Abstract
Non-coding RNAs participate in many cardiac pathophysiological processes, including myocardial infarction (MI). Here we showed the interplay between long non-coding RNA taurine-upregulated gene 1 (lncR-TUG1), miR-9a-5p (miR-9) and Krüppel-like factor 5 (KLF5). LncR-TUG1 was upregulated in ischemic heart and in cultured cardiomyocytes exposed to H2O2. Knockdown of lncR-TUG1 markedly ameliorated impaired cardiac function of MI mice. Further study showed that lncR-TUG1 acted as a competitive endogenous RNA of miR-9, and silencing of lncR-TUG1 inhibited cardiomyocyte apoptosis by upregulating miR-9 expression. Furthermore, the miR-9 overexpression obviously prevented ischemia injury and significantly inhibited H2O2-induced cardiomyocyte apoptosis via inhibition of mitochondrial apoptotic pathway. KLF5, as a target gene of miR-9 by dual-luciferase reporter assay, was involved in the process of miR-9 in regulating cardiomyocyte apoptosis. Our data identified the KLF5 was downregulated by miR-9 overexpression and knockdown of KLF5 inhibited cardiomyocyte apoptosis induced by H2O2. MiR-9 exerts anti-cardiomyocyte apoptotic affects by targeting KLF5. Collectively, our data identify a novel function of lncR-TUG1/miR-9/KLF5 axis in regulating cardiomyocyte apoptosis that affects myocardial infarction progression.
Highlights
Acute myocardial infarction (AMI), caused by the sudden occlusion of coronary flow, is one of the leading causes of morbidity and mortality worldwide
We injected Len-siTUG1 into left ventricular chamber of mice and established MI model for 3 days. 3 days post-MI, echocardiography examination showed that EF and FS were both significantly decreased in MI hearts, indicating the impaired cardiac function (Fig. 1c–e)
It was observed that the percentage of transferase dUTP nick end labeling (TUNEL)-positive cells was significantly increased in the border zone of MI mice hearts, which was diminished by Len-siTUG1 (Fig. 1j, k)
Summary
Acute myocardial infarction (AMI), caused by the sudden occlusion of coronary flow, is one of the leading causes of morbidity and mortality worldwide. The prominent pathological change post-MI is death of cardiomyocytes, which can lead to the irreversible loss of heart function. Numerous studies have suggested that cardiomyocyte in the peri-infarct region may mostly undergo apoptosis, which can be potentially recovered from injury within a certain period of time post-MI if effective therapy. LncRNAs participate in various cellular processes, including RNA processing[3], structural scaffolds[4], chromatin modification[5], modulation of apoptosis and invasion[6]. LncRNAs have been identified in cardiomyocytes and found to be essential for the development and progression of heart diseases[7,8].
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