恩格列净对慢性间歇缺氧大鼠心房纤维化的影响及机制探讨  

Effect and mechanism of empagliflozin in atrial fibrosis of chronic intermittent hypoxic rat

作　　者：刘永政[1] 杨禹 王君[2] 李瑞龄 袁梦[2] 张跃[2] 李广平[2] LIU Yong-zheng;YANG Yu;WANG Jun;LI Rui-ling;YUAN Meng;ZHANG Yue;LI Guang-ping(The No.1 Hospital of Qinhuangdao,Qinhuangdao 066000,Hebei,China;Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease,Department of Cardiology,Tianjin Institute of Cardiology,the Second Hospital of Tianjin Medical University,Tianjin 300211,China)

机构地区：[1]秦皇岛市第一医院心血管内科一病区,河北秦皇岛066000 [2]天津市心血管病离子与分子机能重点实验室,天津医科大学第二医院心脏科,天津心脏病学研究所,天津300211

出　　处：《中国心脏起搏与心电生理杂志》2024年第1期34-39,共6页Chinese Journal of Cardiac Pacing and Electrophysiology

基　　金：国家自然科学基金项目(82270336);天津市卫生健康委员会科技项目(ZC20215);天津医科大学第二医院科学研究基金项目(2019LC01);天津市临床医学重点学科建设项目。

摘　　要：目的研究恩格列净对睡眠呼吸暂停低通气综合征患者心房结构的作用及可能的机制。方法60只SD雄性大鼠随机分为对照组(C组),慢性间歇缺氧组(CIH组)和慢性间歇缺氧-恩格列净干预组(CIH-E组)。CIH、CIH-E组每日接受慢性间歇缺氧程序,其中CIH-E组在每日接受慢性间歇缺氧前给予恩格列净灌胃(2mg/kg)。40天后对各组大鼠进行:(1)心脏超声检测左房内径、室间隔舒张末期厚度、室间隔收缩末期厚度、左室舒张末期内径、左室收缩末期内径、左室射血分数、平均肺动脉压。(2)应用Masson染色观察心房纤维化程度并计算胶原分数。(3)Western blot及RT-qPCR检测微小RNA-21(miR-21)、软脂酰化磷蛋白-1(Spry1)、细胞外信号调节激酶1/2(ERK1/2)及磷酸化ERK1/2(p-ERK1/2)、金属基质蛋白酶-2(MMP-2)、金属基质蛋白酶-9(MMP-9)的表达。结果与C组比较,CIH组平均肺动脉压升高,心房组织纤维化程度加重,胶原分数升高[9.77%±1.88%(n=10)vs 1.62%±0.75%(n=10)],miR-21、ERK1/2、p-ERK1/2、MMP-2、MMP-9上调,Spry1下调;CIH-E组心房组织纤维化加重,胶原分数增高[6.77%±1.81%(n=10)vs 1.62%±0.75%(n=10)],miR-21、ERK1/2、MMP-9明显升高,而平均肺动脉压、Spry1、MMP-2无明显变化。与CIH组比较,CIH-E组体重减轻,舒张压下降,平均肺动脉压下降,心房组织纤维化程度减轻,胶原分数下降[6.77%±1.81%(n=10)vs 9.77%±1.88%(n=10)],miR-21、ERK1/2、p-ERK1/2、MMP-2、MMP-9下调,Spry1上调。结论慢性间歇缺氧可促进心房组织纤维化,恩格列净可能是通过miR-21/ERK1/2信号通路以及MMPs途径改善慢性间歇缺氧所致心房纤维化。.Objective To explore the effect and mechanism of empagliflozin in the atrial structural remodeling of patients with chronic intermittent hypoxia.Methods Sixty SD male rats were randomly divided into control group(C group),chronic intermittent hypoxia group(CIH group) and chronic intermittent hypoxia-empagliflozin intervention group(CIH-E group).The rats in the CIH and CIH-E group received chronic intermittent hypoxia program every day,and the rats in the CIH-E group were given empagliflozin by gavage(2 mg/kg).After 40 days,the rats in each group were examined the left atrial diameter,interventricular septal end-diastolic thickness,interventricular septal end-systolic thickness,left ventricular end-diastolic dimension,left ventricular end-systolic dimension,left ventricular ejection fraction(LVEF)and mean pulmonary artery pressure(mPAP)by echocardiography and examined by atrial histopathology Masson′s stain to visualize atrial fibrosis and calculate collagen fraction and use western blot and RT-qPCR to examine the expression of microRNA-21(miR-21),Sprouty1(Spry1)extracellular signal regulated kinases 1/2(ERK1/2),phosphorylatedERK1/2(p-ERK1/2),matrix metalloproteinase-2(MMP-2)and matrix metalloproteinase-9(MMP-9)to evaluate the atrial fibrosis.Results Compared with the C group,the mPAP of the CIH group was increased,the fibrosis level in the atrial tissue was aggravated,the collagen fraction was increased[9.77%±1.88%(n=10)vs1.62%±0.75%(n=10)],the miR-21,ERK1/2,p-ERK1/2,MMP-2and MMP-9were increased,and Spry1was declined;The fibrosis level in the atrial tissue was aggravated in the CIH-E group,collagen fraction increased [6.77% ± 1.81%(n=10)vs 1.62% ±0.75%(n=10)],and miR-21,ERK1/2,and MMP-9were significantly elevated,while mPAP,Spry1,and MMP-2were not significantly altered.Compared with the CIH group,the fibrosis level in the atrial tissue of the CIH-E group was attenuated,the collagen fraction was declined[6.77%±1.81%(n=10)vs 9.77%±1.88%(n=10)],the miR-21,ERK1/2,p-ERK1/2,MMP-2and MMP-9were down-regulated,and

关 键 词：心血管病学 恩格列净 心房纤维化 心房颤动 MIRNA-21 金属基质蛋白酶 

分 类 号：R541.75[医药卫生—心血管疾病]