Protective effect of hydroxychloroquine on rheumatoid arthritis-associated atherosclerosis
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摘要
Background: Patients with rheumatoid arthritis(RA) have an increased risk for cardiovascular disease. We examined the effect of gut microbiota in a mouse model of RA that develops atherosclerosis.Methods: We created three groups of K/BxN female mice that were positive for the anti-glucose-6-phosphate isomerase(GPI) antibody: control diet(CD), high fat diet(HFD), and HFD with hydroxychloroquine(HFD + HCQ). Serological tests were used to detect the serum levels of total cholesterol(TCHO), low-density lipoprotein cholesterol(LDL-C), triglyceride(TG), high-density lipoprotein cholesterol(HDL-C), antiGPI antibody titers, and serum cytokines. Atherosclerotic plaque was determined by histological analysis, and gut microbiota were determined by 16 sV4 sequencing.Results: Relative to mice given the CD, those receiving the HFD had increased serum levels of LDL-C, TCHO, and TG, decreased serum levels of HDL-C, increased atherosclerotic lesions in the aortic root, and altered gut microbiota. Addition of HCQ to HFD decreased the serum levels of LDL-C, TCHO, and TG, increased serum levels of HDL-C, and decreased the atherosclerotic lesions in the aortic root. Mice receiving HFD + HCQ also had the greatest bacterial diversity among the three experimental groups. Moreover, HCQ treatment significantly increased the abundance of Akkermansia and Parabacteroides, and decreased the abundance of Clostridium sensu stricto cluster 1, and therefore may be responsible for the reduced RA-associated atherosclerosis and dyslipidemia.Conclusion: Our mouse model of RA indicated that HFD increased ankle width and aggravated atherosclerosis and dyslipidemia, and that HCQ alleviated the dyslipidemia and atherosclerosis, but had no effect on ankle width.
Background: Patients with rheumatoid arthritis(RA) have an increased risk for cardiovascular disease. We examined the effect of gut microbiota in a mouse model of RA that develops atherosclerosis.Methods: We created three groups of K/BxN female mice that were positive for the anti-glucose-6-phosphate isomerase(GPI) antibody: control diet(CD), high fat diet(HFD), and HFD with hydroxychloroquine(HFD + HCQ). Serological tests were used to detect the serum levels of total cholesterol(TCHO), low-density lipoprotein cholesterol(LDL-C), triglyceride(TG), high-density lipoprotein cholesterol(HDL-C), antiGPI antibody titers, and serum cytokines. Atherosclerotic plaque was determined by histological analysis, and gut microbiota were determined by 16 sV4 sequencing.Results: Relative to mice given the CD, those receiving the HFD had increased serum levels of LDL-C, TCHO, and TG, decreased serum levels of HDL-C, increased atherosclerotic lesions in the aortic root, and altered gut microbiota. Addition of HCQ to HFD decreased the serum levels of LDL-C, TCHO, and TG, increased serum levels of HDL-C, and decreased the atherosclerotic lesions in the aortic root. Mice receiving HFD + HCQ also had the greatest bacterial diversity among the three experimental groups. Moreover, HCQ treatment significantly increased the abundance of Akkermansia and Parabacteroides, and decreased the abundance of Clostridium sensu stricto cluster 1, and therefore may be responsible for the reduced RA-associated atherosclerosis and dyslipidemia.Conclusion: Our mouse model of RA indicated that HFD increased ankle width and aggravated atherosclerosis and dyslipidemia, and that HCQ alleviated the dyslipidemia and atherosclerosis, but had no effect on ankle width.
