement of cardiac function in the PSS-NP-treated group. Our results revealed that the abnormalities of cardiac systolic and diastolic functions were suppressed by the treatments of prostaglandin E1(PGE1), low molecular weight heparin(LMWH), PSS and PSS-NP. Our comparison analysis indicated that PSS-NP showed the strongest inhibitory effects on microvascular endothelial injuries. Transmission electron microscopy analysis demonstrated that PSS-NP protected the cardiac microvascular endothelium and further improved endothelium dysfunction in DCM rats. ELISA and Western blot assays further showed a high efficiency of improving cardiac microvascular endothelial dysfunction with PSS-NP. Our results demonstrated that PSS-NP increased the protein expression of phosphatidylinositol 3-kinase(PI3K)-p85 and vascular endothelial growth factor(VEGF)-A, and the phosphorylation of protein kinase B(Akt) and endothelial nitric oxide synthase(eNOS), which were involved in the amelioration of cardiac microvascular endothelial dysfunction. These data suggest that PSS-NP may be a novel approach to the treatment the coronary microcirculation disorder diseases such as DCM.
Propylene glycol alginate sodium sulfate-loaded nanoparticles(PSS-NP) has been shown potential to prevent the microvascular endothelial injuries caused by diabetic cardiomyopathy(DCM). In this study, we aimed to investigate the effects of PSS-NP on the dysfunction of cardiac microvascular endothelia in streptozotocin(STZ)-induced DCM rat model. Echocardiographic measurements showed a significant improvement of cardiac function in the PSS-NP-treated group. Our results revealed that the abnormalities of cardiac systolic and diastolic functions were suppressed by the treatments of prostaglandin E1(PGE1), low molecular weight heparin(LMWH), PSS and PSS-NP. Our comparison analysis indicated that PSS-NP showed the strongest inhibitory effects on microvascular endothelial injuries. Transmission electron microscopy analysis demonstrated that PSS-NP protected the cardiac microvascular endothelium and further improved endothelium dysfunction in DCM rats. ELISA and Western blot assays further showed a high efficiency of improving cardiac microvascular endothelial dysfunction with PSS-NP. Our results demonstrated that PSS-NP increased the protein expression of phosphatidylinositol 3-kinase(PI3K)-p85 and vascular endothelial growth factor(VEGF)-A, and the phosphorylation of protein kinase B(Akt) and endothelial nitric oxide synthase(eNOS), which were involved in the amelioration of cardiac microvascular endothelial dysfunction. These data suggest that PSS-NP may be a novel approach to the treatment the coronary microcirculation disorder diseases such as DCM.
引文
Alp,N.J.,Mussa,S.,Khoo,J.,Cai,S.,Guzik,T.,Jefferson,A.,Goh,N.,Rockett,K.A.,and Channon,K.M.,2003.Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression.Journal of Clinical Investigation,112(5):725-735,DOI:10.1172/JCI17786.
Chen,J.,Somanath,P.R.,Razorenova,O.,Chen,W.S.,Hay,N.,Bornstein,P.,and Byzova,T.V.,2005.Akt1 regulates pathological angiogenesis,vascular maturation and permeability in vivo.Nature Medicine,11(11):1188-1196,DOI:10.1038/nm1307.
Dong,B.,Yu,Q.T.,Dai,H.Y.,Gao,Y.Y.,Zhou,Z.L.,Zhang,L.,Jiang,H.,Gao,F.,Li,S.Y.,Zhang,Y.H.,Bian,H.J.,Liu,C.X.,Wang,N.,Xu,H.,Pan,C.M.,Song,H.D.,Zhang,C.,and Zhang,Y.,2012.Angiotensin-converting enzyme-2 overexpression improves left ventricular remodeling and function in a rat model of diabetic cardiomyopathy.Journal of the American College of Cardiology,59(8):739-747,DOI:10.1016/j.jacc.2011.09.071.
Elsabahy,M.,Heo,G.S.,Lim,S.M.,Sun,G.,and Wooley,K.L.,2015.Polymeric Nanostructures for Imaging and Therapy.Chemical Reviews,115(19):10967-11011,DOI:10.1021/acs.chemrev.5b00135.
