沙库巴曲/缬沙坦对心肌肥厚兔半乳糖凝集素-3以及基质金属蛋白酶-9表达的影响
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摘要
目的:研究沙库巴曲/缬沙坦对压力负荷诱导的心肌肥厚新西兰兔半乳糖凝集素-3(Gal-3)、基质金属蛋白酶-9(MMP-9)表达的影响。方法:24只健康雄性8周龄新西兰兔随机分为假手术组(Sham)、模型组(Model)、沙库巴曲/缬沙坦组(Sacu/Vals),每组8只,后两组行腹主动脉缩窄术构建心肌肥厚模型,8周建模成功后沙库巴曲/缬沙坦组予以药物灌胃,其余两组予以等体积生理盐水。16周末取所有兔心,测左心室质量指数和全心质量指数以及取左心室心肌组织行HE染色评估心肌肥厚水平,western blot检测心肌组织Gal-3、MMP-9的表达。结果:⑴与假手术组相比,模型组、沙库巴曲/缬沙坦组HMI、LVMI增加(P<0.05);与模型组相比,沙库巴曲/缬沙坦组HMI、LVMI降低(P<0.05)。⑵假手术组心肌纤维排列整齐,呈束状排列,形态完整,未见明显纤维组织。模型组心肌纤维排列紊乱,大部分断裂,细胞水肿,心肌间质可见纤维结缔组织。沙库巴曲/缬沙坦组与模型组相比,心肌纤维排列基本整齐,细胞水肿明显减轻。⑶与假手术相比,模型组、沙库巴曲/缬沙坦组Gal-3、MMP-9蛋白表达量增加(P<0.05);与模型组相比,沙库巴曲/缬沙坦组Gal-3、MMP-9蛋白表达量降低(P<0.05)。结论:沙库巴曲/缬沙坦能减轻兔心肌肥厚,其机制可能跟下调Gal-3、 MMP-9蛋白表达相关。
Objective: To investigate the effects of sacubitril/valsartan on the expression of Galectin-3(Gal-3) and Matrix metalloproteinase-9(MMP-9) in New Zealand rabbits with stress-induced cardiac hypertrophy.Methods: Twenty-four healthy male 8-week-old New Zealand rabbits were randomly divided into sham operation group(Sham), model group(Model), and sacubitril/valsartan group(Sacu/Vals), with 8 rats in each group. Abdominal aortic coarctation was used to construct a model of cardiac hypertrophy. After 8 weeks of successful modeling, the acubitril/valsartan group was administered with the drug, and the other two groups were given an equal volume of normal saline. All rabbit hearts were sacrificed at the end of the 16th week. The left ventricular mass index and the whole heart mass index were measured. The left ventricular myocardial tissue was evaluated by HE staining to evaluate the cardiac hypertrophy. The expression of Gal-3 and MMP-9 in the myocardial tissue was detected by western blot. Results:(1) Compared with the sham operation group, the HMI and LVMI of the model group and the sacubitril/valsartan group increased(P<0.05). Compared with the model group, the HBA and LVMI decreased in the sacubitril/valsartan group.(P<0.05);(2) In the sham operation group, the myocardial fibers were arranged neatly, arranged in a bundle, and the morphology was intact, and no obvious fibrous tissue was observed. The myocardial fibers in the model group were disordered, most of them were broken, the cells were edematous, and the myocardial interstitial showed fibrous connective tissue. Compared with the model group, the sacubitril/valsartan group had a neat arrangement of myocardial fibers and a significant reduction in cell edema;(3) Compared with sham operation, the expression of Gal-3 and MMP-9 protein in the model group and the sacubitril/valsartan group increased(P<0.05); Compared with the model group, sacubitril/valsartan The expression levels of Gal-3 and MMP-9 in the tan group were decreased(P<0.05).Conclusion: Sacubitril/valsartancan alleviate cardiac hypertrophy in rabbits, and its mechanism may be related to down-regulation of Gal-3 and MMP-9 protein expression.
