Effects Of Angiotensin-(1-7) On The Expression Of Inflammatory Factors And P38MAPK In A Canine Model Of Rapid Atrial Pacing

Objective: Atrial fibrillation is a common arrhythmia disease in clinical practice,which seriously affects human health.In recent years,great progress has been made in the treatment of atrial fibrillation and its complications,but its pathogenesis has not been fully understood.The inflammatory response is involved in the occurrence and development of atrial fibrillation.The p38 MAPK signaling pathway is a classical inflammatory signaling pathway.After exogenous stimulation,p38 MAPK phosphorylation is activated,which increases the expression of pro-inflammatory factors and enhances the inflammatory response.Angiotensin(1-7)is obtained by angiotensin-converting enzyme 2 cleavage of angiotensin II.Angiotensin-(1-7)has been observed to have an anti-inflammatory effect in non-cardiac tissues and it can affect the activation of p38 MAPK.But the anti-inflammatory effect of angiotensin(1-7)in myocardial tissue is not clear.This study was to investigate whether there is an inflammatory reaction in the atrial tissue of chronic atrial fibrillation,whether the inflammatory response is related to the activation of p38 MAPK,and whether angiotensin(1-7)interferes with it.Methods: Fifteen mongrel dogs of either sex were randomly assigned to the shamoperated group(S,n=5),paced group(P,n=5)and intervention group(A,n=5).All dogs were placed a programmable atrial pacemakers,except for the S group,the other two groups were given 500 beats per minute for continuously right atrial pacing.Dogs in group A were additional given Ang-(1-7)as 6 ?g/(kg·h).After 2 weeks of pacing,the animals were sacrificed and venous blood and left and right atrial tissue were taken.Western blotting was used to detect the expression of p38 MAPK and phosphorylated p38 MAPK in the left and right atrial tissues of each group,and the changes of inflammatory factors CRP,IL-8 and TGF-?1 in atrial myocardium.Real-time quantitative PCR was used to detect the expression of p38 MAPK,NF-?B and TGF-?1 in the left atrial tissue.The levels of inflammatory factors IL-6,TNF-? and MCP-1 in plasma were determined by ELISA.Results: The pacemaker worked normally during the experiment,and the pacing group and the intervention group were pacing rhythms.There was no change in the left atrial diameter of the three groups,but the LVEF of the pacing group was significantly reduced.1.At the protein level,rapid right atrial pacing increased the total p38 MAPK protein in the left and right atrium slightly,but did not reach statistical significance.The reduction of total p38 MAPK was not significant with Ang-(1-7)intervention.However,the proportion of phosphorylated p38 MAPK protein in the pacing group was significantly increased(P<0.05).The intervention of Ang-(1-7)significantly decreased the phosphorylation level of p38 MAPK protein(P<0.05).The expression of CRP,IL-8 and TGF-?1 in the pacing group was also significantly increased(P<0.05),and Ang-(1-7)significantly inhibited this change.2.As with protein changes,at the m RNA level,the change of p38 MAPK was not obvious in the three groups,but the m RNA levels of NF-?B and TGF-?1 were increased in the pacing group(P<0.05).The expression of the two factors decreased significantly after Ang-(1-7)intervention(P<0.05).3.The levels of plasma inflammatory factors IL-6,TNF-? and MCP-1 were higher in the pacing group than in the sham operation(P<0.05),and this change was reversed in the intervention group.Conclusion: 1.Rapid right atrial pacing can increase the expression of inflammatory factors CRP,IL-8 and TGF-?1 in myocardium and IL-6,TNF-? and MCP-1 in plasma.It also elevates the phosphorylation of p38 MAPK and induces the NF-?B and TGF-?1 m RNA expression.The atrial myocardium develops an inflammatory response,and the p38 MAPK pathway is involved in the pro-inflammatory process.2.Angiotensin-(1-7)can inhibit the activation of p38 MAPK in atrial tissue of rapid atrial pacing dogs,and decrease the level of pro-inflammatory factors in atrial tissue at protein and m RNA levels,accompanied by a decrease in plasma inflammatory factors,indicating that Ang-(1-7)has anti-inflammatory effects in myocardium,which is associated with inhibition of p38 MAPK activation.