Fang,Z.Y.,Prins,J.B.,and Marwick,T.H.,2004.Diabetic cardiomyopathy:evidence,mechanisms,and therapeutic implications.Endocrine Reviews,25(4):543-567,DOI:10.1210/er.2003-0012.
Farhangkhoee,H.,Khan,Z.A.,Kaur,H.,Xin,X.,Chen,S.,and Chakrabarti,S.,2006.Vascular endothelial dysfunction in diabetic cardiomyopathy:pathogenesis and potential treatment targets.Pharmacology&Therapeutics,111(2):384-399,DOI:10.1016/j.pharmthera.2005.10.008.
Feng,S.S.,Mei,L.,Anitha,P.,Gan,C.W.,and Zhou,W.,2009.Poly(lactide)-vitamin E derivative/montmorillonite nanoparticle formulations for the oral delivery of Docetaxel.Biomaterials,30(19):3297-3306,DOI:10.1016/j.biomaterials.2009.02.045.
Forbes,J.M.,and Cooper,M.E.,2013.Mechanisms of diabetic complications.Physiological Reviews,93(1):137-188,DOI:10.1152/physrev.00045.2011.
Green,D.,Hirsh,J.,Heit,J.,Prins,M.,Davidson,B.,and Lensing,A.W.,1994.Low molecular weight heparin:A critical analysis of clinical trials.Physiological Reviews,46(1):89-109.
Hasegawa,H.,and Ichioka,S.,2015.Effects of lipo-prostaglandin E1 on wound bed microcirculation.Journal of Wound Care,24(7):293-294,296,298-299,DOI:10.12968/jowc.2015.24.7.293.
Hoehn,K.L.,Hohnen-Behrens,C.,Cederberg,A.,Wu,L.E.,Turner,N.,Yuasa,T.,Ebina,Y.,and James,D.E.,2008.IRS1-independent defects define major nodes of insulin resistance.Cell Metabolism,7(5):421-433,DOI:10.1016/j.cmet.2008.04.005.
Huynh,K.,Bernardo,B.C.,McMullen,J.R.,and Ritchie,R.H.,2014.Diabetic cardiomyopathy:Mechanisms and new treatment strategies targeting antioxidant signaling pathways.Pharmacology&Therapeutics,142(3):375-415,DOI:10.1016/j.pharmthera.2014.01.003.
Kawamura,M.,Paulsen,M.J.,Goldstone,A.B.,Shudo,Y.,and Woo,Y.J.,2017.Tissue-engineered smooth muscle cell and endothelial progenitor cell bi-level cell sheets prevent progression of cardiac dysfunction,microvascular dysfunction,and interstitial fibrosis in a rodent model of type 1 diabetes-induced cardiomyopathy.Cardiovascular Diabetology,16(1):142,DOI:10.1186/s12933-017-0625-4.
Li,P.L.,Li,C.X.,Xue,Y.T.,Li,H.H.,Liu,H.B.,He,X.X.,Yu,G.L.,and Guan,H.S.,2013.An HPLC method for microanalysis and pharmacokinetics of marine sulfated polysaccharide PSS-loaded poly lactic-co-glycolic acid(PLGA)nanoparticles in rat plasma.Marine Drugs,11(4):1113-1125,DOI:10.3390/md11041113.
Litwin,S.E.,Raya,T.E.,Anderson,P.G.,Daugherty,S.,and Goldman,S.,1990.Abnormal cardiac function in the streptozotocin-diabetic rat.Changes in active and passive properties of the left ventricle.Journal of Clinical Investigation,86(2):481-488,DOI:10.1172/JCI114734.
Liu,Y.,Lei,S.,Gao,X.,Mao,X.,Wang,T.,Wong,G..T.,Vanhoutte,P.M.,Irwin,M.G.,and Xia,Z.,2012.PKCbeta inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfunction in rats with streptozotocin-induced diabetes.Clinical Science,122(4):161-173,DOI:10.1042/CS20110176.
Maillet,M.,van Berlo,J.H.,and Molkentin,J.D.,2013.Molecular basis of physiological heart growth:Fundamental concepts and new players.Nature Reviews Molecular Cell Biology,14(1):38-48,DOI:10.1038/nrm3495.
Mizrahy,S.,and Peer,D.,2012.Polysaccharides as building blocks for nanotherapeutics.Chemical Society Reviews,41(7):2623-2640,DOI:10.1039/c1cs15239d.