Objective: To investigate the effects of sacubitril/valsartan on the expression of Galectin-3(Gal-3) and Matrix metalloproteinase-9(MMP-9) in New Zealand rabbits with stress-induced cardiac hypertrophy.Methods: Twenty-four healthy male 8-week-old New Zealand rabbits were randomly divided into sham operation group(Sham), model group(Model), and sacubitril/valsartan group(Sacu/Vals), with 8 rats in each group. Abdominal aortic coarctation was used to construct a model of cardiac hypertrophy. After 8 weeks of successful modeling, the acubitril/valsartan group was administered with the drug, and the other two groups were given an equal volume of normal saline. All rabbit hearts were sacrificed at the end of the 16th week. The left ventricular mass index and the whole heart mass index were measured. The left ventricular myocardial tissue was evaluated by HE staining to evaluate the cardiac hypertrophy. The expression of Gal-3 and MMP-9 in the myocardial tissue was detected by western blot. Results:(1) Compared with the sham operation group, the HMI and LVMI of the model group and the sacubitril/valsartan group increased(P<0.05). Compared with the model group, the HBA and LVMI decreased in the sacubitril/valsartan group.(P<0.05);(2) In the sham operation group, the myocardial fibers were arranged neatly, arranged in a bundle, and the morphology was intact, and no obvious fibrous tissue was observed. The myocardial fibers in the model group were disordered, most of them were broken, the cells were edematous, and the myocardial interstitial showed fibrous connective tissue. Compared with the model group, the sacubitril/valsartan group had a neat arrangement of myocardial fibers and a significant reduction in cell edema;(3) Compared with sham operation, the expression of Gal-3 and MMP-9 protein in the model group and the sacubitril/valsartan group increased(P<0.05); Compared with the model group, sacubitril/valsartan The expression levels of Gal-3 and MMP-9 in the tan group were decreased(P<0.05).Conclusion: Sacubitril/valsartancan alleviate cardiac hypertrophy in rabbits, and its mechanism may be related to down-regulation of Gal-3 and MMP-9 protein expression.
引文
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2 McMurray JJ,PackerM,Desai AS,et al.Dual angiotensin receptor and neprilysininhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure:rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)[J].Eur J Heart Fail,2013,15(9):1062-1073.
3 Ito S,Satoh M,Tamaki Y,et al.Safety and efficacy of LCZ696,a first-in-class angiotensin receptor neprilysin inhibitor,in Japanese patients with hypertension and renal dysfunction[J].HypertensRes,2015,38(4):269-275.
4 Chunduri RH,Dannana GS.Development and validation of a reliable and rapid LC-MS/MS method for simultaneous quantification of sacubitril and valsartan in rat plasma and its application to a pharmacokinetic study[J].Biomed Chromatogr,2016,30(9):1467-1475.
5 van der Velde AR,Meijers WC,Ho JE,et al.Serial galectin-3 and future cardiovascular disease in the general population[J].Heart,2016,102(14):1134-1141.
6 Polat V,Bozcali E,Uygun T,et al.Diagnostic significance of serum galectin-3 levels in heart failure with preserved ejection fraction[J].Acta Cardiol,2016,71(2):191-197.
7 Morishita T,Uzui H,Mitsuke Y,et al.Association between matrix metalloproteinase-9 and worsening heart failure events in patients with chronic heart failure[J].ESC Heart Fail,2017,4(3):321-330.
8 Suematsu Y,Jing WH,Nunes A,et al.LCZ696 (Sacubitril/Valsartan),an angiotensin-receptor neprilysininhibitor,attenuates cardiac hypertrophy,fibrosis,and vasculopathy in a rat model of chronic kidney disease[J].J Card Fail,2018,24(4):266-275.
9 Tham YK,Bernardo BC,Ooi JY,et al.Pathophysiology of cardiac hypertrophy and heart failure:signaling pathways and novel therapeutic targets[J].Arch Toxicol,2015,89(9):1401-1438.
10 Vilela-Martin JF.Spotlight on valsartan-sacubitril fixed-dose combination for heart failure:the evidence to date[J].Drug Des Devel Ther,2016,10:1627-1639.