Background: Patients with rheumatoid arthritis(RA) have an increased risk for cardiovascular disease. We examined the effect of gut microbiota in a mouse model of RA that develops atherosclerosis.Methods: We created three groups of K/BxN female mice that were positive for the anti-glucose-6-phosphate isomerase(GPI) antibody: control diet(CD), high fat diet(HFD), and HFD with hydroxychloroquine(HFD + HCQ). Serological tests were used to detect the serum levels of total cholesterol(TCHO), low-density lipoprotein cholesterol(LDL-C), triglyceride(TG), high-density lipoprotein cholesterol(HDL-C), antiGPI antibody titers, and serum cytokines. Atherosclerotic plaque was determined by histological analysis, and gut microbiota were determined by 16 sV4 sequencing.Results: Relative to mice given the CD, those receiving the HFD had increased serum levels of LDL-C, TCHO, and TG, decreased serum levels of HDL-C, increased atherosclerotic lesions in the aortic root, and altered gut microbiota. Addition of HCQ to HFD decreased the serum levels of LDL-C, TCHO, and TG, increased serum levels of HDL-C, and decreased the atherosclerotic lesions in the aortic root. Mice receiving HFD + HCQ also had the greatest bacterial diversity among the three experimental groups. Moreover, HCQ treatment significantly increased the abundance of Akkermansia and Parabacteroides, and decreased the abundance of Clostridium sensu stricto cluster 1, and therefore may be responsible for the reduced RA-associated atherosclerosis and dyslipidemia.Conclusion: Our mouse model of RA indicated that HFD increased ankle width and aggravated atherosclerosis and dyslipidemia, and that HCQ alleviated the dyslipidemia and atherosclerosis, but had no effect on ankle width.
引文
1.Gonzalez-Gay MA,Gonzalez-Juanatey C,Martin J.Rheumatoid arthritis:a disease associated with accelerated atherogenesis.Semin Arthritis Rheum.2005;35:8-17.
2.Ljung L,Askling J,Rantap??-Dahlqvist S,Jacobsson L;ARTIS Study Group.The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population:a national cohort study.Arthritis Res Ther.2014;16:R127.
3.Peters M,Symmons D,McCarey D,et al.EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis.Ann Rheum Dis.2010;69:325-331.
4.Arida A,Protogerou AD,Konstantonis G,Fragiadaki K,Kitas GD,Sfikakis PP.Atherosclerosis is not accelerated in rheumatoid arthritis of low activity or remission,regardless of antirheumatic treatment modalities.Rheumatology.2017;56:934-939.
5.Lauper K,Gabay C.Cardiovascular risk in patients with rheumatoid arthritis.Semin Immunopathol.2017;39:447-459.
6.Im CH,Kim NR,Kang JW,et al.Inflammatory burden interacts with conventional cardiovascular risk factors for carotid plaque formation in rheumatoid arthritis.Rheumatology.2015;54:808-815.
7.Rempenault C,Combe B,Barnetche T,et al.Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis:a systematic review and meta-analysis.Ann Rheum Dis.2017;77:98-103.
8.Ruiz-Irastorza G,Ramos-Casals M,Brito-Zeron P,Khamashta MA.Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus:a systematic review.Ann Rheum Dis.2009;69:20-28.
9.Hu C,Lu L,Wan J,Wen C.The pharmacological mechanisms and therapeutic activities of hydroxychloroquine in rheumatic and related diseases.Curr Med Chem.2017;24:2241-2249.
10.Emami J,Gerstein HC,Pasutto FM,Jamali F.Insulin-sparing effect of hydroxychloroquine in diabetic rats is concentration dependent.Can J Physiol Pharmacol.1999;77:118-123.
11.Fox RI.Mechanism of action of hydroxychloroquine as an antirheumatic drug.Semin Arthritis Rheum.1993;23:82-91.
12.Kasselman LJ,Vernice NA,Deleon J,Reiss AB.The gut microbiome and elevated cardiovascular risk in obesity and autoimmunity.Atherosclerosis.2018;271:203-213.
13.Koeth RA,Wang Z,Levison BS,et al.Intestinal microbiota metabolism of l-carnitine,a nutrient in red meat,promotes atherosclerosis.Nat Med.2013;19:576-585.
14.Matsumoto I,Staub A,Benoist C,Mathis D.Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme.Science.1999;286:1732-1735.
15.Korganow A,Ji H,Mangialaio S,et al.From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins.Immunity.1999;10:451-461.
