Abstract:
Objective To assess the effects of telmisartan on susceptibility of atrial fibrillation(AF) in pressure overload rats, and to probe the underlying molecular mechanism and signal pathways. Methods Forty nine 12-week-old male SD rats were randomly divided into control group(sham operation group, n=15), abdominal aorta coarctation(AAC) model group(model group, n=17) and telmisartan group(n=17). AAC model was established using 0.7 mm diameter needles in model group and telmisartan group, while AAC was not performed in the control group. Rats in the telmisartan group were treated with telmisartan 10 mg/(kg·d) by gavage for 4 weeks after AAC. Four weeks after operation, the indexes of echocardiography and hemodynamics(5 rats in each group), as well as cardiac electrophysiological indexes(6 rats in each group) of P wave dispersion, left atrial condution time(LACT), interatrial conduction time(IACT) were observed. Atrial fibrillation susceptibility was analyzed. The mRNA was extracted from left atrial tissues of the above 3 groups and the differentially expressed genes(DEGs) were screened by genome sequencing. The potential molecular targets were explored by enrichment analysis and Venn analysis. Results Systolic left ventricular pressure(LVSP), systolic aortic pressure(ASP), left atrial diameters, systolic interventricular septal thickness and diasolic interventricular septal thickness in model group were higher than those in control group(all P<0.05), while the above indexes in telmisartan group were lower than those in model group(all P<0.05). There was no significant difference in P wave dispersion among three groups(P>0.05). LACT and IACT were significantly increased in model group, which were ameliorated by telmisartan treatment LACT was(34.40±4.04),(51.00±3.24),(38.00±1.91) ms and IACT was(21.2±1.92),(30.4±4.39),(23.3±1.70) ms respectively in control, model, telmisartan group, F=37.590, 11.232; both P<0.001. In isolated Langendorff perfused heart, AF sustained duration induced by Burst-stimulation administered at high-right-atria was(1.83±1.33),(15.17±2.48),(10.20±1.10) s respectively in control, model and telmisrtan group, there was significant difference among three groups(F=75.334, P<0.001); the ratios of non-self-terminating AF was 8.3%(5/60) in model group, while which was 0 in the control group and telmisartan group. Total 897 DEGs down-regulated in model group(compared with control group) and up-regulated in telmisratan group(compared with control group) were clustered into a gene set and named down/up897 gene set, 1 542 DEGs up-regulated in model group while down-regulated in telmisratan group were clustered into up/down1542 gene set. The intersection genes of the two gene sets were screened by enrichment analysis and Venn analysis. The results showed that the five target genes screened in the down/up897 gene set were the key rate limiting enzymes of fatty acid oxidation, five target genes screened in the up/down1542 gene set involved Wnt/β-catenin signal pathway and typeⅠ and Ⅱ collagen components. Conclusions Telmisartan can effectively lower AF susceptibility via suppressing the left atrial enlargement and shortening atrial conduction time. The molecular mechanism is closely related to the improvement of fatty acid oxidation, down-regulation of the over-activated Wnt/β-catenin pathway and alleviating the over-expression of collagen.