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Abstract：
MicroRNAs and the WNT signaling cascade regulate the pathogenetic mechanisms of atherosclerotic coronary artery disease (CAD) development.
OBJECTIVE: To evaluate the expression of microRNAs (miR-21a, miR-145, and miR-221) and the role of the WNT signaling cascade (WNT1, WNT3a, WNT4, and WNT5a) in obstructive CAD and ischemia with no obstructive coronary arteries (INOCA).
METHODS: The cross-sectional observational study comprised 94 subjects. The expression of miR-21a, miR-145, miR-221 (RT-PCR) and the protein levels of WNT1, WNT3a, WNT4, WNT5a, LRP6, and SIRT1 (ELISA) were estimated in the plasma of 20 patients with INOCA (66.5 [62.8; 71.2] years; 25% men), 44 patients with obstructive CAD (64.0 [56.5; 71,0] years; 63.6% men), and 30 healthy volunteers without risk factors for cardiovascular diseases (CVD).
RESULTS: Higher levels of WNT1 (0.189 [0.184; 0.193] ng/mL vs. 0.15 [0.15-0.16] ng/mL, p < 0.001) and WNT3a (0.227 [0.181; 0.252] vs. 0.115 [0.07; 0.16] p < 0.001) were found in plasma samples from patients with obstructive CAD, whereas the INOCA group was characterized by higher concentrations of WNT4 (0.345 [0.278; 0.492] ng/mL vs. 0.203 [0.112; 0.378] ng/mL, p = 0.025) and WNT5a (0.17 [0.16; 0.17] ng/mL vs. 0.01 [0.007; 0.018] ng/mL, p < 0.001). MiR-221 expression level was higher in all CAD groups compared to the control group (p < 0.001), whereas miR-21a was more highly expressed in the control group than in the obstructive (p = 0.012) and INOCA (p = 0.003) groups. Correlation analysis revealed associations of miR-21a expression with WNT1 (r = -0.32; p = 0.028) and SIRT1 (r = 0.399; p = 0.005) protein levels in all CAD groups. A positive correlation between miR-145 expression and the WNT4 protein level was observed in patients with obstructive CAD (r = 0.436; p = 0.016). Based on multivariate regression analysis, a mathematical model was constructed that predicts the type of coronary lesion. WNT3a and LRP6 were the independent predictors of INOCA (p < 0.001 and p = 0.002, respectively).
CONCLUSIONS: Activation of the canonical cascade of WNT-β-catenin prevailed in patients with obstructive CAD, whereas in the INOCA and control groups, the activity of the non-canonical pathway was higher. It can be assumed that miR-21a has a negative effect on the formation of atherosclerotic CAD. Alternatively, miR-145 could be involved in the development of coronary artery obstruction, presumably through the regulation of the WNT4 protein. A mathematical model with WNT3a and LRP6 as predictors allows for the prediction of the type of coronary artery lesion.
OBJECTIVE: To evaluate the expression of microRNAs (miR-21a, miR-145, and miR-221) and the role of the WNT signaling cascade (WNT1, WNT3a, WNT4, and WNT5a) in obstructive CAD and ischemia with no obstructive coronary arteries (INOCA).
METHODS: The cross-sectional observational study comprised 94 subjects. The expression of miR-21a, miR-145, miR-221 (RT-PCR) and the protein levels of WNT1, WNT3a, WNT4, WNT5a, LRP6, and SIRT1 (ELISA) were estimated in the plasma of 20 patients with INOCA (66.5 [62.8; 71.2] years; 25% men), 44 patients with obstructive CAD (64.0 [56.5; 71,0] years; 63.6% men), and 30 healthy volunteers without risk factors for cardiovascular diseases (CVD).
RESULTS: Higher levels of WNT1 (0.189 [0.184; 0.193] ng/mL vs. 0.15 [0.15-0.16] ng/mL, p < 0.001) and WNT3a (0.227 [0.181; 0.252] vs. 0.115 [0.07; 0.16] p < 0.001) were found in plasma samples from patients with obstructive CAD, whereas the INOCA group was characterized by higher concentrations of WNT4 (0.345 [0.278; 0.492] ng/mL vs. 0.203 [0.112; 0.378] ng/mL, p = 0.025) and WNT5a (0.17 [0.16; 0.17] ng/mL vs. 0.01 [0.007; 0.018] ng/mL, p < 0.001). MiR-221 expression level was higher in all CAD groups compared to the control group (p < 0.001), whereas miR-21a was more highly expressed in the control group than in the obstructive (p = 0.012) and INOCA (p = 0.003) groups. Correlation analysis revealed associations of miR-21a expression with WNT1 (r = -0.32; p = 0.028) and SIRT1 (r = 0.399; p = 0.005) protein levels in all CAD groups. A positive correlation between miR-145 expression and the WNT4 protein level was observed in patients with obstructive CAD (r = 0.436; p = 0.016). Based on multivariate regression analysis, a mathematical model was constructed that predicts the type of coronary lesion. WNT3a and LRP6 were the independent predictors of INOCA (p < 0.001 and p = 0.002, respectively).
