Ann Marie Karam

Introduction: Heart Failure (HF) contributes to 1 in 8 deaths in America, with a risk of 1 in 5 of developing HF in one’s lifetime. In addition, HF can be difficult to diagnose, especially since most patients who develop HF have multiple comorbidities and present with varying symptoms.¹ Current treatments for heart failure (HF) are focused on diuretics that reduce the load on the heart and do not significantly reduce morbidity and/or mortality in patients.^2,3 A change in direction for the treatment of HF is warranted, leading to research into microRNAs (miRs). miRs regulate and fine-tune nearly all normal and pathological processes by downregulating proteins at key points in biological networks. By targeting miRs that are dysregulated during HF, novel therapeutic targets can be found.^4,5  Methods: Research articles looking at the effects of miRs, specifically miR-25, on HF within the past 5 years were found searching key words in PubMed. The absence, increase, and decrease of miR-25 was analyzed for its effects on specific molecules of the body and how these affected HF specifically.^6,7,8  Results: miR-25 affects multiple pathways in the progression to HF. miR-25 is decreased in cholesterol-fed rat hearts and miRNA-25 is an important regulator of NADPH oxidase 4 (NOX4) expression and thereby cardiac oxidative/nitrative stress, a known contributor of myocardial dysfunction induced by hypercholesterolemia.⁸ Inhibition of miR-25 evokes cardiac dysfunction in a Heart- and neural crest derivatives-expressed protein 2 (Hand2)-dependent manner.⁶ miR-25 is a critical repressor of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and cardiac function during HF.⁷  Conclusions: miR-25 is an important factor in myocardial dysfunction and therefore HF due to hypercholesterolemia. Injection of miR-25 may help to reverse the underlying cause of HF and cardiac dysfunction. In contrast, injection of anti-miR-25, which would inhibit miR-25 in the body, would enhance cardiac contractility via de-repressing SERCA2a and could possibly be used as a treatment for HF. While miR-25 could potentially be a more effective therapy to help re-structure HF patients’ hearts, more research is needed for miR-25 and its interactions with each part of the heart before it can be used to either help prevent HF or to treat it.

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2. Oni-Orisan A, Lanfear D. Pharmacogenomics in Heart Failure: Where Are We Now and How Can We Reach Clinical Application. Cardiology in review. 2014;22(5):193-198.
3. Talameh JA, Lanfear D. Pharmacogenetics in Chronic Heart Failure: New Developments and Current Challenges. Current heart failure reports. 2012;9(1):23-32.
4. Akodad M, Mericskay M, Roubille F. Micro-RNAs as promising biomarkers in cardiac diseases. Annals of Translational Medicine. 2016;4(24):551.
5. van Rooij E, Kauppinen S. Development of microRNA therapeutics is coming of age. EMBO Mol Med. 2014;6:851–864.
6. Dirkx E, Gladka MM, Philippen LE, et al. Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure. Nature Cell Biology. 2013;15(11):1282–1293.
7. Wahlquist C, Jeong D, Rojas-Muñoz A, et al. Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart. Nature. 2014;508(7497):531-535.
8. Varga, Zoltan V, et al. MicroRNA-25-dependent up-regulation of NADPH oxidase 4 (NOX4) mediates hypercholesterolemia-induced oxidative/nitrative stress and subsequent dysfunction in the heart. Journal of Molecular and Cellular Cardiology. 2013;62:111-121.