MiR-145-5p alleviates hypoxia/reoxygenation- induced cardiac microvascular endothelial cell injury in coronary heart disease by inhibiting Smad4 expression.

OBJECTIVE To investigate the effects and mechanism of miR-145-5p on hypoxia/reoxygenation (H/R)-induced cardiac microvascular endothelial cell (CMEC) injury in coronary heart disease (CHD). PATIENTS AND METHODS Patients with CHD (n=96) and healthy volunteers (n=96) were enrolled, and H/R injury model of CMECs was established. The expression of miR-145-5p and mothers against decapentaplegic homolog 4 (Smad4) mRNA in cells was quantified with reverse transcription polymerase chain reaction (RT-PCR). Then, miR-145-5p mimics and Smad4 inhibitor were transfected into CMECs. Cell counting kit-8 (CCK-8) was employed for proliferation detection, flow cytometry for apoptosis detection, and Western Blot for measuring the expression of apoptosis-related proteins and Smad4 protein. RESULTS The expression of serum miR-145-5p in patients with CHD was significantly lower than that in healthy individuals. The area under the curve (AUC) of miR-145-5p in diagnosing CHD was 0.894, and the expression of miR-145-5p was negatively correlated with that of Smad4 (p<0.05). Over-expression of miR-145-5p promoted the proliferation, inhibited the apoptosis, and reduced inflammatory responses and oxidative stress in H/R-injured CMECs. Moreover, miR-145-5p might negatively regulate the expression of Smad4 in CMECs. Dual-Luciferase reporter assay determined the targeting relation between miR-145-5p and Smad4. CONCLUSIONS MiR-145-5p is lowly expressed in patients with CHD, and its over-expression effectively alleviates H/R-induced CMEC injury by inhibiting Smad4.

[1]  Shiguo Liu,et al.  SMAD4 Y353C promotes the progression of PDAC , 2019, BMC Cancer.

[2]  A. Takano,et al.  Deficiency of MicroRNA miR‐1954 Promotes Cardiac Remodeling and Fibrosis , 2019, Journal of the American Heart Association.

[3]  J. Spears.  Reperfusion Microvascular Ischemia After Prolonged Coronary Occlusion: Implications And Treatment With Local Supersaturated Oxygen Delivery , 2019, Hypoxia.

[4]  Ming Sun,et al.  Circular RNA CEP128 promotes bladder cancer progression by regulating Mir‐145‐5p/Myd88 via MAPK signaling pathway , 2019, International journal of cancer.

[5]  Hui Ding,et al.  Circulating miR-106a may Function as Potential Biomarkers in Patients with Coronary Artery Disease. , 2019, Clinical laboratory.

[6]  Qifeng Jin,et al.  RETRACTED ARTICLE: Silencing circular RNA circ_0010729 protects human cardiomyocytes from oxygen–glucose deprivation-induced injury by up-regulating microRNA-145-5p , 2019, Molecular and Cellular Biochemistry.

[7]  Florence Mei Kuen Tang,et al.  microRNA-1 inhibits cardiomyocyte proliferation in mouse neonatal hearts by repressing CCND1 expression , 2019 .

[8]  T. Force,et al.  Cardiomyocyte SMAD4-Dependent TGF-β Signaling is Essential to Maintain Adult Heart Homeostasis , 2019, JACC. Basic to translational science.

[9]  A. Fatica,et al.  Argonaute 2 drives miR-145-5p-dependent gene expression program in breast cancer cells , 2019, Cell Death & Disease.

[10]  Xiang Jin,et al.  Teneligliptin protects against hypoxia/reoxygenation-induced endothelial cell injury. , 2019, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[11]  H. Khan,et al.  Sleep Duration and Risk of Fatal Coronary Heart Disease, Sudden Cardiac Death, Cancer Death, and All-Cause Mortality. , 2018, The American journal of medicine.

[12]  Haiming Xu,et al.  Downregulated microRNA‐224 aggravates vulnerable atherosclerotic plaques and vascular remodeling in acute coronary syndrome through activation of the TGF‐β/Smad pathway , 2018, Journal of cellular physiology.

[13]  L. Herranz,et al.  Toe Brachial Pressure Index as Alternative Method to Correlate Arteriosclerotic Disease in Type 2 Diabetes. , 2018, The Journal of the Association of Physicians of India.

[14]  Daokang Xiang,et al.  MicroRNA-495 Ameliorates Cardiac Microvascular Endothelial Cell Injury and Inflammatory Reaction by Suppressing the NLRP3 Inflammasome Signaling Pathway , 2018, Cellular Physiology and Biochemistry.

[15]  P. Nowacki,et al.  Risk factors for ischemic stroke in patients with non-valvular atrial fibrillation and therapeutic international normalized ratio range , 2018, Archives of medical science : AMS.

[16]  M. J. Jacob,et al.  Diagnostic Accuracy of Stress Myocardial Perfusion Imaging in Diagnosing Stable Ischemic Heart Disease. , 2018, The Journal of the Association of Physicians of India.

[17]  Nihong Lu,et al.  MiR-130a inhibition protects rat cardiac myocytes from hypoxia-triggered apoptosis by targeting Smad4. , 2018, Kardiologia polska.

[18]  Guoqing Zhang,et al.  Schisandrin B attenuates CCl4-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-β/Smad signaling pathways , 2017, Drug design, development and therapy.

[19]  J. O’Keefe,et al.  Impact of persistence and non-persistence in leisure time physical activity on coronary heart disease and all-cause mortality: The Copenhagen City Heart Study , 2017, European journal of preventive cardiology.

[20]  Chuan-yu Gao,et al.  Protective Effects of MicroRNA-126 on Human Cardiac Microvascular Endothelial Cells Against Hypoxia/Reoxygenation-Induced Injury and Inflammatory Response by Activating PI3K/Akt/eNOS Signaling Pathway , 2017, Cellular Physiology and Biochemistry.

[21]  Feifei Yang,et al.  MiR-145-5p regulates hypoxia-induced inflammatory response and apoptosis in cardiomyocytes by targeting CD40 , 2017, Molecular and Cellular Biochemistry.

[22]  K. Trott,et al.  Late proliferating and inflammatory effects on murine microvascular heart and lung endothelial cells after irradiation. , 2015, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[23]  W. Guo,et al.  Double-negative feedback loop between ZEB2 and miR-145 regulates epithelial-mesenchymal transition and stem cell properties in prostate cancer cells , 2014, Cell and Tissue Research.

[24]  M. Penn,et al.  miR-145 is differentially regulated by TGF-β1 and ischaemia and targets Disabled-2 expression and wnt/β-catenin activity , 2012, Journal of cellular and molecular medicine.

[25]  G. Mills,et al.  miR-145 participates with TP53 in a death-promoting regulatory loop and targets estrogen receptor-α in human breast cancer cells , 2010, Cell Death and Differentiation.