CONCLUSIONS: Activation of the canonical cascade of WNT-β-catenin prevailed in patients with obstructive CAD, whereas in the INOCA and control groups, the activity of the non-canonical pathway was higher. It can be assumed that miR-21a has a negative effect on the formation of atherosclerotic CAD. Alternatively, miR-145 could be involved in the development of coronary artery obstruction, presumably through the regulation of the WNT4 protein. A mathematical model with WNT3a and LRP6 as predictors allows for the prediction of the type of coronary artery lesion.
摘要：
MicroRNAs和WNT信号级联调节动脉粥样硬化性冠状动脉疾病（CAD）发展的发病机制。
目的：评估microRNAs的表达（miR-21a，miR-145和miR-221）和WNT信号传导级联的作用（WNT1，WNT3a，WNT4和WNT5a）在阻塞性CAD和无阻塞性冠状动脉（INOCA）的缺血中。
方法：横断面观察研究包括94名受试者。miR-21a的表达，miR-145、miR-221(RT-PCR)和WNT1、WNT3a、WNT4,WNT5a,LRP6和SIRT1（ELISA）在20名INOCA患者（66.5[62.8;71.2]年;25％男性）的血浆中进行了估计，44例阻塞性CAD患者（64.0[56.5;71,0]年；63.6%男性），和30名没有心血管疾病（CVD）危险因素的健康志愿者。
结果：更高水平的WNT1（0.189[0.184;0.193]ng/mL与0.15[0.15-0.16]ng/mL，p<0.001）和WNT3a（0.227[0.181;0.252]vs.在阻塞性CAD患者的血浆样本中发现0.115[0.07;0.16]p<0.001），而INOCA组的特征是WNT4的浓度较高（0.345[0.278;0.492]ng/mLvs.0.203[0.112;0.378]ng/mL，p=0.025）和WNT5a（0.17[0.16;0.17]ng/mL与0.01[0.007;0.018]ng/mL，p<0.001)。与对照组相比，所有CAD组的MiR-221表达水平均较高（p<0.001），而miR-21a在对照组中的表达高于阻塞性(p=0.012)和INOCA(p=0.003)组。相关分析显示所有CAD组中miR-21a表达与WNT1(r=-0.32;p=0.028)和SIRT1(r=0.399;p=0.005)蛋白水平相关。在梗阻性CAD患者中，miR-145表达与WNT4蛋白水平呈正相关（r=0.436；p=0.016）。基于多元回归分析，建立了预测冠状动脉病变类型的数学模型.WNT3a和LRP6是INOCA的独立预测因子(分别为p<0.001和p=0.002)。
结论：阻塞性CAD患者普遍存在WNT-β-catenin的典型级联激活，而在INOCA和对照组中，非规范途径的活性较高。可以假定miR-21a对动脉粥样硬化性CAD的构成具有负面影响。或者，miR-145可能参与冠状动脉阻塞的发展,推测是通过调节WNT4蛋白。以WNT3a和LRP6为预测因子的数学模型可以预测冠状动脉病变的类型。
目的：评估microRNAs的表达（miR-21a，miR-145和miR-221）和WNT信号传导级联的作用（WNT1，WNT3a，WNT4和WNT5a）在阻塞性CAD和无阻塞性冠状动脉（INOCA）的缺血中。
方法：横断面观察研究包括94名受试者。miR-21a的表达，miR-145、miR-221(RT-PCR)和WNT1、WNT3a、WNT4,WNT5a,LRP6和SIRT1（ELISA）在20名INOCA患者（66.5[62.8;71.2]年;25％男性）的血浆中进行了估计，44例阻塞性CAD患者（64.0[56.5;71,0]年；63.6%男性），和30名没有心血管疾病（CVD）危险因素的健康志愿者。
结果：更高水平的WNT1（0.189[0.184;0.193]ng/mL与0.15[0.15-0.16]ng/mL，p<0.001）和WNT3a（0.227[0.181;0.252]vs.在阻塞性CAD患者的血浆样本中发现0.115[0.07;0.16]p<0.001），而INOCA组的特征是WNT4的浓度较高（0.345[0.278;0.492]ng/mLvs.0.203[0.112;0.378]ng/mL，p=0.025）和WNT5a（0.17[0.16;0.17]ng/mL与0.01[0.007;0.018]ng/mL，p<0.001)。与对照组相比，所有CAD组的MiR-221表达水平均较高（p<0.001），而miR-21a在对照组中的表达高于阻塞性(p=0.012)和INOCA(p=0.003)组。相关分析显示所有CAD组中miR-21a表达与WNT1(r=-0.32;p=0.028)和SIRT1(r=0.399;p=0.005)蛋白水平相关。在梗阻性CAD患者中，miR-145表达与WNT4蛋白水平呈正相关（r=0.436；p=0.016）。基于多元回归分析，建立了预测冠状动脉病变类型的数学模型.WNT3a和LRP6是INOCA的独立预测因子(分别为p<0.001和p=0.002)。
结论：阻塞性CAD患者普遍存在WNT-β-catenin的典型级联激活，而在INOCA和对照组中，非规范途径的活性较高。可以假定miR-21a对动脉粥样硬化性CAD的构成具有负面影响。或者，miR-145可能参与冠状动脉阻塞的发展,推测是通过调节WNT4蛋白。以WNT3a和LRP6为预测因子的数学模型可以预测冠状动脉病变的类型。
