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    MiR-25 Shuts Down The Overworked Heart
    By Jennifer Wong | April 15th 2014 02:43 PM | Print | E-mail | Track Comments
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    Cardiovascular disease often causes the heart to work harder than usual, a condition that triggers the chronic buildup of cardiac pressure and the onset of heart failure.

    A new study now shows that microRNA-25 is a new molecular switch that is activated in the overworked heart to drive the onset of heart failure.

    Heart failure is the progressive decline in heart’s contractile function, and is commonly caused by a number of cardiovascular diseases including hypertension, atherosclerosis, and many others1. These cardiovascular conditions hinder cardiac function, and can cause the heart to work harder to meet oxygen and nutrient demands in the body.

    The resulting chronic build-up of the heart’s ventricles, known as cardiac pressure overload, can contribute to the thickening of heart muscles in the ventricular wall, and the onset of contractile dysfunction2. Although it remains unclear as to how cardiac pressure overload can contribute to contractile dysfunction in the heart, current studies suggest that the culprit lies in the misregulation of intracellular calcium in cardiac myocytes3,4.


    MicroRNA 25. Source: NIH

    Cardiac myocytes are heart cells that undergo synchronous and rhythmic contractions to drive the beating of the heart. These contractions are triggered by the release of intracellular calcium in a process known as excitation-contraction coupling. In this process, electrical stimulation triggers the depolarization of cardiac myocytes, which in turn drives voltage-dependent calcium influx via the L-type calcium channels, followed by the calcium-dependent release of intracellular calcium from the sarcoplasmic reticulum (SR) via ryanodine receptors1,5.

    The released calcium binds to calcium-responsive switches known as troponins and tropomyosins that activate myofilaments, which are actin-myosin assemblies, to produce contractions in cardiac myocytes1,5. While the release of intracellular calcium triggers cardiac myocyte contractions, the active recycling of calcium back into the SR is necessary to terminate contraction in cardiac myocytes and to allow for muscle relaxation 5. 
    In order to maintain a constant rhythm of cardiac muscle contraction and relaxation, the released calcium needs to be actively recycled back into the SR via a calcium-transporting ATPase pump known as SERCA2A. The constant balance of intracellular calcium release and recycling is crucial for sustaining constant cardiac muscle contractions in the steady beating of the heart5.

    One of the most prominent features of cardiac myocytes in heart failure is the downregulation of SERCA2A, which impairs calcium recycling in the SR3,4. Interestingly, cardiovascular diseases are also associated with the downregulation of microRNAs6, which are small RNA sequences that selectively inhibit gene transcription by binding to the 3’untranslated region (UTR) of target messenger RNAs. An interesting question is whether microRNAs might serve as molecular switches that are activated by cardiac pressure overload to trigger heart failure, and whether these microRNAs work by shutting down intracellular calcium recycling in cardiac myocytes.

    In the March 12th online issue of Nature, Wahlquist et al7 discover that microRNA-25 (miR-25) upregulation is associated with cardiac pressure overload in cardiovascular diseases, and is implicated in driving SERCA2A downregulation and the onset of heart failure. The study involves using a genome wide approach to establish that miR-25 is upregulated in human cases of heart failure, as well as in an established mouse model of heart failure triggered by transaortic constriction (TAC).

    The study shows that miR-25 can specifically inhibit SERCA2A expression by targeting the 3’UTR of SERCA2A messenger RNA, and that injection of miR-25-expressing viral vectors in vivo can suppress SERCA2A expression in mouse cardiac myocytes, and consequently disrupt the calcium kinetics involved in cardiac contractions. Furthermore, the inhibition of miR-25 function using antagomirs, which are small engineered oligonucleotides that prevent miR-25 from inhibiting SERCA2A expression, can effectively restore SERCA2A expression and prevent the onset of heart failure in mice following TAC.

    The study suggests that miR-25 is a SERCA2A repressor that is aberrantly expressed in response to cardiac pressure overload, and is responsible for calcium misregulation in cardiac myocytes, and consequently contractile dysfunction and heart failure.

     The discovery of miR-25-SERCA2A pathway provides the first mechanistic link between cardiovascular diseases and heart failure. The study shows that the cardiac pressure overload in cardiovascular diseases can actively suppress the heart’s contractile function by activating miR-25 expression- a molecular switch that triggers the onset of heart failure by upsetting the calcium recycling process in cardiac myocytes. A recent model suggests that the balance in intracellular calcium release and reuptake in cardiac myocytes depends on the heart’s workload, and that this balance is maintained by a complex intracellular network 8.

    Since microRNAs are known to fine-tune complex biological processes by suppressing the expression of key protein modulators9, the study by Wahlquist et al7 provides the first compelling evidence that microRNAs may be part of an intracellular network that controls the calcium balance in cardiac myocytes in relation to the heart’s workload. The study here will pave the way towards further studies to understand how the microRNA network regulates the delicate balance between workload and contractility in the heart, and how this balance is disrupted in cardiovascular diseases. 

     Heart failure is the leading cause of illness and death among the aging population. Although angiotensin inhibitors are the prevalent drug to treat heart failure, there is an urgent need to novel drugs to effectively combat heart failure particularly at its advanced stages10. As an answer to that need, recent preclinical and clinical studies have since demonstrated that gene therapy to restore SERCA2A expression is an effective way to reverse heart failure11,12. Following along these footsteps, Wahlquist et al introduces miR-25 antagomirs as an effective way to reverse heart failure by inhibiting miR-25-mediated SERCA2A suppression.

    MicroRNAs are very attractive therapeutic targets in a drug development standpoint mainly because they are short RNA sequences that can be easily isolated and manipulated13, a feature that can help streamline the development of antagomir-based therapeutics. Moreover, the highly conserved nature of microRNAs can also streamline the transition of therapeutic antagomirs from rodent to human studies. Therefore, the development of miR-25 antagomirs to treat heart failure is an ideal strategy to rapidly generate the much needed treatment for heart failure, and to pave the way towards developing microRNAs as a new class of therapeutics to effectively treat this deadly disease.

    References:

    1. Bers, D. M. Excitation–Contraction Coupling and Cardiac Contractile Force edn 2 (Kluwer Academic,

    Dordrecht, Netherlands, 2001).

    2. Esposito G. et al. Circulation. 105, 85-92 (2002)

    3. Ver Heyen M. et al. Circ Res. 89, 838-46 (2001)

    4. Meyer, M. et al. Circulation 92, 778–784 (1995).

    5. Bers DM. Nature. 415, 198-205. (2002)

    6. Ikeda, S. et al. Physiol. Genomics 31, 367–373 (2007).

    7. Wahlquist, C.  et al. Nature. in press (2014)

    8. Greenstein, J. L.&Winslow, R. L. Circ. Res. 108, 70–84 (2011).

    9. Bartel, D. P. Cell. 136, 215–233 (2009).

    10. Mudd, J. O.&Kass, D. A. Nature. 451, 919–928 (2008).

    11 Jessup, M. et al. Circulation 124, 304–313 (2011).

    12. Kawase, Y. et al. J. Am. Coll. Cardiol. 51, 1112–1119 (2008).

    13. van Rooij E, Purcell AL, Levin AA. Circ Res. 110, 496-507. (2012)