11 Bayés-Genís A,Barallat J,GalánA,et al.Soluble neprilysinis predictive of cardiovascular death and heart failure hospitalization in heart failure patients[J].J Am Coll Cardiol,2015,65(7):657-665.
12 von LuederTG,Krum H.New medical therapies for heart failure[J].Nat Rev Cardiol,2015,12(12):730-740.
13 Yandrapalli S,Aronow WS,Mondal P,et al.The evolution of natriuretic peptide augmentation in management of heart failure and the role of sacubitril/valsartan[J].Arch Med Sci,2017,13(5):1207-1216.
14 Wang YT,Seto SW,Golledge J.Angiotensin II,sympathetic nerve activity and chronic heart failure[J].Heart Fail Rev,2014,19(2):187-198.
15 Desai AS,Claggett BL,Packer M,et al.Influence of Sacubitril/Valsartan (LCZ696) on 30-day readmission after heart failure hospitalization[J].J Am Coll Cardiol,2016,68(3):241-248.
16 2016 ACC/AHA/HFSAfocused update on new pharmacological therapy for heart failure:an update of the 2013 ACCF/AHAguideline for the management of heart failure:A report of the american college of Cardiology/American heart association task force on clinical practice guidelines and the heart failure society of america[J].J Card Fail,2016,22(9):659-669.
17 Solomon SD,Zile M,Pieske B,et al.The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction:a phase 2 double-blind randomised controlled trial[J].Lancet,2012,380(9851):1387-1395.
18 Polat V,Bozcali E,Uygun T,etal.Diagnostic significance of serum galectin-3 levels in heart failure with preserved ejection fraction[J].Acta Cardiol,2016,71(2):191-197.
19 Chen YS,Gi WT,Liao TY,et al.Using the galectin-3 test to predict mortality in heart failure patients:a systematic review and meta-analysis[J].Biomark Med,2016,10(3):329-342.
20 Imran TF,Shin HJ,Mathenge N,et al.Meta-analysis of the usefulness of plasma galectin-3 to predict the risk of mortality in patients with heart failure and in the general population[J].Am J Cardiol,2017,119(1):57-64.
21 Chen K,Jiang RJ,Wang CQ,et al.Predictive value of plasma galectin-3 in patients with chronic heart failure[J].Eur Rev Med Pharmacol Sci,2013,17(8):1005-1011.
22 Yamamoto K,Murphy G,Troeberg L.Extracellular regulation of metalloproteinases[J].Matrix Biol,2015,44/45/46:255-263.
23 Wang YS,Wu BT,Dong LL,et al.Circulating matrix metalloproteinase patterns in association with aortic dilatation in bicuspid aortic valve patients with isolated severe aortic stenosis[J].Heart Vessels,2016,31(2):189-197.
24 Wang S,Cheng M,Hu ZQ,et al.Angiotensin II facilitates matrix metalloproteinase-9-mediated myosin light chain kinase degradation in pressure overload-induced cardiac hypertrophy[J].Cell PhysiolBiochem,2017,44(6):2281-2295.
2 McMurray JJ,PackerM,Desai AS,et al.Dual angiotensin receptor and neprilysininhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure:rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)[J].Eur J Heart Fail,2013,15(9):1062-1073.
3 Ito S,Satoh M,Tamaki Y,et al.Safety and efficacy of LCZ696,a first-in-class angiotensin receptor neprilysin inhibitor,in Japanese patients with hypertension and renal dysfunction[J].HypertensRes,2015,38(4):269-275.
4 Chunduri RH,Dannana GS.Development and validation of a reliable and rapid LC-MS/MS method for simultaneous quantification of sacubitril and valsartan in rat plasma and its application to a pharmacokinetic study[J].Biomed Chromatogr,2016,30(9):1467-1475.
5 van der Velde AR,Meijers WC,Ho JE,et al.Serial galectin-3 and future cardiovascular disease in the general population[J].Heart,2016,102(14):1134-1141.
6 Polat V,Bozcali E,Uygun T,et al.Diagnostic significance of serum galectin-3 levels in heart failure with preserved ejection fraction[J].Acta Cardiol,2016,71(2):191-197.
