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    The Role of Phospholamban in Heart Failure

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    Lora Maxwell - University of Leeds

     

     

     

    A pair of phospho-specific antibodies to PLN were first described in 1994 [1]. These have been in continual use by the entire cardiac excitation-contraction coupling research community since that time, and have underpinned a series of discoveries concerning the aetiology and potential management of heart failure.

     

    In the early days, research focused on defining the normal physiological situation in the heart and the role of PLN phosphorylation in the response to stress. PLN is a small transmembrane protein expressed in the sarcoplasmic reticulum (SR) of cardiac myocytes, which interacts with the Ca2+-pump of the SR and inhibits Ca2+ transport by this pump. This inhibition is relieved upon PLN phosphorylation at Ser-16 or Thr-17 sites, Ca2+-transport into the SR is accelerated and the contraction cycle quickens and generates more force [2-4].

     

    Next, the focus turned to a comparison between normal and disease states in an effort to define the molecular basis of dysfunction. These studies were performed in many mammalian species, including man, and found that PLN was overbearing in heart failure. PLN concentration was maintained, whilst its state of phosphorylation was reduced [4-6]. At the same time SERCA expression was reduced, and thus Ca2+-pumping was reduced by both the relative lack of SERCA and the relative overbearing activity of dephosphorylated PLN [7-12]. This combination underpinned small Ca2+-transients in the myocytes, leading to low contractile force and slow kinetics: phenomena central to the poor muscle performance in this disease. It should be noted this pattern of changes in protein abundance was not universally observed, with existing reports of unchanged levels of PLN and SERCA in HF [5, 6, 13, 14].

     

    Low phosphorylation of PLN makes it overbearing in HF

    What prompts low PLN phosphorylation in HF? HF is a disorder of low contractile performance of the heart. The fight or flight response (or sympathetic drive) is a response deployed to increase muscle performance at times of stress. In HF, this normally transient response is deployed chronically as the muscle is underperforming chronically. Beta-adrenergic receptors (the target of sympathetic ligands epinephrine and nor-epinephrine) are down-regulated in the plasma membrane, a consequence of the chronic exposure to ligand [13]. This reduces the stimulus for Ser-16 phosphorylation of PLN. In addition, the protein phosphatases focused on PLN (PP1, PP2A, and calcineurin (PP2B)) are up-regulated [5, 13, 15, 16] and the natural inhibitors of these phosphatases are down-regulated [17]. These adaptations together suppress the phosphorylation of PLN at Ser-16 and Thr-17 and suppress Ca2+-pump performance. This cascade of events is summarized in Figure 1.

     

    Following establishment of the molecular basis underlying heart failure, research turned to new therapeutic approaches. Benefits have accrued from strategies that inhibit PLN function, strategies that increase PLN phosphorylation, and strategies that increase SERCA expression.

     

     

     

    Figure 1. Involvement of Protein Phosphatases (PP’s) and their inhibitors (PPI’s) in HF.

     

    Strategies that depress PLN expression relative to SERCA include exercise training (ET), ET in combination with beta blocker use, [10, 18, 19] and gene transfer inhibiting overexpression of PLN [11].

     

    Approaches that have allowed us to enhance phosphorylation of PLN include targeted inhibition of protein phosphatases delivered by increased expression of their natural inhibitors [17]. Other therapies increasing PLN phosphorylation include: B-type natriuretic peptide (BNP) infusion combined with b-blocker use [20], gene transfer, exercise training (ET) alone and ET in combination with beta-blocker.

     

    The final strategy which is closest to clinical application, bypasses PLN altogether, and increases the concentration of SERCA protein in cardiac muscle cells by gene therapy. A clinical trial led by Roger Hajjar in New York (CUPID2 study: Calcium Up-regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b) is currently underway.

     

    Clinical trials involving SERCA2 gene therapy in humans

    This trial is exploring the ability of a single intracoronary infusion of DRP AAV1/SERCA2a to improve the clinical outcome in HF patients with reduced ejection fraction [21]. Enhanced SERCA2 expression in the heart appears safe (in man) and improves left ventricular function, whilst reducing cardiovascular events. Completion of the phase 2b trial is expected by mid2015 [21].

     

    Over the last 21 years, our knowledge and understanding of the role of PLN and its modulation of sarcoplasmic reticulum (SR) function has advanced significantly. It is clear that PLN modulation appears to be of paramount importance in humans, and further detailed investigation into PLN function may provide insights into its potential as a therapeutic target in heart failure. Many challenges remain but patients with heart disease will benefit from the worldwide research effort and together we look forward to another 21 years of innovative PLN discoveries.

