| Background Hypobaric and Hypoxia is main features of high altitude.When the supply of oxygen could not meet the needs of the body,the heart becomes the most affected organ.The research on the impact of plateau hypoxia on the cardiovascular system has attracted more and more attention.However,there is no uniform conclusion on the mechanism of myocardial injury caused by high altitude hypoxia.Micro RNA(mi RNA)is a single-stranded RNA fragment of 21 to 25 nt in length.It is a highly conserved non-coding RNA that induces m RNA degradation or inhibits its translation into protein by binding to a specific complementary sequence in the target gene m RNA.It was reported that mi RNA could not only regulate the proliferation and differentiation of cardiomyocytes,but also play a key regulatory role in the pathophysiological development of cardiovascular diseases.At present,the research on mi RNA and cardiovascular diseases mainly focuses on heart failure,myocardial infarction,congenital heart disease,arrhythmia and hypertension.There were few reports on mi RNA and the pathological process of myocardial injury caused by high altitude hypoxia.Objects 1.To explore the mi RNA expression profile of myocardium exposed to high altitude hypoxia,and to explore the mechanism of myocardial injury induced by differently regulated mi RNA.2.To screen potential drugs for prevention and treatment myocardial injury induced by hypobaric hypoxia based on m RNA expression profile of myocardium and CMAP databaseMethods 1.Using a hypobaric hypoxic experimental chamber to simulate the plateau environment.Rat model of high altitude hypoxic myocardial injury was constructed.The model was evaluated using histopathology and echocardiography.2.The expression profiles of mi RNA and m RNA in rat myocardium were detected by RNA-Seq.Differentially expressed mi RNA and m RNA were screened and functions were analyzed by bioinformatics.3.To analyze the correlation between differentially expressed mi RNA and pathological scores of acute myocardial injury,EF% and FS%,as well as the correlation between plasma mi RNA and RBC and HGB.4.CMAP database was used to compare the differentially expressed m RNA of myocardium,and to predict the potential drugs for prevention and treatment of high altitude hypoxic myocardial injury.Results 1.Effects of high altitude hypoxia on rat heart structure and function Echocardiography indicated that EF%,FS%,PV Peak Velocity,and PV Peak Gradient decreased most significantly in 7 d of high-altitude hypoxia exposure(P<0.01).Electrocardiogram indicated that the depression of ST segment was the most significant in 7 d(P<0.05).Myocardial edema and necrosis with inflammatory cell infiltration were observed at 3 d and 7 d in histopathology.2.RNA-Seq screened differentially expressed mi RNA and m RNA 18 significantly differentially expressed mi RNAs were screened,of which 15 mi RNAs were up-regulated and 3 mi RNAs down-regulated.1084 significantly differentially expressed m RNAs were screened,of which 457 m RNA was up-regulated and 627 m RNA down-regulated.GO and KEGG analysis were done based on bioinformatics.Five differentially expressed mi RNAs(mi R-132-3p,mi R-144-3p,mi R-144-5p,mi R-212-5p,mi R-672-3p)were detected for q PCR validation.The results of q PCR showed that the expression of mi R-144-3p and mi R-144-5p were significantly increased in myocardial tissue and plasma on the seven day exposed to hypobaric hypoxia.The expression of mi R-144-3p and mi R-144-5p were significantly increased in the myocardium of rats on 3 d and 7 d exposed to hypoxia(P<0.05),The expression of mi R-144-3p and mi R-144-5p was gradually increased with the prolongation of hypoxia time in plasma(P<0.01).3.Correlation between mi R-144-3p/5p expression and cardiac function The correlation analysis suggested that the expression of mi R-144-3p was positively correlated with the pathological score of acute myocardial injury(r=0.77,P<0.05),as well as mi R-144-5p(r=0.87,P<0.05).The expression of mi R-144-3p was negatively correlated with EF% and FS% respectively(r=-0.9266/-0.9264,P<0.05).The expression of mi R-144-5p was negatively correlated with EF% and FS% respectively(r=-0.8843/-0.8834,P<0.05).The expression mi R-144-3p in plasma was positively correlated with RBC and HGB respectively(r= 0.9591/0.9600,P<0.01).The expression of mi R-144-5p in plasma was positively correlated with RBC and HGB respectively(r= 0.9369/ 0.9436,P<0.01)4.SB203580 alleviate high altitude hypoxic myocardial injury and myocardial edema It was predicted that SB203580 should prevent high altitude hypoxic myocardial injury based on CMAP database.Myocardial edema was significantly reduced in SB203580 group(P<0.01).The expression of AQP1 m RNA and protein in myocardium were significantly decreased(P<0.05).The expression of mi R-144-3p was significantly decreased in myocardium(P<0.05).It was speculated that SB203580 could alleviate myocardial edema caused by high altitude hypoxia by interfering with mi R-144-3p/AQP1 expression.Conclusion Plateau hypoxic environment could cause changes in rat heart structure and function.The heart function of rats decreased most significantly on the seven days exposed to hypobaric hypoxia.The expression of mi R-144-3p/5p in myocardium was positively correlated with the pathological score of acute myocardial injury and negatively correlated with EF% and FS%.The expression of mi R-144-3p/5p in Plasma were positively correlated with RBC and HGB.mi R-144-3p/5p may be a new biomarker and intervention target for hypoxia-related diseases in the future.SB203580 could alleviate myocardial edema and down-regulate the expression of mi R-144-3p and AQP1 in myocardium. |
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