You have full access to this article via your institution. Download PDF A recent study shows that a novel approach to gene therapy for heart failure, which focuses on restoring S100A1 to

normal levels, works in a rat model. These striking results might pave the way for future clinical trials. Congestive heart failure is a disease that has reached epidemic proportions in the

US and Europe, and even though novel pharmacological agents and devices have improved survival, a real cure has been elusive so far. In the last 10 years, with the availability for study of

explanted failing human hearts at the time of cardiac transplantation and numerous transgenic and knockout models of heart failure, our understanding of the pathogenesis of heart failure has

calcium-binding protein, S100A1, improves calcium (Ca2+) cycling in a rat model of heart failure and normalizes many contractile parameters.2 Calcium movement is central to the process of

excitation–contraction coupling in cardiac myocytes.3 Membrane depolarization results in the entry of calcium via the L-type calcium channel (see Figure 1a). This triggers release of

intracellular stores of calcium from the sarcoplasmic reticulum (SR) via the cardiac ryanodine receptors (RYR), which are calcium-release channels. The resulting rise in intracellular

calcium causes myofilament activation and muscle contraction. Conversely, a fall in intracellular calcium initiates relaxation. Two factors drive the drop in intracellular Ca2+ that

initiates relaxation: reuptake into the SR via SR Ca2+-ATPase (SERCA2a) and the pumping of Ca2+ out of the cell in exchange for Na+ via the sodium–calcium exchanger (NCX). Phospholamban,

which in its unphosphorylated state inhibits SERCA2a, influences the Ca2+-pumping activity of SERCA2a. So what goes wrong with Ca2+ cycling during heart failure? Studies in single

cardiomyocytes isolated from failing human hearts have revealed a decrease in SERCA2a protein levels and activity and an uncoupling of the L-type Ca2+ channels from the RYR due to

hyperphosphorylation of the RYR.4, 5 There is also an augmentation in NCX and an increase in intracellular Na+.6, 7 These changes in Ca2+-cycling proteins shown in Figure 1a result in a

prolongation of the calcium transient, an increase in diastolic Ca2+, a decrease in systolic Ca2+ and a reduced SR Ca2+ content. The failing heart is further burdened by having a decreased

energy supply due to deficient creatine kinase activity and by an inefficient usage of the diminished energy it has available.8 Previous gene therapy studies have shown just how important

these changes in Ca2+-cycling proteins are to contractile dysfunction in the failing heart. In particular, restoration of SERCA2a by gene transfer improved contractility, energetics and

survival, while decreasing arrhythmias in animal models of heart failure.9, 10, 11, 12, 13 Interestingly, clinically used pharmacological agents that increase cAMP to increase contractility

(inotropic agents) in heart failure induce worsening energetic imbalance, arrhythmias and worsening survival.14, 15 In fact, these types of agents have been shown to worsen morbidity and

mortality in patients with heart failure. Therefore, gene therapy strategies that specifically target Ca2+ cycling in heart failure might have great advantage over standard inotropic agents.

The delivery of S100A1 transgenes to failing myocytes is one such strategy. S100A1 is a member of a multigenic family of low molecular weight Ca2+-cycling proteins, which is abundantly

expressed in the myocardium with multiple intracellular targets.16 In heart failure, the expression of S100A1 is reduced. Now, the authors of this new study show that its transgene-induced

overexpression increases SERCA2a and RYR activities, decreases intracellular Na+ concentration and NCX activity, and restores intracellular creatine phosphate levels (Figure 1b). Moreover,

these changes lead to improved intracellular calcium handling and overall enhanced systolic and diastolic ventricular function in rats following cryoinfarction.2 While encouraging, the

results of this study still leave unanswered a number of questions about the applicability of such strategies in humans. First-generation adenoviruses were used to induce the expression of

S100A1 and the time points studied following gene transfer were relatively short. Further studies using adeno-associated vectors for long-term expression would be useful. In addition, large

animal studies are warranted since the response to enhancing Ca2+ cycling may be very different between rodents and mammals. The contribution of SERCA2a and NCX for lowering cytosolic Ca2+

varies with species. In humans, ∼75% of the Ca2+ is removed by SERCA2a and ∼25% by the Na+/Ca2+ exchanger, whereas in rodents close to 95% is removed by SERCA2a.3 Furthermore, the potential

of S100A1 overexpression to cause arrthymia was not assessed. Finally, S100A1 has multiple targets within the cardiac cell, and, even though overall Ca2+ cycling is improved, the effects on

all targets should be carefully dissected. This last point is particularly important since S100A1 is expressed in multiple tissues and the effects of its overexpression in other organs are

unknown. Overall, this is a significant study showing that molecular targeting enhances Ca2+ cycling and so increases contractility in the failing heart. This type of strategy, once tested

with novel vectors and cardiac-specific promoters in large animals, may represent a novel treatment for the failing heart, which will ultimately lead to clinical trials in gene therapy for

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CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Cardiology Laboratory of Integrative Physiology & Imaging at the Cardiovascular Research Center,

Massachusetts General Hospital, 149 13th Street, CNY 4 Room 4215, Charlestown, MA, 02129-2060, USA R J Hajjar Authors * R J Hajjar View author publications You can also search for this

author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to R J Hajjar. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hajjar, R. Cardiac gene

therapy: Kick-starting calcium cycling in rats. _Gene Ther_ 12, 730–732 (2005). https://doi.org/10.1038/sj.gt.3302499 Download citation * Published: 24 February 2005 * Issue Date: 01 May

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