ABSTRACT
AIMS: Myocardial infarction (MI) is a major cause of death worldwide. Effective treatments are required to improve recovery of cardiac function following MI, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile region bordering an infarct is functionally distinct from the remote surviving myocardium and is a determinant of adverse remodelling and cardiac contractility. Expression of the transcription factor RUNX1 is increased in the border zone 1-day after MI, suggesting potential for targeted therapeutic intervention. OBJECTIVE: This study sought to investigate whether an increase in RUNX1 in the border zone can be therapeutically targeted to preserve contractility following MI. METHODS AND RESULTS: In this work we demonstrate that Runx1 drives reductions in cardiomyocyte contractility, calcium handling, mitochondrial density, and expression of genes important for oxidative phosphorylation. Both tamoxifen-inducible Runx1-deficient and essential co-factor common ß subunit (Cbfß)-deficient cardiomyocyte-specific mouse models demonstrated that antagonizing RUNX1 function preserves the expression of genes important for oxidative phosphorylation following MI. Antagonizing RUNX1 expression via short-hairpin RNA interference preserved contractile function following MI. Equivalent effects were obtained with a small molecule inhibitor (Ro5-3335) that reduces RUNX1 function by blocking its interaction with CBFß. CONCLUSIONS: Our results confirm the translational potential of RUNX1 as a novel therapeutic target in MI, with wider opportunities for use across a range of cardiac diseases where RUNX1 drives adverse cardiac remodelling.
Subject(s)
Heart Failure , Myocardial Infarction , Animals , Mice , Core Binding Factor Alpha 2 Subunit/genetics , Core Binding Factor Alpha 2 Subunit/metabolism , Heart Failure/metabolism , Myocardial Infarction/genetics , Myocardial Infarction/prevention & control , Myocardial Infarction/drug therapy , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Ventricular RemodelingABSTRACT
OBJECTIVES: To investigate the circulating levels of microRNA-34a (miRNA-34a) as a novel non-invasive biomarker of breast cancer (BC). Methods: The case-control study was conducted at the Department of Chemistry and Biochemistry, College of Medicine, Al-Nahrain University, Baghdad, Iraq, from December 2018 to April 2019. Real-time quantitative polymerase chain reaction has been employed to analyze miRNA-34a expression in the samples of serum from 90 participants (30 patients with BC 30 patients with benign breast tumors and 30 control subjects) after RNA extraction and reverse transcription. Cancer antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA) were measured by ELISA. Additionally, we analyzed the receiver operating characteristic curves of various markers, including miRNA -34a, CA15-3, and CEA, to assess the diagnostic power of each marker. Results: The expression of miRNA-34a has been significantly lower in the group of breast cancer compared with that in the group of control, and miRNA-34a expression has been significantly reduced in the group of benign breast tumor compared as that in the group of control. Receiver operating characteristics analysis showed a very good discriminative power of combined miRNA-34a and CA15-3 (specificity=77.7%; sensitivity=83.3% and areas under the curve =0.842) for BC patients. Conclusion: MicroRNA-34a expression is significantly decreased in the patients' serum with the cancer of breast, and miRNA-34a can be employed as a potential non-invasive molecular marker for the early diagnosis of BC.