Saito,H.,Godo,S.,Sato,S.,Ito,A.,Ikumi,Y.,Tanaka,S.,Ida,T.,Fujii,S.,Akaike,T.,and Shimokawa,H.,2018.Important role of endothelial caveolin-1 in the protective role of endothelium-dependent hyperpolarization against Nitric Oxide-mediated nitrative stress in microcirculation in mice.Journal of Cardiovascular Pharmacology,71(2):113-126,DOI:10.1097/FJC.0000000000000552.
Sasso,F.C.,Torella,D.,Carbonara,O.,Ellison,G.M.,and Salvatore,T.,2005.Increased vascular endothelial growth factor expression but impaired vascular endothelial growth factor receptor signaling in the myocardium of type 2 diabetic patients with chronic coronary heart disease.Journal of the American College of Cardiology,46(5):827-834,DOI:10.1016/j.jacc.2005.06.007.
Simons,M.,Gordon,E.,and Claesson-Welsh,L.,2016.Mechanisms and regulation of endothelial VEGF receptor signalling.Nature Reviews Molecular Cell Biology,17(10):611-625,DOI:10.1038/nrm.2016.87.
Stefek,M.,Sotnikova,R.,Okruhlicova,L.,Volkovova,K.,Kucharska,J.,Gajdosik,A.,Tribulova,N.,and Gvozdjakova,A.,2000.Effect of dietary supplementation with the pyridoindole antioxidant stobadine on antioxidant state and ultrastructure of diabetic rat myocardium.Acta Diabetologica,37(3):111-117.
Wang,D.,Luo,P.,Wang,Y.,Li,W.,Wang,C.,Sun,D.,Zhang,R.,Su,T.,Ma,X.,Zeng,C.,Wang,H.,Ren,J.,and Cao,F.,2013.Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism.Diabetes,62(5):1697-1708,DOI:10.2337/db12-1025.
Wong,P.T.,and Choi,S.K.,2015.Mechanisms of drug release in nanotherapeutic delivery systems.Chemical Reviews,115(9):3388-3432,DOI:10.3390/ijms16011772.
Wu,B.,Zhang,Z.,Lui,W.,Chen,X.,Wang,Y.,Chamberlain,A.A.,Moreno-Rodriguez,R.A.,and Zhou,B.,2012.Endocardial cells form the coronary arteries by angiogenesis through myocardial-endocardial VEGF signaling.Cell,151(5):1083-1096,DOI:10.1016/j.cell.2012.10.023.
Wu,Y.T.,Tan,H.L.,Huang,Q.,Ong,C.N.,and Shen,H.M.,2009.Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy.Autophagy,5(6):824-834.
Wu,Z.,Huang,A.,Yan,J.,Liu,B.,Liu,Q.,Zhang,J.,Zhang,X.,Ou,C.,and Chen,M.,2017.Resveratrol ameliorates cardiac dysfunction by inhibiting apoptosis via the PI3K/Akt/FoxO3a pathway in a rat model of diabetic cardiomyopathy.Journal of Cardiovascular Pharmacology,70(3):184-193,DOI:10.1097/FJC.0000000000000504.
Xin,H.,Zhong,C.,Nudleman,E.,and Ferrara,N.,2016.Evidence for pro-angiogenic functions of VEGF-Ax.Cell,167(1):275-284,DOI:10.1016/j.cell.2016.08.054.
Xin,M.,Ren,L.,Sun,Y.,Li,H.H.,Guan,H.S.,He,X.X.,and Li,C.X.,2016.Anticoagulant and antithrombotic activities of low-molecular-weight propylene glycol alginate sodium sulfate(PSS).European Journal of Medicinal Chemistry,114:33-40,DOI:10.1016/j.ejmech.2016.02.063.
Yin,Y.,Qi,F.,Song,Z.,Zhang,B.,and Teng,J.,2014.Ferulic acid combined with astragaloside IV protects against vascular endothelial dysfunction in diabetic rats.Bioscience Trends,8(4):217-226.
Zeng,Y.,Yang,D.,Qiu,P.,Han,Z.,Zeng,P.,He,Y.,Guo,Z.,Xu,L.,Cui,Y.,Zhou,Z.,Zhang,M.,Hao,J.,and Zhang,L.,2016.Efficacy of heparinoid pss in treating cardiovascular diseases and beyond-A review of 27 years clinical experiences in China.Clinical and Applied Thrombosis/Hemostasis,22(3):222-229,DOI:10.1177/1076029614551822.
