MicroRNA-145 (miR-145) has been shown to play an important role in cardiovascular system disorders; however, the underlying mechanism is not completely understood. The purpose of this study was aimed at elucidating the cardioprotective effects of miR-145 against myocardial ischemia/reperfusion (I/R) injury. We established a rat myocardial I/R model with 45 min left anterior descending coronary artery (LAD) occlusion and 2 h reperfusion. The levels of myocardial enzymes, apoptotic, inflammatory, and oxidative indices were determined. The arrhythmia score was assessed by programmed electrical stimulation (PES). Quantitative real-time PCR and western blot were applied to evaluate the expression levels of miR-145 and related target proteins, respectively. I/R injury decreased the expression of miR-145; however, upregulated miR-145 markedly reduced the elevation of ST segment, decreased corrected QT (QTc) intervals, and attenuated I/R-induced electrophysiological instability. Furthermore, miR-145 suppressed myocardium apoptotic, inflammatory, and oxidative response as well as the phosphorylation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), ryanodine receptor2 (RyR2 Ser2814), apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinases (JNK), and nuclear translocation of nuclear factor kappa-B (NF-κB) p65. In summary, overexpression of miR-145 alleviates I/R-induced myocardial electrophysiological instability and apoptotic and inflammatory response via inhibition of the CaMKII-mediated ASK1 antiapoptotic pathway and NF-κB p65 anti-inflammatory pathways.

Background: Sepsis is a systemic inflammatory syndrome induced by several infectious agents. Multiple organs are affected by sepsis, including the liver, which plays an important role in metabolism and immune homeostasis. Fibroblast growth factors (FGFs) participate in several biological processes, although the role of FGF5 in sepsis is unclear. Methods: In this study, lipopolysaccharide (LPS) was administrated to mice to establish a sepsis-induced liver injury. A similar in vitro study was conducted using L-02 hepatocytes. Western blot and immunohistochemistry staining were performed to evaluate the FGF5 expression level in liver tissues and cells. Inflammatory cell infiltrations, cleaved-caspase-3 expressions, reactive oxygen species and levels of inflammatory cytokines were detected by immunofluorescence, dihydroethidium staining, and reverse transcription quantitative polymerase chain reaction analysis, respectively. Flow cytometry was used to detect the apoptosis level of cells. In addition, ribonucleic acid (RNA)-sequencing was applied to explore the possible mechanism by which FGF5 exerted effects. Results: LPS administration caused FGF5 down-regulation in the mouse liver as well as in L-02 hepatocytes. Additionally, with FGF5 overexpression, liver injury and the level of hepatocyte apoptosis were ameliorated. Further, RNA sequencing performed in hepatocytes revealed the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) pathway as a possible pathway regulated by FGF5. This was supported using an inhibitor of the PI3K/AKT pathway, which abrogated the protective effect of FGF5 in LPS-induced hepatocyte injury. Conclusion: The anti-apoptotic effect of FGF5 on hepatocytes suffering from LPS has been demonstrated and was dependent on the activation of the PI3K/AKT signaling pathway.

Numerous studies have highlighted the crucial role of microRNA-145 (miR-145) in coronary atherosclerosis and myocardial ischemia reperfusion injury. However, effects of miR-145 on β-adrenergic signaling and cardiac remodeling in heart failure (HF) remains unclarified. We established HF model in rats with left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD ligation, rats showed substantial aggravation of cardiac dilation and electrophysiological instability. Up-regulation of miR-145 ameliorated HF-induced myocardial fibrosis and prolonged action potential duration. Echocardiography revealed increased basal contractility and decreased left ventricular inner-diameter in miR-145 over-expressed heart, while cardiac response to β-adrenergic receptor (βAR) stimulation was reduced. Furthermore, miR-145 increased L-type calcium current (ICa) density while decreased ICa response to β-adrenergic stimulation with isoproterenol. The alterations in βAR signaling might be predominant due to miR-145-mediated activation of Akt/CREB cascades. At high frequency pacing, Ca2+ transient, cell shortening and frequency of Ca2+ waves were significantly improved in AD-miR-145 group. Western blotting revealed that increased expression of Cav1.2, Ca2+-ATPase, β2AR, GNAI3 and decreased level of CaMKII might be attributed to the cardioprotective effects of miR-145. miR-145 effectively alleviates HF-related cardiac remodeling by improving cardiac dilation, fibrosis, intracellular Ca2+ mishandling and electrophysiological instability.