Aliskiren单用及联用氟伐他汀对动脉粥样硬化斑块稳定性的影响
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摘要
目的:观察和比较肾素抑制剂aliskiren单用或与氟伐他汀(fluvastatin)联用对动脉粥样硬化斑块稳定性的影响。方法:选择4周龄雄性ApoE-/-小鼠通过喂以高脂饮食8周建立动脉粥样硬化模型,将其随机分为5组:模型对照组、aliskiren组、肼屈嗪组、氟伐他汀组、aliskiren与氟伐他汀联合用药组,所有组别均治疗12周。取主动脉根部组织评估斑块面积(HE染色)、斑块内新生血管数量(CD31染色)及斑块稳定性指标(胶原蛋白染色、弹力纤维染色、Mac-3染色、MCP-1染色)。结果:与模型对照组比较,aliskiren单用显著降低动脉粥样硬化斑块面积,减少斑块内新生血管数量以及巨噬细胞浸润、炎症因子表达,增加斑块内弹力纤维及胶原蛋白含量(P<0.05或P<0.01)。与aliskiren单用组比较,aliskiren与氟伐他汀联用进一步降低斑块面积,改善斑块的稳定性(P<0.05或P<0.01)。与aliskiren组比较,肼屈嗪组降压幅度相似(P>0.05)。与模型对照组比较,肼屈嗪没有明显抑制斑块进展以及改善斑块的稳定性(P>0.05)。结论:Aliskiren能够抑制动脉粥样硬化斑块的进展,减少斑块内新生血管形成,改善斑块的稳定性,而其与氟伐他汀联用的治疗效果更佳。
Objective: To investigate the effects of renin inhibitor aliskiren alone or in combination with fluvastatin on the stability of atherosclerotic plaque. Methods: Four-wk-old ApoE-/-mice were fed a high-fat diet until 12 weeks, and the mice were randomly assigned to one of five groups, including model group, hydralazine group, aliskiren group, fluvastatin group, aliskiren and fluvastatin combined group, for an additional 12 weeks. Plaque area(HE staining), number of neovascularization(CD31 staining) and plaque stability(collagen staining, elastic fiber staining, Mac-3 staining and MCP-1 staining) were assessed from aortic root tissue. Results: Compared with the model control group, aliskiren alone significantly reduced atherosclerotic plaque area, decreased the number of neovascularization(CD31 staining), macrophage infiltration and expression of inflammatory factors(MCP-1 staining), and increased the content of elastic fibers and collagen in the plaque(P<0.05 or P<0.01). Compared with aliskiren group, aliskiren combined with fluvastatin group further decreased the plaque area and improved the stability of atherosclerotic plaque(P<0.05 or P<0.01). Compared with aliskiren group, hydralazine group had a similar extent of lowering systolic blood pressure(P>0.05). Compared with model control group, hydralazine did not significantly inhibit plaque progression or improve plaque stability(P>0.05). Conclusions: Aliskiren can inhibit the development of atherosclerotic plaque, reduce plaque neovessel formation and improve the stability of atherosclerotic plaque. Combination of aliskiren and fluvastatin may have a better therapeutic effect in atherosclerosis-based diseases.
Objective: To investigate the effects of renin inhibitor aliskiren alone or in combination with fluvastatin on the stability of atherosclerotic plaque. Methods: Four-wk-old ApoE-/-mice were fed a high-fat diet until 12 weeks, and the mice were randomly assigned to one of five groups, including model group, hydralazine group, aliskiren group, fluvastatin group, aliskiren and fluvastatin combined group, for an additional 12 weeks. Plaque area(HE staining), number of neovascularization(CD31 staining) and plaque stability(collagen staining, elastic fiber staining, Mac-3 staining and MCP-1 staining) were assessed from aortic root tissue. Results: Compared with the model control group, aliskiren alone significantly reduced atherosclerotic plaque area, decreased the number of neovascularization(CD31 staining), macrophage infiltration and expression of inflammatory factors(MCP-1 staining), and increased the content of elastic fibers and collagen in the plaque(P<0.05 or P<0.01). Compared with aliskiren group, aliskiren combined with fluvastatin group further decreased the plaque area and improved the stability of atherosclerotic plaque(P<0.05 or P<0.01). Compared with aliskiren group, hydralazine group had a similar extent of lowering systolic blood pressure(P>0.05). Compared with model control group, hydralazine did not significantly inhibit plaque progression or improve plaque stability(P>0.05). Conclusions: Aliskiren can inhibit the development of atherosclerotic plaque, reduce plaque neovessel formation and improve the stability of atherosclerotic plaque. Combination of aliskiren and fluvastatin may have a better therapeutic effect in atherosclerosis-based diseases.
