姜黄素下调高血压病大鼠心房颤动易感性及基于基因测序分子机制研究

Curcumin Alleviates Atrial Fibrillation Susceptibility in Hypertensive Rats and Intimate Molecular Mechanism Based on Gene Sequencing

目的探讨姜黄素对高血压病相关的心房颤动(AF)易感性的影响,分析其内在机制。方法将45只雄性SD大鼠随机分为对照组(n=15)、模型组(n=15)和姜黄素组(n=15)。模型组和姜黄素组制备腹主动脉缩窄(AAC)模型,对照组不进行AAC,姜黄素组AAC术后予姜黄素300 mg/(kg·d)连续灌胃4周。术后4周比较3组间心脏超声、血流动力学指标和心房胶原容积分数(CVF)、AF诱发率变化。提取大鼠左心房组织mRNA,通过基因组高通量测序筛选3组间差异表达mRNA,并依次进行京都基因与基因组百科全书(KEGG)、基因本体(GO)富集分析、蛋白互作网络(PPI)分析。结果与对照组比较,模型组左心房内径(LAD)、舒张期室间隔厚度(IVSd)、收缩期室间隔厚度(IVSs)、左心室压力(LVP)_(max)、LVP_(min)、主动脉压力(AP)_(max)、AP_(min)、左心房(LA)-CVF、右心房(RA)-CVF、高位右房(HRA)个体AF诱发率、非自行终止AF发生率、阵发性AF发生率升高,左心室射血分数(LVEF)、LVP变化速率(LVdP/dt)_(max)、|LVdP/dt_(min)|降低(P<0.05,P<0.01)。与模型组比较,姜黄素组LAD、LVP_(max)、LVP_(min)、AP_(max)、AP_(min)、LA-CVF、RA-CVF、HRA个体AF诱发率、非自行终止AF发生率、阵发性AF发生率降低,LVdP/dt_(max)和|LVdP/dt_(min)|升高(P<0.05,P<0.01)。左心房组织基因测序和生物信息分析显示,3组间差异表达基因7305个,经KEGG、GO富集分析和PPI分析,共筛选出关键靶基因22个,涉及三羧酸循环、线粒体呼吸链调控、成纤维细胞周期调控。结论姜黄素灌胃4周能有效降低高血压病大鼠左心室及动脉压力、减少心房胶原沉积、缩小左房内径,并降低AF易感性;其机制可能与姜黄素改善左心房组织代谢障碍、线粒体功能及抑制左心房成纤维细胞异常增殖有关。

Objective To study the impacts of curcumin on susceptibility of hypertension associated-atrial fibrillation(AF),and to explore the underlying molecular mechanism.Methods Totally 4512-week-old male SD rats were randomly divided into control group(n=15),abdominal aorta coarctation(AAC)model group(model group,n=15)and curcumin group(n=15).The AAC model was established in model group and curcumin group,while rats in the control group was not given AAC.Rats in the curcumin group were given 300 mg/(kg·d)curcumin by gavage for 4 weeks after AAC.Echocardiological,hemodynamic indexes,collagen volume fraction(CVF)and AF susceptibility were compared at 4 weeks after operation.The differently expressed mRNA extracted from left atrial tissues of the above 3 groups were quantified with high throughput sequencing.Then key molecular targets were identified by Kyoto Encyclopedia of Genes and Genomes(KEGG),Gene Ontology(GO)enrichment and protein-to-protein interact(PPI)analysis.Results In model group,the parameters including left atrial diameter(LAD),diastolic thickness of inter-ventricular septum(IVSd),systolic thickness of inter-ventricular septum(IVSs),maximum left ventricular pressure(LVP)_(max),LVP_(min),maximum aortic pressure(AP)max,APmin,CVF of left atrial(LA-CVF),CVF of right atrial(RA-CVF),and ratiosor of individual AF,paroxysmal AF,non-self-terminating AF at high-right-atria(HRA)were higher than those in control group(P<0.05,P<0.01);while left ventricular ejection fraction(LVEF)and rate of left ventricular pressure change(LVdP/dt)_(max)and|LVdP/dt_(min)|were lower than those in control group(P<0.05,P<0.01).Compared with model group,LAD,LVP_(max) and LVP_(min),APmax and AP_(min),LA-CVF and RA-CVF,ratios of individual AF,paroxysmal AF,non-self-terminating AF at HRA decreased,LVdP/dt_(max)and|LVdP/dt_(min)|increased in curcumin group(P<0.05,P<0.01).In summary,there were 7305 differentially expressed genes among the 3 groups according to gene sequencing and bioinformation analysis of left atrial tissue.Based on KEGG,GO enrichment and PPI analysis,22 key molecular targets were selected finally which were associated with tricarboxylic acid cycle(TAC),mitochondrial respiratory chain and the fibroblast cycle regulation.Conclusions Curcumin administered by gavage for 4 weeks can effectively reduce LA and arterial pressure,atrial collagen deposition,LA diameter,and the susceptibility to AF in hypertensive rats.The underlying mechanism might involve in improvement of metabolic abnormality,mitochondrial function and in the fibroblast proliferation of left atrial tissue.