Association Between Circulating MiR-143/145 And The Severity Of Coronary Artery Stenosis In Patients With Acute Coronary Syndrome

BackgroundAcute Coronary Syndrome(ACS)refers to the acute ischemic heart disease caused by the occlusion of coronary artery after the rupture or erosion of vulnerable atheromatous plaque.It is classified as unstable angina,ST-segment elevation myocardial infarction(STEMI)and non-ST-segment elevation myocardial infarction(NSTEMI).According to the Chinese Cardiovascular Disease Report,the morbidity and mortality of cardiovascular disease in China shows uptrend,accounting for over 40%of overall mortality.And the mortality of ACS increased every year in the past decade.Thus the key point is attributed to diagnose and therapy of ACS.According to researchers,coronary atherosclerosis is the underlying cause for ACS which begins from endothelial injury.Under pathological conditions(risk factors,mechanical injury,etc.),the endothelium becomes dysfunctional,leading to the accumulation of circulating lipids into intimal layer,and promoting the activation and adhesion of monocytes to the dysfunctional area where monocytes differentiate into macrophage further.Multiple chemokines and growth factors released by dysfunctional endothelium and macrophage then act on neighboring smooth muscle cells to induce their proliferation and synthesis of extracellular matrix components and thus generate a fibrous cap outside the lipid core.Inflammatory substances such as tissue factors and matrix metalloproteases create a thinner plaque cap making atherosclerotic lesions more prone to rupture which happens to be the pathological basis for ACS.Therefore the interaction between dysfunctional endothelium and the rest cells can be the important target for the therapy of ACS.Over the years,a certain kind of non-coding RNAs called microRNAs(miRNAs)have attracted researcher's attention for their promising role in various diseases.MiRNAs are a class of abundant endogenous RNAs of 18-24 nucleotides length,able to paring bind to the 3' UTR,5' URT,open reading frame,promotor or RNA-binding proteins,which then negatively regulate gene expression at post-transcriptional level by translational repression or degradation of target mRNAs.Circulating miRNAs can maintain their stability through extracellular vesicles or binding to Ago2 and quantification showed tissue-specific and time-dependent expression pattern,turning them into leading new biomarkers in diseases.Researches in oncology and nephrology demonstrated that circulating miRNAs can be biomarkers of certain tumors and their diagnostic value has also been validated in cardiovascular field.Researches demonstrated that endothelial-derived miR-143/145-containing vesicles are able to induce an atherosclerosis protective smooth muscle cell phenotype,meanwhile smooth muscle cell-derived miR-143/145 can also regulate the angiogenesis of endothelium.We conclude miR-143/145 can mediate the intercellular communication between endothelium and smooth muscle cells,the level of which is related to its anti-atherosclerotic role.Here we aim to quantify the circulating miR-143/145 content and explore the association between their content and the severity of coronary artery stenosis.Objectives1.To explore the differentialexpression level between ACS patients and control group..2.To explore the correlation between miR-143/145 content and the severity of coronary artery stenosis.3.To explore the influence of circulating miR-143/145 on acute coronary event.4.To explore the value of miR-143/145 in evaluating coronary lesion.MethodsAccording to the inclusion criteria and exclusion criteria of the research,we have admitted 279 hospitalized patients diagnosed with ACS(ACS group)in Qilu Hospital of Shandong University,including patients with unstable angina pectoris(UA,n=201)and patients with acute myocardial infarction(AMI,n=78).Hospitalized patients with coronary stenosis no more than 50%were admitted to control group(n=65).5ml arterial blood samples were collected right before coronary angiography,and then platelet-poor plasma was obtained by ultracentrifugation.Next we use column absorption for the extraction of small RNAs in plasma,followed by real-time quanltitative reverse transcription polymerase chain reaction(RT-qPCR)to detect the expression level of plasma miR-143/145.The clinical characteristics of patients including demographic characteristics,pharmacological therapy,laboratory test results and coronary angiography results were collected.SPSS 19.0 software was used for statistical analysis of all data and p<0.05 was considered statistically significant.Results1.According to the statistics,there were no significant differences in age,gender,blood pressure,BMI,alcohol use,hypertension and family history of CAD at admission between UA group,AMI group and control group.Compared with control group,patients in UA group had a higher proportion of diabetes,previous myocardial infarction and previous PCI(p<0.001),while patients in AMI groups also showed a higher proportion of smoking,diabetes,previous myocardial infarction and previous PCI(p<0.001).Meanwhile,diabetes prevalence showeda significant difference between AMI group and UA group(p<0.001).The level of hs-cTnIof AMI group was significantly higher than the rest groups(p<0.05),and was also higher in UA group compared with control gr-oup(p<-0.01).Gensini scores of UA group and AMI group were both significantly higher than that of control group(p<0.01?0.001),and compared with UA group,gensini scores of AMI group were also higher(p<0.05).2.The level of circulating miR-143/145 in ACS group was significantly lower than that of control group(p<0.05).After further grouping,the level of miR-143/145 in UA group and AMI group were also significantly lower than that of control group,whereas there was no sign:ificant difference between UA group and AMI group.3.Multivariable linear regression analysis showed the level of miR-143 was negatively correlated with the use of ?-blockers,while the use of nitrates,statins,and LMWH were positively correlated with miR-143 content.The level of miR-145 was negatively correlated with age,gender,and serum LDL-c level,while the use of nitrates was positively correlated with miR-145 content.4.The linear regression analysis showed a negative linear correlation between miR-143/145 content and gensini scores.5.According to logistic regression analysis,miR-143 and miR-145 were protective factors for ACS,UA and AMI respectively.6.Analyzed with ROC curve to explore the two miRNAs in estimating coronary stenosis above 50%,the AUC of miR-143 was 0.786 while the sensitivity was 53.3%and the specificity was 89.2%.The AUC of miR-145 was 0.793 wh:ile the sensitivity was 73.9%and the specificity was74.6%.Conclusions1.The circulating miR-143/145 level were significant decreased..2.The level of circulating miR-143/145 was negatively correlated with coronary stenosis and could reflect the severity of coronary stenosis.3.Circulating miR-143 and miR-145 were protective factors of acute coronary event.4.Circulating miR-143/145 could contribute to the evaluation of coronary lesion and be promising biomarkers for coronary lesion.