引文
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[25]宫柏琪,高凌根,马晶莹,等.阿托伐他汀钙对无动脉硬化原发性高血压患者血脂和颈动脉内膜中层厚度的影响[J].现代生物医学进展,2015,15(15):2941-2943
[26]Natarajan P,Young R,Stitziel NO,et al.Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting[J].Circulation,2017,135(22):2091-2101
[27]Zhong P,Wu D,Ye X,et al.Secondary prevention of major cerebrovascular events with seven different statins:A multi-treat ment meta-analysis[J].Drug Des Devel Ther,2017,11:2517-2526
[28]Li Z,Iwai M,Wu L,et al.Fluvastatin enhances the inhibitory effects of a selective at1 receptor blocker,valsartan,on atherosclerosis[J].Hypertension,2004,44(5):758-763
[29]Horiuchi M,Cui TX,Li Z,et al.Fluvastatin enhances the inhibitory effects of a selective angiotensin ii type 1 receptor blocker,valsartan,on vascular neointimal formation[J].Circulation,2003,107(1):106-112
[30]Lee HY,Sakuma I,Ihm SH,et al.Statins and renin-angiotensin system inhibitor combination treatment to prevent cardiovascular disease[J].Circ J,2014,78(2):281-287
[31]Koh KK,Sakuma I,Hayashi T,et al.Renin-angiotensin system inhibitor and statins combination therapeutics-what have we learnt?[J].Expert Opin Pharmacother,2015,16(7):949-953
[2]Ranjbar R,Shafiee M,Hesari A,et al.The potential therapeutic use of renin-angiotensin system inhibitors in the treatment of inflammatory diseases[J].J Cell Physiol,2019,234(3):2277-2295
[3]Wu CH,Mohammadmoradi S,Chen JZ,et al.Renin-angiotensin system and cardiovascular functions[J].Arterioscler Thromb Vasc Biol,2018,38(7):e108-e116
[4]Daugherty A,Cassis L.Angiotensin ii-mediated development of vascular diseases[J].Trends Cardiovasc Med,2004,14(3):117-120
[5]Cheng J,Zhang W,Zhang X,et al.Effect of angiotensin-con verting enzyme inhibitors and angiotensin ii receptor blockers on all-cause mortality,cardiovascular deaths,and cardiovascular events in patients with diabetes mellitus:A meta-analysis[J].JAMA Intern Med,2014,174(5):773-785
[6]Elgendy IY,Huo T,Chik V,et al.Efficacy and safety of angiotensin receptor blockers in older patients:A meta-analysis of randomized trials[J].Am J Hypertens,2015,28(5):576-585
[7]Hoang V,Alam M,Addison D,et al.Efficacy of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in coronary artery disease without heart failure in the modern statin era:Ameta-analysis of randomized-controlled trials[J].Cardiovasc Drugs Ther,2016,30(2):189-198
[8]Morisawa N,Sugano N,Yamakawa T,et al.Successful long-term effects of direct renin inhibitor aliskiren in a patient with atherosclerotic renovascular hypertension[J].CEN Case Rep,2017,6(1):66-73
[9]Wu H,Cheng XW,Hu L,et al.Renin inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques[J].Atherosclerosis,2014,237(2):739-747
[10]Kazi DS,Penko JM,Bibbins-Domingo K.Statins for primary prevention of cardiovascular disease:Review of evidence and recommendations for clinical practice[J].Med Clin North Am,2017,101(4):689-699
[11]Arnett DK,Blumenthal RS,Albert MA,et al.2019 acc/aha guideline on the primary prevention of cardiovascular disease:Executive summary[J].Circulation,2019,CIR0000000000000677.[Epub ahead of print]