     

    References

    1. Drago, G.A. and J. Colyer, Discrimination between 2 sites of phosphorylation on adjacent amino-acids by phosphorylation site-specific antibodies to phospholamban. Journal of Biological Chemistry, 1994. 269(40): p. 25073-25077. 
    2. Simmerman, H.K. and L.R. Jones, Phospholamban: protein structure, mechanism of action, and role in cardiac function. Physiol Rev, 1998. 78(4): p. 921-47. 
    3. Kaumann, A., et al., Activation of beta2-adrenergic receptors hastens relaxation and mediates phosphorylation of phospholamban, troponin I, and C-protein in ventricular myocardium from patients with terminal heart failure. Circulation, 1999. 99(1): p. 65-72. 
    4. Munch, G., et al., SERCA2a activity correlates with the force-frequency relationship in human myocardium. Am J Physiol Heart Circ Physiol, 2000. 278(6): p. H1924-32. 
    5. Sande, J.B., et al., Reduced level of serine(16) phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity. Cardiovascular Research, 2002. 53(2): p. 382-391. 
    6. Brixius, K., et al., Ser16-, but not Thr17-phosohorylation of phospholamban influences frequency-dependent force generation in human myocardium. European Heart Journal, 2003. 24: p. 16-16.
    7. Michael, A., et al., Glycogen synthase kinase-3beta regulates growth, calcium homeostasis, and diastolic function in the heart. J Biol Chem, 2004. 279(20): p. 21383-93. 
    8. Mishra, S., et al., Reduced sarcoplasmic reticulum Ca2+ uptake and increased Na+-Ca2+ exchanger expression in left ventricle myocardium of dogs with progression of heart failure. Heart Vessels, 2005. 20(1): p. 23-32. 
    9. Quaile, M.P., et al., Reduced sarcoplasmic reticulum Ca(2+) load mediates impaired contractile reserve in right ventricular pressure overload. J Mol Cell Cardiol, 2007. 43(5): p. 552-63. 
    10. Rolim, N.P., et al., Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure. Physiol Genomics, 2007. 29(3): p. 246-52. 
    11. Zhao, X.Y., et al., rAAV-asPLB transfer attenuates abnormal sarcoplasmic reticulum Ca2+ -ATPase activity and cardiac dysfunction in rats with myocardial infarction. Eur J Heart Fail, 2008. 10(1): p. 47-54. 
    12. Jiao, Q.B., et al., Sarcalumenin plays a critical role in age-related cardiac dysfunction due to decreases in SERCA2a expression and activity. Cell Calcium, 2012. 51(1): p. 31-39. 
    13. Briston, S.J., et al., Impaired beta-adrenergic responsiveness accentuates dysfunctional excitation-contraction coupling in an ovine model of tachypacing-induced heart failure. J Physiol, 2011. 589(Pt 6): p. 1367-82. 
    14. Munch, G., et al., Evidence for calcineurin-mediated regulation of SERCA 2a activity in human myocardium. J Mol Cell Cardiol, 2002. 34(3): p. 321-34. 
    15. Boknik, P., et al., Protein phosphatase activity is increased in a rat model of long-term beta-adrenergic stimulation. Naunyn-Schmiedebergs Archives of Pharmacology, 2000. 362(3): p. 222-231. 
    16. Munch, G., et al., Evidence for calcineurin-mediated regulation of SERCA 2a activity in human myocardium. Journal of Molecular and Cellular Cardiology, 2002. 34(3): p. 321-334. 
    17. El-Armouche, A., et al., Ouabain treatment is associated with upregulation of phosphatase inhibitor-1 and Na+/Ca2+-exchanger and β-adrenergic sensitization in rat hearts. Biochemical and Biophysical Research Communications, 2004. 318(1): p. 219-226. 
    18. Medeiros, A., et al., Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice. J Appl Physiol (1985), 2008. 104(1): p. 103-9. 
    19. Vanzelli, A.S., et al., Integrative Effect of Carvedilol and Aerobic Exercise Training Therapies on Improving Cardiac Contractility and Remodeling in Heart Failure Mice. Plos One, 2013. 8(5). 
    20. Thireau, J., et al., beta- Adrenergic blockade combined with subcutaneous B-type natriuretic peptide: a promising approach to reduce ventricular arrhythmia in heart failure? Heart, 2014. 100(11): p. 833-841. 
    21. Greenberg, B., et al., Design of a Phase 2b Trial of Intracoronary Administration of AAV1/SERCA2a in Patients With Advanced Heart FailureThe CUPID 2 Trial (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b). JACC: Heart Failure, 2014. 2(1): p. 84-92.

     

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