Zhang,X.,Pan,L.,Yang,K.,Fu,Y.,Liu,Y.,Chi,J.,Zhang,X.,Hong,S.,Ma,X.,and Yin,X.,2017.H3 relaxin protects against myocardial injury in experimental diabetic cardiomyopathy by inhibiting myocardial apoptosis,fibrosis and inflammation.Cellular Physiology and Biochemistry,43(4):1311-1324,DOI:10.1159/000481843.
Zhao,M.M.,Li,Z.,Teng,Z.,Zhao,J.S.,Yu,X.H.,Watanabe,Y.,and Zhao,L.M.,2007.Repeated oral treatment with polysaccharide sulfate reduces insulin resistance and dyslipidemia in diabetic dyslipidemic rat model.Acta Pharmaceutica Sinica,42(5):488-491.
Zoungas,S.,Patel,A.,Chalmers,J.,de Galan,B.E.,Li,Q.,Billot L.,Woodward,M.,Ninomiya,T.,Neal,and Group,A.C.,2010.Severe hypoglycemia and risks of vascular events and death.New England Journal of Medicine,363(15):1410-1418,DOI:10.1056/NEJMoa1003795.(Edited by Ji Dechun)
Chen,J.,Somanath,P.R.,Razorenova,O.,Chen,W.S.,Hay,N.,Bornstein,P.,and Byzova,T.V.,2005.Akt1 regulates pathological angiogenesis,vascular maturation and permeability in vivo.Nature Medicine,11(11):1188-1196,DOI:10.1038/nm1307.
Dong,B.,Yu,Q.T.,Dai,H.Y.,Gao,Y.Y.,Zhou,Z.L.,Zhang,L.,Jiang,H.,Gao,F.,Li,S.Y.,Zhang,Y.H.,Bian,H.J.,Liu,C.X.,Wang,N.,Xu,H.,Pan,C.M.,Song,H.D.,Zhang,C.,and Zhang,Y.,2012.Angiotensin-converting enzyme-2 overexpression improves left ventricular remodeling and function in a rat model of diabetic cardiomyopathy.Journal of the American College of Cardiology,59(8):739-747,DOI:10.1016/j.jacc.2011.09.071.
Elsabahy,M.,Heo,G.S.,Lim,S.M.,Sun,G.,and Wooley,K.L.,2015.Polymeric Nanostructures for Imaging and Therapy.Chemical Reviews,115(19):10967-11011,DOI:10.1021/acs.chemrev.5b00135.
Fang,Z.Y.,Prins,J.B.,and Marwick,T.H.,2004.Diabetic cardiomyopathy:evidence,mechanisms,and therapeutic implications.Endocrine Reviews,25(4):543-567,DOI:10.1210/er.2003-0012.
Farhangkhoee,H.,Khan,Z.A.,Kaur,H.,Xin,X.,Chen,S.,and Chakrabarti,S.,2006.Vascular endothelial dysfunction in diabetic cardiomyopathy:pathogenesis and potential treatment targets.Pharmacology&Therapeutics,111(2):384-399,DOI:10.1016/j.pharmthera.2005.10.008.
Feng,S.S.,Mei,L.,Anitha,P.,Gan,C.W.,and Zhou,W.,2009.Poly(lactide)-vitamin E derivative/montmorillonite nanoparticle formulations for the oral delivery of Docetaxel.Biomaterials,30(19):3297-3306,DOI:10.1016/j.biomaterials.2009.02.045.
Forbes,J.M.,and Cooper,M.E.,2013.Mechanisms of diabetic complications.Physiological Reviews,93(1):137-188,DOI:10.1152/physrev.00045.2011.
Green,D.,Hirsh,J.,Heit,J.,Prins,M.,Davidson,B.,and Lensing,A.W.,1994.Low molecular weight heparin:A critical analysis of clinical trials.Physiological Reviews,46(1):89-109.
Hasegawa,H.,and Ichioka,S.,2015.Effects of lipo-prostaglandin E1 on wound bed microcirculation.Journal of Wound Care,24(7):293-294,296,298-299,DOI:10.12968/jowc.2015.24.7.293.