[12]Malhotra K,Safouris A,Goyal N,et al.Association of statin pretreatment with collateral circulation and final infarct volume in acute ischemic stroke patients:A meta-analysis[J].Atherosclerosis,2019,282:75-79
[13]Kuzuya M,Nakamura K,Sasaki T,et al.Effect of mmp-2 deficiency on atherosclerotic lesion formation in apoe-deficient mice[J].Arterioscler Thromb Vasc Biol,2006,26(5):1120-1125
[14]敬馥宇,陈明.血管紧张素受体拮抗剂在心血管病中应用研究的进展[J].中华高血压杂志,2018,26(04):96-101
[15]Kim YH,Her AY,Jeong MH,et al.Impact of renin-angiotensin system inhibitors on long-term clinical outcomes in patients with acute myocardial infarction treated with successful percutaneous coronary intervention with drug-eluting stents:Comparison between STEMIand NSTEMI[J].Atherosclerosis,2019,280:166-173
[16]Ibanez B,James S,Agewall S,et al.2017 esc guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[J].Rev Esp Cardiol(Engl Ed),2017,70(12):1082
[17]Lu H,Rateri DL,Feldman DL,et al.Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice[J].J Clin Invest,2008,118(3):984-993
[18]Imanishi T,Tsujioka H,Ikejima H,et al.Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes[J].Hypertension,2008,52(3):563-572
[19]Aono J,Suzuki J,Iwai M,et al.Deletion of the angiotensin ii type 1a receptor prevents atherosclerotic plaque rupture in apolipoprotein e-/-mice[J].Arterioscler Thromb Vasc Biol,2012,32(6):1453-1459
[20]Andrews JPM,Fayad ZA,Dweck MR.New methods to image unstable atherosclerotic plaques[J].Atherosclerosis,2018,272:118-128
[21]Moulton KS,Heller E,Konerding MA,et al.Angiogenesis inhibitors endostatin or tnp-470 reduce intimal neovascularization and plaque growth in apolipoprotein e-deficient mice[J].Circulation,1999,99(13):1726-1732
[22]Moulton KS,Vakili K,Zurakowski D,et al.Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis[J].Proc Natl Acad Sci U S A,2003,100(8):4736-4741
[23]Parma L,Baganha F,Quax PHA,et al.Plaque angiogenesis and intraplaque hemorrhage in atherosclerosis[J].Eur J Pharmacol,2017,816:107-115
[24]王康,徐亚伟,彭文辉,等.心血管疾病在他汀类药物多效性中的获益[J].现代生物医学进展,2015,15(16):3149-3153
[25]宫柏琪,高凌根,马晶莹,等.阿托伐他汀钙对无动脉硬化原发性高血压患者血脂和颈动脉内膜中层厚度的影响[J].现代生物医学进展,2015,15(15):2941-2943
[26]Natarajan P,Young R,Stitziel NO,et al.Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting[J].Circulation,2017,135(22):2091-2101
[27]Zhong P,Wu D,Ye X,et al.Secondary prevention of major cerebrovascular events with seven different statins:A multi-treat ment meta-analysis[J].Drug Des Devel Ther,2017,11:2517-2526
[28]Li Z,Iwai M,Wu L,et al.Fluvastatin enhances the inhibitory effects of a selective at1 receptor blocker,valsartan,on atherosclerosis[J].Hypertension,2004,44(5):758-763
[29]Horiuchi M,Cui TX,Li Z,et al.Fluvastatin enhances the inhibitory effects of a selective angiotensin ii type 1 receptor blocker,valsartan,on vascular neointimal formation[J].Circulation,2003,107(1):106-112
[30]Lee HY,Sakuma I,Ihm SH,et al.Statins and renin-angiotensin system inhibitor combination treatment to prevent cardiovascular disease[J].Circ J,2014,78(2):281-287
[31]Koh KK,Sakuma I,Hayashi T,et al.Renin-angiotensin system inhibitor and statins combination therapeutics-what have we learnt?[J].Expert Opin Pharmacother,2015,16(7):949-953