16.Rose S,Eren M,Murphy S,et al.A novel mouse model that develops spontaneous arthritis and is predisposed towards atherosclerosis.Ann Rheum Dis.2012;72:89-95.
17.Chafin CB,Regna NL,Hammond SE,Reilly CM.Cellular and urinary microRNA alterations in NZB/W mice with hydroxychloroquine or prednisone treatment.Int Immunopharmacol.2013;17:894-906.
18.Floris A,Piga M,Mangoni AA,Bortoluzzi A,Erre GL,Cauli A.Protective effects of hydroxychloroquine against accelerated atherosclerosis in systemic lupus erythematosus.Mediators Inflamm.2018;2018:3424136.
19.Shukla AM,Bose C,Karaduta OK,et al.Impact of hydroxychloroquine on atherosclerosis and vascular stiffness in the presence of chronic kidney disease.PLoS One.2015;10:e139226.
20.Munro R,Morrison E,Mcdonald AG,Hunter JA,Madhok R,Capell HA.Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis.Ann Rheum Dis.1997;56:374-377.
21.Restrepo JF,Del Rincon I,Molina E,Battafarano DF,Escalante A.Use of hydroxychloroquine is associated with improved lipid profile in rheumatoid arthritis patients.J Clin Rheumatol.2017;23:144-148.
22.Solomon DH,Garg R,Lu B,et al.Effect of hydroxychloroquine on insulin sensitivity and lipid parameters in rheumatoid arthritis patients without diabetes mellitus:a randomized,blinded crossover trial.Arthritis Care Res.2014;66:1246-1251.
23.Zong M,Lu T,Fan S,et al.Glucose-6-phosphate isomerase promotes the proliferation and inhibits the apoptosis in fibroblast-like synoviocytes in rheumatoid arthritis.Arthritis Res Ther.2015;17:100.
24.Maccioni M,Zeder-Lutz G,Huang H,et al.Arthritogenic monoclonal antibodies from K/BxN mice[J].J Exp Med.2002;195:1071-1077.
25.Wu X,He B,Liu J,et al.Molecular insight into gut microbiota and rheumatoid arthritis.Int J Mol Sci.2016;17:431.
26.W?gielska I,Suliburska J.The role of intestinal microbiota in the pathogenesis of metabolic diseases.Acta Sci Pol Technol Aliment.2015;15:201-211.
27.Vaahtovuo J,Munukka E,Korkeam?ki M,Luukkainen R,Toivanen P.Fecal microbiota in early rheumatoid arthritis.J Rheumatol.2008;35:1500-1505.
28.Kellermayer R,Dowd SE,Harris RA,et al.Colonic mucosal DNAmethylation,immune response,and microbiome patterns in Tolllike receptor 2-knockout mice.FASEB J.2011;25:1449-1460.
29.Derrien M,Vaughan EE,Plugge CM,de Vos WM.Akkermansia mu-ciniphila gen.nov.,sp.nov.,a human intestinal mucin-degrading bacterium.Int J Syst Evol Microbiol.2004;54:1469-1476.
30.Everard A,Belzer C,Geurts L,et al.Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.Proc Natl Acad Sci USA.2013;110:9066-9071.
31.Shin N,Lee J,Lee H,et al.An increase in the Akkermansia spp.population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice.Gut.2014;63:727-735.
32.Li J,Lin S,Vanhoutte PM,Woo CW,Xu A.Akkermansia muciniph-ila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation inApoe-/-mice.Circulation.2016;133:2434-2446.
33.Zhu L,Zhang D,Zhu H,et al.Berberine treatment increases Akkermansia in the gut and improves high-fat diet-induced atherosclerosis in Apoe-/-mice.Atherosclerosis.2018;268:117-126.
34.Plovier H,Everard A,Druart C,et al.A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice.Nat Med.2017;23:107-113.
35.Bland J.Intestinal microbiome,Akkermansia muciniphila,and medical nutrition therapy.Integr Med.2016;15:14-16.
36.Johansson ME,Phillipson M,Petersson J,Velcich A,Holm L,Hansson GC.The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria.Proc Natl Acad Sci USA.2008;105:15064-15069.