Hoehn,K.L.,Hohnen-Behrens,C.,Cederberg,A.,Wu,L.E.,Turner,N.,Yuasa,T.,Ebina,Y.,and James,D.E.,2008.IRS1-independent defects define major nodes of insulin resistance.Cell Metabolism,7(5):421-433,DOI:10.1016/j.cmet.2008.04.005.
Huynh,K.,Bernardo,B.C.,McMullen,J.R.,and Ritchie,R.H.,2014.Diabetic cardiomyopathy:Mechanisms and new treatment strategies targeting antioxidant signaling pathways.Pharmacology&Therapeutics,142(3):375-415,DOI:10.1016/j.pharmthera.2014.01.003.
Kawamura,M.,Paulsen,M.J.,Goldstone,A.B.,Shudo,Y.,and Woo,Y.J.,2017.Tissue-engineered smooth muscle cell and endothelial progenitor cell bi-level cell sheets prevent progression of cardiac dysfunction,microvascular dysfunction,and interstitial fibrosis in a rodent model of type 1 diabetes-induced cardiomyopathy.Cardiovascular Diabetology,16(1):142,DOI:10.1186/s12933-017-0625-4.
Li,P.L.,Li,C.X.,Xue,Y.T.,Li,H.H.,Liu,H.B.,He,X.X.,Yu,G.L.,and Guan,H.S.,2013.An HPLC method for microanalysis and pharmacokinetics of marine sulfated polysaccharide PSS-loaded poly lactic-co-glycolic acid(PLGA)nanoparticles in rat plasma.Marine Drugs,11(4):1113-1125,DOI:10.3390/md11041113.
Litwin,S.E.,Raya,T.E.,Anderson,P.G.,Daugherty,S.,and Goldman,S.,1990.Abnormal cardiac function in the streptozotocin-diabetic rat.Changes in active and passive properties of the left ventricle.Journal of Clinical Investigation,86(2):481-488,DOI:10.1172/JCI114734.
Liu,Y.,Lei,S.,Gao,X.,Mao,X.,Wang,T.,Wong,G..T.,Vanhoutte,P.M.,Irwin,M.G.,and Xia,Z.,2012.PKCbeta inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfunction in rats with streptozotocin-induced diabetes.Clinical Science,122(4):161-173,DOI:10.1042/CS20110176.
Maillet,M.,van Berlo,J.H.,and Molkentin,J.D.,2013.Molecular basis of physiological heart growth:Fundamental concepts and new players.Nature Reviews Molecular Cell Biology,14(1):38-48,DOI:10.1038/nrm3495.
Mizrahy,S.,and Peer,D.,2012.Polysaccharides as building blocks for nanotherapeutics.Chemical Society Reviews,41(7):2623-2640,DOI:10.1039/c1cs15239d.
Saito,H.,Godo,S.,Sato,S.,Ito,A.,Ikumi,Y.,Tanaka,S.,Ida,T.,Fujii,S.,Akaike,T.,and Shimokawa,H.,2018.Important role of endothelial caveolin-1 in the protective role of endothelium-dependent hyperpolarization against Nitric Oxide-mediated nitrative stress in microcirculation in mice.Journal of Cardiovascular Pharmacology,71(2):113-126,DOI:10.1097/FJC.0000000000000552.
Sasso,F.C.,Torella,D.,Carbonara,O.,Ellison,G.M.,and Salvatore,T.,2005.Increased vascular endothelial growth factor expression but impaired vascular endothelial growth factor receptor signaling in the myocardium of type 2 diabetic patients with chronic coronary heart disease.Journal of the American College of Cardiology,46(5):827-834,DOI:10.1016/j.jacc.2005.06.007.
Simons,M.,Gordon,E.,and Claesson-Welsh,L.,2016.Mechanisms and regulation of endothelial VEGF receptor signalling.Nature Reviews Molecular Cell Biology,17(10):611-625,DOI:10.1038/nrm.2016.87.
Stefek,M.,Sotnikova,R.,Okruhlicova,L.,Volkovova,K.,Kucharska,J.,Gajdosik,A.,Tribulova,N.,and Gvozdjakova,A.,2000.Effect of dietary supplementation with the pyridoindole antioxidant stobadine on antioxidant state and ultrastructure of diabetic rat myocardium.Acta Diabetologica,37(3):111-117.
