Overexpression of microRNA-135b-5p attenuates acute myocardial infarction injury through its anti-oxidant and anti-apptotic properties

Objective:Myocardial infarction(MI)remains the leading cause of morbidity and mortality due partly to the limited regenerative capacity of cardiomyocytes to replace cardiomyocyte lost due to apoptosis.Inhibiting cardiomyocyte apoptosis is recognized as an effective therapeutic approach for MI.MicroRNAs(miRNAs,miRs),which regulate target genes at the post-transcriptional level,play a significant role in the regulation of cardiovascular diseases such as MI.MicroRNA-135b(miR-135b)has a protective effect on cardiomyocytes.However,the role of miR-135b in cardiomyocyte apoptosis in infarct myocardium needs further clarification.Methods:We generatedα-MHC-miR-135b transgenic mice to investigate the role of miR-135b in myocardial injury after MI.MiR-135b mimic and negative control(NC)were transfected into H2O2-induced cardiomyocytes to evaluate the effect of overexpression of miR-135b on the levels of reactive oxygen species(ROS)and apoptosis.Results:Our results showed that overexpression of miR-135b had protective effect on cardiomyocyte injury both in vivo and in vitro.MiR-135b inhibited cardiomyocyte apoptosis and ROS generation,downregulated pro-apoptosis proteins(cleaved-caspase-3 and Bax),and increased anti-apoptosis protein(Bcl-2).Moreover,miR-135b showed an inhibitory effect on apoptosis-related protein target transient receptor potential vanilloid-type 4(TRPV4)cation channel.Conclusion:MiR-135b might be considered a new molecular target for potential replacement therapy as antiapoptotic cardioprotection in the setting of MI.

LncRNA CCRR maintains Ca^(2+)homeostasis against myocardial infarction through the FTO-SERCA2a pathway

Cardiac conduction regulatory RNA(CCRR)has been documented as an antiarrhythmic lncRNA in our earlier investigation.This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca^(2+)homeostasis in myocardial infarction(MI).Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca^(2+)homeostasis and reduced the heightened methylation level of SERCA2a following MI.These effects were also observed in CCRR overexpressing transgenic mice.A conserved sequence domain of CCRR mimicked the protective function observed with the full length.Furthermore,silencing CCRR in healthy mice led to intracellular Ca^(2+)overloading of cardiomyocytes.CCRR increased SERCA2a protein stability by upregulating FTO expression.The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation(RIP)analysis and RNA pulldown experiments.Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI.This study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO,thereby reducing the m^(6)A RNA methylation level of SERCA2a,ultimately preserving calcium homeostasis for myocardial contractile function in MI.Therefore,CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.

Circulating CCRR serves as potential novel biomarker for predicting acute myocardial infarction

Objective:Cold regions exhibit a high prevalence of cardiovascular disease,particularly acute myocardial infarction(AMI),which is one of the leading causes of death associated with cardiovascular conditions.Cardiovascular disease is closely linked to the abnormal expression of long non-coding RNA(lncRNA).This study investigates whether circulating levels of lncRNA cardiac conduction regulatory RNA(CCRR)could serve as a biomarker for AMI.Materials and methods:We measured circulating CCRR from whole blood samples collected from 68 AMI patients and 69 non-AMI subjects.An AMI model was established using C57BL/6 mice.Quantitative reverse transcription PCR(qRT-PCR)was used to assess CCRR expression.Exosomes were isolated from cardiomyocytes,and their characteristics were evaluated using electron microscope and nanoparticle tracking analysis.The exosome inhibitor GW4869 was employed to examine the effect of exosomal CCRR on cardiac function using echocardiography.Protein expression was detected using Western blot and immunofluorescence staining.Results:The circulating level of CCRR was significantly higher in AMI patients(1.93±0.13)than in non-AMI subjects(1.00±0.05,P<0.001).The area under the ROC curve(AUC)of circulating CCRR was 0.821.Similar changes in circulating CCRR levels were consistently observed in an AMI mouse model.Exosomal CCRR derived from hypoxia-induced cardiomyocytes and cardiac tissue after AMI were increased,a change that was reversed by GW4869.Additionally,CCRR-overexpressing exosomes improved cardiac function in AMI.Conclusion:Circulating lncRNA CCRR is a potential predictor of AMI.Exosomal CCRR plays a role in the communication between the heart and other organs through circulation.