37.Matziouridou C,Marungruang N,Nguyen TD,Nyman M,F?k F.Lingonberries reduce atherosclerosis in Apoe-/-mice in association with altered gut microbiota composition and improved lipid profile.Mol Nutr Food Res.2016;60:1150-1160.
38.Wang Y,Xu L,Liu J,Zhu W,Mao S.A high grain diet dynamically shifted the composition of mucosa-associated microbiota and induced mucosal injuries in the colon of sheep.Front Microbiol.2017;8:1-13.
39.Garcia JP,Adams V,Beingesser J,et al.Epsilon toxin is essential for the virulence of clostridium perfringens type d infection in sheep,goats,and mice.Infect Immun.2013;81:2405-2414.
2.Ljung L,Askling J,Rantap??-Dahlqvist S,Jacobsson L;ARTIS Study Group.The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population:a national cohort study.Arthritis Res Ther.2014;16:R127.
3.Peters M,Symmons D,McCarey D,et al.EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis.Ann Rheum Dis.2010;69:325-331.
4.Arida A,Protogerou AD,Konstantonis G,Fragiadaki K,Kitas GD,Sfikakis PP.Atherosclerosis is not accelerated in rheumatoid arthritis of low activity or remission,regardless of antirheumatic treatment modalities.Rheumatology.2017;56:934-939.
5.Lauper K,Gabay C.Cardiovascular risk in patients with rheumatoid arthritis.Semin Immunopathol.2017;39:447-459.
6.Im CH,Kim NR,Kang JW,et al.Inflammatory burden interacts with conventional cardiovascular risk factors for carotid plaque formation in rheumatoid arthritis.Rheumatology.2015;54:808-815.
7.Rempenault C,Combe B,Barnetche T,et al.Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis:a systematic review and meta-analysis.Ann Rheum Dis.2017;77:98-103.
8.Ruiz-Irastorza G,Ramos-Casals M,Brito-Zeron P,Khamashta MA.Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus:a systematic review.Ann Rheum Dis.2009;69:20-28.
9.Hu C,Lu L,Wan J,Wen C.The pharmacological mechanisms and therapeutic activities of hydroxychloroquine in rheumatic and related diseases.Curr Med Chem.2017;24:2241-2249.
10.Emami J,Gerstein HC,Pasutto FM,Jamali F.Insulin-sparing effect of hydroxychloroquine in diabetic rats is concentration dependent.Can J Physiol Pharmacol.1999;77:118-123.
11.Fox RI.Mechanism of action of hydroxychloroquine as an antirheumatic drug.Semin Arthritis Rheum.1993;23:82-91.
12.Kasselman LJ,Vernice NA,Deleon J,Reiss AB.The gut microbiome and elevated cardiovascular risk in obesity and autoimmunity.Atherosclerosis.2018;271:203-213.
13.Koeth RA,Wang Z,Levison BS,et al.Intestinal microbiota metabolism of l-carnitine,a nutrient in red meat,promotes atherosclerosis.Nat Med.2013;19:576-585.
14.Matsumoto I,Staub A,Benoist C,Mathis D.Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme.Science.1999;286:1732-1735.
15.Korganow A,Ji H,Mangialaio S,et al.From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins.Immunity.1999;10:451-461.
16.Rose S,Eren M,Murphy S,et al.A novel mouse model that develops spontaneous arthritis and is predisposed towards atherosclerosis.Ann Rheum Dis.2012;72:89-95.
17.Chafin CB,Regna NL,Hammond SE,Reilly CM.Cellular and urinary microRNA alterations in NZB/W mice with hydroxychloroquine or prednisone treatment.Int Immunopharmacol.2013;17:894-906.
18.Floris A,Piga M,Mangoni AA,Bortoluzzi A,Erre GL,Cauli A.Protective effects of hydroxychloroquine against accelerated atherosclerosis in systemic lupus erythematosus.Mediators Inflamm.2018;2018:3424136.
19.Shukla AM,Bose C,Karaduta OK,et al.Impact of hydroxychloroquine on atherosclerosis and vascular stiffness in the presence of chronic kidney disease.PLoS One.2015;10:e139226.