7 Morishita T,Uzui H,Mitsuke Y,et al.Association between matrix metalloproteinase-9 and worsening heart failure events in patients with chronic heart failure[J].ESC Heart Fail,2017,4(3):321-330.
8 Suematsu Y,Jing WH,Nunes A,et al.LCZ696 (Sacubitril/Valsartan),an angiotensin-receptor neprilysininhibitor,attenuates cardiac hypertrophy,fibrosis,and vasculopathy in a rat model of chronic kidney disease[J].J Card Fail,2018,24(4):266-275.
9 Tham YK,Bernardo BC,Ooi JY,et al.Pathophysiology of cardiac hypertrophy and heart failure:signaling pathways and novel therapeutic targets[J].Arch Toxicol,2015,89(9):1401-1438.
10 Vilela-Martin JF.Spotlight on valsartan-sacubitril fixed-dose combination for heart failure:the evidence to date[J].Drug Des Devel Ther,2016,10:1627-1639.
11 Bayés-Genís A,Barallat J,GalánA,et al.Soluble neprilysinis predictive of cardiovascular death and heart failure hospitalization in heart failure patients[J].J Am Coll Cardiol,2015,65(7):657-665.
12 von LuederTG,Krum H.New medical therapies for heart failure[J].Nat Rev Cardiol,2015,12(12):730-740.
13 Yandrapalli S,Aronow WS,Mondal P,et al.The evolution of natriuretic peptide augmentation in management of heart failure and the role of sacubitril/valsartan[J].Arch Med Sci,2017,13(5):1207-1216.
14 Wang YT,Seto SW,Golledge J.Angiotensin II,sympathetic nerve activity and chronic heart failure[J].Heart Fail Rev,2014,19(2):187-198.
15 Desai AS,Claggett BL,Packer M,et al.Influence of Sacubitril/Valsartan (LCZ696) on 30-day readmission after heart failure hospitalization[J].J Am Coll Cardiol,2016,68(3):241-248.
16 2016 ACC/AHA/HFSAfocused update on new pharmacological therapy for heart failure:an update of the 2013 ACCF/AHAguideline for the management of heart failure:A report of the american college of Cardiology/American heart association task force on clinical practice guidelines and the heart failure society of america[J].J Card Fail,2016,22(9):659-669.
17 Solomon SD,Zile M,Pieske B,et al.The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction:a phase 2 double-blind randomised controlled trial[J].Lancet,2012,380(9851):1387-1395.
18 Polat V,Bozcali E,Uygun T,etal.Diagnostic significance of serum galectin-3 levels in heart failure with preserved ejection fraction[J].Acta Cardiol,2016,71(2):191-197.
19 Chen YS,Gi WT,Liao TY,et al.Using the galectin-3 test to predict mortality in heart failure patients:a systematic review and meta-analysis[J].Biomark Med,2016,10(3):329-342.
20 Imran TF,Shin HJ,Mathenge N,et al.Meta-analysis of the usefulness of plasma galectin-3 to predict the risk of mortality in patients with heart failure and in the general population[J].Am J Cardiol,2017,119(1):57-64.
21 Chen K,Jiang RJ,Wang CQ,et al.Predictive value of plasma galectin-3 in patients with chronic heart failure[J].Eur Rev Med Pharmacol Sci,2013,17(8):1005-1011.
22 Yamamoto K,Murphy G,Troeberg L.Extracellular regulation of metalloproteinases[J].Matrix Biol,2015,44/45/46:255-263.
23 Wang YS,Wu BT,Dong LL,et al.Circulating matrix metalloproteinase patterns in association with aortic dilatation in bicuspid aortic valve patients with isolated severe aortic stenosis[J].Heart Vessels,2016,31(2):189-197.
24 Wang S,Cheng M,Hu ZQ,et al.Angiotensin II facilitates matrix metalloproteinase-9-mediated myosin light chain kinase degradation in pressure overload-induced cardiac hypertrophy[J].Cell PhysiolBiochem,2017,44(6):2281-2295.