MiR-484 Protects Rat Myocardial Cells from Ischemia-Reperfusion Injury by Inhibiting Caspase-3 and Caspase-9 during Apoptosis

Background and Objectives To reveal the detail mechanism of miR-484 on myocardial ischemia-reperfusion (MI/R) injury. Methods Rats model of MI/R injury was established based on control (Con; sham operate) group, ischemia-reperfusion (I/R) group, miR-484 treatment (miR) group, and I/R-negative control (IR-C) group, followed by pathological and interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β expression evaluation. Then the myocardial apoptosis, as well as the expression of miR-484, caspase-3, and caspase-9 in myocardium were examined. Finally, the regulatory relation between miR-484 and SMAD family member 7 (SMAD7) was predicated, followed by verification analysis. Results Compared with Con group, the expression of miR-484 in I/R and IR-C group was decreased. Compared with I/R and IR-C group, the expression of miR-484 was increased in miR group. Compared with Con group, the expression levels of IL-6, TNF-α, and IL-1β in cardiac myocytes of I/R group and IR-C group were increased. Compared with Con group, the apoptotic index, membrane potential of I/R, and the expression of caspase-3/9 were increased in IR-C group. Compared with the I/R and IR-C groups, the apoptotic index of myocardial cells in the ischemic region was decreased, the membrane potential was increased, and the expression of caspase-3/9 was decreased significantly in the miR group. SMAD7 was the target gene of miR-484. Conclusions MiR-484 protected myocardial cells from I/R injury by suppressing caspase-3 and caspase-9 expression during cardiomyocyte apoptosis. MiR-484 reduced the expression of IL-6, TNF-α, and IL-1β in MI/R. MiR-484 might alleviate the decreasing of mitochondrial membrane potential in MI/R cells.

[1]  Xun Li,et al.  Long noncoding RNA LINC00339 aggravates doxorubicin-induced cardiomyocyte apoptosis by targeting MiR-484. , 2018, Biochemical and biophysical research communications.

[2]  Ming Lei,et al.  miR-25 inhibits sepsis-induced cardiomyocyte apoptosis by targetting PTEN , 2018, Bioscience reports.

[3]  Yulong Zheng,et al.  MiR-484 promotes non-small-cell lung cancer (NSCLC) progression through inhibiting Apaf-1 associated with the suppression of apoptosis. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[4]  Fang-bao Ding,et al.  MicroRNA-15a inhibition protects against hypoxia/reoxygenation-induced apoptosis of cardiomyocytes by targeting mothers against decapentaplegic homolog 7 , 2017, Molecular medicine reports.

[5]  A. Richards,et al.  Discovery of Potential Therapeutic miRNA Targets in Cardiac Ischemia–Reperfusion Injury , 2016, Journal of cardiovascular pharmacology and therapeutics.

[6]  R. Mach,et al.  PET imaging of in vivo caspase-3/7 activity following myocardial ischemia-reperfusion injury with the radiolabeled isatin sulfonamide analogue [(18)F]WC-4-116. , 2016, American journal of nuclear medicine and molecular imaging.

[7]  I. Pogribny,et al.  The role for microRNAs in drug toxicity and in safety assessment , 2015, Expert opinion on drug metabolism & toxicology.

[8]  B. O’Rourke,et al.  Mitochondrial instability during regional ischemia-reperfusion underlies arrhythmias in monolayers of cardiomyocytes. , 2015, Journal of molecular and cellular cardiology.

[9]  K. Ye,et al.  Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation. , 2014, The Journal of clinical investigation.

[10]  Qiang Zhao,et al.  MicroRNA-92a Inhibition Attenuates Hypoxia/Reoxygenation-Induced Myocardiocyte Apoptosis by Targeting Smad7 , 2014, PloS one.

[11]  Z. Shao,et al.  Abstract P4-07-11: Dual characteristics of microRNA-484 modulated cytidine deaminase (CDA) axis in breast cancer: Chemo-resistance and regulating cell proliferation , 2013 .

[12]  D. Sudan,et al.  Upregulation of IL-1&bgr;, IL-6, and CCL-2 by a Novel Mouse Model of Pancreatic Ischemia-Reperfusion Injury , 2013, Transplantation.

[13]  J. Heckenlively,et al.  Age-related retinal inflammation is reduced by 670 nm light via increased mitochondrial membrane potential , 2013, Neurobiology of Aging.

[14]  D. Yellon,et al.  Myocardial ischemia-reperfusion injury: a neglected therapeutic target. , 2013, The Journal of clinical investigation.

[15]  E. Olson,et al.  MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca²⁺ overload and cell death. , 2012, The Journal of clinical investigation.

[16]  R. Mutharasan,et al.  microRNA-210 is upregulated in hypoxic cardiomyocytes through Akt- and p53-dependent pathways and exerts cytoprotective effects. , 2011, American journal of physiology. Heart and circulatory physiology.

[17]  M. Medvedovic,et al.  MicroRNA-494 Targeting Both Proapoptotic and Antiapoptotic Proteins Protects Against Ischemia/Reperfusion-Induced Cardiac Injury , 2010, Circulation.

[18]  Lei Shi,et al.  Reduction of miR-21 induces glioma cell apoptosis via activating caspase 9 and 3. , 2010, Oncology reports.

[19]  Farid E Ahmed,et al.  Diagnostic microRNA markers for screening sporadic human colon cancer and active ulcerative colitis in stool and tissue. , 2009, Cancer genomics & proteomics.

[20]  Nirmal Singh,et al.  Protective effects of caspase-9 and poly(ADP-ribose) polymerase inhibitors on ischemia-reperfusion-induced myocardial injury , 2009, Archives of pharmacal research.

[21]  Yao‐Hua Song,et al.  Glucose induces apoptosis of cardiomyocytes via microRNA-1 and IGF-1. , 2008, Biochemical and biophysical research communications.

[22]  Cheuk-Kwan Sun,et al.  Change in mitochondrial membrane potential is the key mechanism in early warm hepatic ischemia-reperfusion injury. , 2005, Microvascular research.

[23]  Chen Ying-wei.  Smad7 and Fibrotic Disorders , 2005 .

[24]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[25]  John Calvin Reed,et al.  Caspase-3 is essential for procaspase-9 processing and cisplatin-induced apoptosis of MCF-7 breast cancer cells. , 2000, Cancer research.

[26]  I. Hassinen,et al.  Intracellular free calcium and mitochondrial membrane potential in ischemia/reperfusion and preconditioning. , 2000, Journal of molecular and cellular cardiology.

[27]  M. Matsuzaki,et al.  Effect of caspase-3 inhibitor on myocyte apoptosis and left ventricular remodeling in the ischemia-reperfused rat heart , 1999 .

[28]  A. Porter,et al.  Emerging roles of caspase-3 in apoptosis , 1999, Cell Death and Differentiation.

[29]  T. Starzl,et al.  Protective Effect of TNF-α and IL-1β Inhibitor FR167653 on Ischemia-Reperfusion Injury in Rat Small Intestinal Transplantation , 1998 .