20.Munro R,Morrison E,Mcdonald AG,Hunter JA,Madhok R,Capell HA.Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis.Ann Rheum Dis.1997;56:374-377.
21.Restrepo JF,Del Rincon I,Molina E,Battafarano DF,Escalante A.Use of hydroxychloroquine is associated with improved lipid profile in rheumatoid arthritis patients.J Clin Rheumatol.2017;23:144-148.
22.Solomon DH,Garg R,Lu B,et al.Effect of hydroxychloroquine on insulin sensitivity and lipid parameters in rheumatoid arthritis patients without diabetes mellitus:a randomized,blinded crossover trial.Arthritis Care Res.2014;66:1246-1251.
23.Zong M,Lu T,Fan S,et al.Glucose-6-phosphate isomerase promotes the proliferation and inhibits the apoptosis in fibroblast-like synoviocytes in rheumatoid arthritis.Arthritis Res Ther.2015;17:100.
24.Maccioni M,Zeder-Lutz G,Huang H,et al.Arthritogenic monoclonal antibodies from K/BxN mice[J].J Exp Med.2002;195:1071-1077.
25.Wu X,He B,Liu J,et al.Molecular insight into gut microbiota and rheumatoid arthritis.Int J Mol Sci.2016;17:431.
26.W?gielska I,Suliburska J.The role of intestinal microbiota in the pathogenesis of metabolic diseases.Acta Sci Pol Technol Aliment.2015;15:201-211.
27.Vaahtovuo J,Munukka E,Korkeam?ki M,Luukkainen R,Toivanen P.Fecal microbiota in early rheumatoid arthritis.J Rheumatol.2008;35:1500-1505.
28.Kellermayer R,Dowd SE,Harris RA,et al.Colonic mucosal DNAmethylation,immune response,and microbiome patterns in Tolllike receptor 2-knockout mice.FASEB J.2011;25:1449-1460.
29.Derrien M,Vaughan EE,Plugge CM,de Vos WM.Akkermansia mu-ciniphila gen.nov.,sp.nov.,a human intestinal mucin-degrading bacterium.Int J Syst Evol Microbiol.2004;54:1469-1476.
30.Everard A,Belzer C,Geurts L,et al.Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.Proc Natl Acad Sci USA.2013;110:9066-9071.
31.Shin N,Lee J,Lee H,et al.An increase in the Akkermansia spp.population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice.Gut.2014;63:727-735.
32.Li J,Lin S,Vanhoutte PM,Woo CW,Xu A.Akkermansia muciniph-ila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation inApoe-/-mice.Circulation.2016;133:2434-2446.
33.Zhu L,Zhang D,Zhu H,et al.Berberine treatment increases Akkermansia in the gut and improves high-fat diet-induced atherosclerosis in Apoe-/-mice.Atherosclerosis.2018;268:117-126.
34.Plovier H,Everard A,Druart C,et al.A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice.Nat Med.2017;23:107-113.
35.Bland J.Intestinal microbiome,Akkermansia muciniphila,and medical nutrition therapy.Integr Med.2016;15:14-16.
36.Johansson ME,Phillipson M,Petersson J,Velcich A,Holm L,Hansson GC.The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria.Proc Natl Acad Sci USA.2008;105:15064-15069.
37.Matziouridou C,Marungruang N,Nguyen TD,Nyman M,F?k F.Lingonberries reduce atherosclerosis in Apoe-/-mice in association with altered gut microbiota composition and improved lipid profile.Mol Nutr Food Res.2016;60:1150-1160.
38.Wang Y,Xu L,Liu J,Zhu W,Mao S.A high grain diet dynamically shifted the composition of mucosa-associated microbiota and induced mucosal injuries in the colon of sheep.Front Microbiol.2017;8:1-13.
39.Garcia JP,Adams V,Beingesser J,et al.Epsilon toxin is essential for the virulence of clostridium perfringens type d infection in sheep,goats,and mice.Infect Immun.2013;81:2405-2414.