Wang,D.,Luo,P.,Wang,Y.,Li,W.,Wang,C.,Sun,D.,Zhang,R.,Su,T.,Ma,X.,Zeng,C.,Wang,H.,Ren,J.,and Cao,F.,2013.Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism.Diabetes,62(5):1697-1708,DOI:10.2337/db12-1025.
Wong,P.T.,and Choi,S.K.,2015.Mechanisms of drug release in nanotherapeutic delivery systems.Chemical Reviews,115(9):3388-3432,DOI:10.3390/ijms16011772.
Wu,B.,Zhang,Z.,Lui,W.,Chen,X.,Wang,Y.,Chamberlain,A.A.,Moreno-Rodriguez,R.A.,and Zhou,B.,2012.Endocardial cells form the coronary arteries by angiogenesis through myocardial-endocardial VEGF signaling.Cell,151(5):1083-1096,DOI:10.1016/j.cell.2012.10.023.
Wu,Y.T.,Tan,H.L.,Huang,Q.,Ong,C.N.,and Shen,H.M.,2009.Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy.Autophagy,5(6):824-834.
Wu,Z.,Huang,A.,Yan,J.,Liu,B.,Liu,Q.,Zhang,J.,Zhang,X.,Ou,C.,and Chen,M.,2017.Resveratrol ameliorates cardiac dysfunction by inhibiting apoptosis via the PI3K/Akt/FoxO3a pathway in a rat model of diabetic cardiomyopathy.Journal of Cardiovascular Pharmacology,70(3):184-193,DOI:10.1097/FJC.0000000000000504.
Xin,H.,Zhong,C.,Nudleman,E.,and Ferrara,N.,2016.Evidence for pro-angiogenic functions of VEGF-Ax.Cell,167(1):275-284,DOI:10.1016/j.cell.2016.08.054.
Xin,M.,Ren,L.,Sun,Y.,Li,H.H.,Guan,H.S.,He,X.X.,and Li,C.X.,2016.Anticoagulant and antithrombotic activities of low-molecular-weight propylene glycol alginate sodium sulfate(PSS).European Journal of Medicinal Chemistry,114:33-40,DOI:10.1016/j.ejmech.2016.02.063.
Yin,Y.,Qi,F.,Song,Z.,Zhang,B.,and Teng,J.,2014.Ferulic acid combined with astragaloside IV protects against vascular endothelial dysfunction in diabetic rats.Bioscience Trends,8(4):217-226.
Zeng,Y.,Yang,D.,Qiu,P.,Han,Z.,Zeng,P.,He,Y.,Guo,Z.,Xu,L.,Cui,Y.,Zhou,Z.,Zhang,M.,Hao,J.,and Zhang,L.,2016.Efficacy of heparinoid pss in treating cardiovascular diseases and beyond-A review of 27 years clinical experiences in China.Clinical and Applied Thrombosis/Hemostasis,22(3):222-229,DOI:10.1177/1076029614551822.
Zhang,X.,Pan,L.,Yang,K.,Fu,Y.,Liu,Y.,Chi,J.,Zhang,X.,Hong,S.,Ma,X.,and Yin,X.,2017.H3 relaxin protects against myocardial injury in experimental diabetic cardiomyopathy by inhibiting myocardial apoptosis,fibrosis and inflammation.Cellular Physiology and Biochemistry,43(4):1311-1324,DOI:10.1159/000481843.
Zhao,M.M.,Li,Z.,Teng,Z.,Zhao,J.S.,Yu,X.H.,Watanabe,Y.,and Zhao,L.M.,2007.Repeated oral treatment with polysaccharide sulfate reduces insulin resistance and dyslipidemia in diabetic dyslipidemic rat model.Acta Pharmaceutica Sinica,42(5):488-491.
Zoungas,S.,Patel,A.,Chalmers,J.,de Galan,B.E.,Li,Q.,Billot L.,Woodward,M.,Ninomiya,T.,Neal,and Group,A.C.,2010.Severe hypoglycemia and risks of vascular events and death.New England Journal of Medicine,363(15):1410-1418,DOI:10.1056/NEJMoa1003795.(Edited by Ji Dechun)