Manipulating Intracellular Calcium to Prevent Cardiac Pathologies

COMMENTARY Return of calcium: Manipulating intracellular calcium to prevent cardiac pathologies Yibin Wang*†‡ and Joshua I. Goldhaber†‡ Departments of *Anesthesiology and †Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 eart failure resulting from isch- cal membrane currents. A variety of ion function is a common finding in heart emia͞reperfusion and other channels, ATP-dependent pumps, and failure (23). Thus, all aspects of calcium forms of injury is characterized transporter proteins serve as the major cycling are inviting targets for antiarrhyth- H by a variety of pathological control points of calcium regulation in the mic strategies. manifestations, including cellular hypertro- heart, including L-type calcium channels Overexpressing SERCA dramatically phy, contractile dysfunction, and electrical and ryanodine receptors (RyR) for cal- alters the balance between the major cal- instability. Abnormal calcium signaling cium entry and release from SR, as well cium-handling proteins. Like digoxin, leading to cytoplasmic calcium overload is as SERCA and sodium–calcium ex- SERCA overexpression favors sequestra- thought to be a critical and perhaps com- changer (NCX) for calcium uptake or ex- tion of calcium by the SR instead of being mon mechanism underlying these abnor- trusion (see Fig. 1 for details) (8–10). extruded by the NCX. What are the im- malities. Since the 1980s, it has been plications of this larger SR store for E–C known that inhibition of cardiac metabo- Calcium-Mediated Arrhythmias coupling and arrhythmogenesis? Eisner et lism leads to increased intracellular cal- The role of abnormal calcium signaling in al. (24) have pointed out that although a cium (1), and that pharmacologic thera- the genesis of cardiac arrhythmias has larger SR store will initially lead to an pies aimed at blocking calcium entry into generated considerable interest over the increase in the calcium transient, autoreg- cells not only reduce cellular injury (2), past three decades [for review, see Clusin ulation is ensured by (i) more rapid inacti- but also decrease the frequency of ventric- (11)]. The classic calcium-mediated ar- vation of subsequent calcium currents and, ular arrhythmias (3). More recently, stud- rhythmia is produced by excessive doses of therefore, (ii) reduced calcium entry ies using targeted genetic approaches have cardiac glycosides such as digitalis. These through L-type calcium channels. The net demonstrated that manipulating cardiomy- agents work by raising intracellular so- effect is to reduce transarcolemmal cal- ocyte calcium handling can prevent or dium, which in turn reduces calcium ef- cium flux while maintaining a normal sys- reduce the progression of hypertrophy and flux by the NCX, and thus favors net tolic transient. Thus, one might expect cardiac dysfunction associated with aging, calcium uptake by the SR (12). At toxic SERCA overexpression to reduce the L- ischemia, reperfusion, and pressure over- doses, cardiac glycosides produce calcium type current, recapitulating the effects of load [see Sobie et al. (4) for review] but overload of the SR, which results in spon- calcium channel blockade on arrhythmia have also raised concerns about the po- taneous release of calcium by RyRs, prevention. Further experiments will be tential for worsening heart failure (5, 6). thereby generating a depolarizing inward required to test this hypothesis. In a recent issue of PNAS, del Monte et current mediated by NCX (which is elec- Is it advantageous to genetically in- al. (7) use a genetic strategy to modify trogenic, exchanging three Naϩ ions for crease SERCA activity rather than cellular calcium handling during ischemia one Ca2ϩ ion) (13). These spontaneous directly blocking the L-type calcium by overexpressing sarcoplasmic reticulum events are known as delayed afterdepolar- channel? One potential advantage is the ATPase via an adenovirus vector. Similar izations (DADs), and they underlie so- preservation of blood pressure, a key limi- to pharmacologic strategies for reducing called triggered arrhythmias seen in tation to the clinical utility of calcium cytosolic free calcium, such as calcium some heart failure models (14, 15). NCX channel blockers, which are not unequivo- channel blockers and beta-blockers, up-regulation during heart failure further cally beneficial in humans with ischemic SERCA overexpression not only reduces increases the likelihood of effective de- syndromes (11). Another advantage of infarct size and preserves cardiac function, polarization by spontaneous SR calcium SERCA overexpression is superior relax- but also reduces arrhythmia frequency. release (15). DADs may also be generated ation kinetics of the calcium transient, The success of this approach once again under conditions of abnormal diastolic which protects the diastolic filling period supports the long-held notion that calcium calcium leak through hyperphosphorylated and thus limits the duration of exposure cycling is an important therapeutic target RyRs, such as may occur in the setting of of cytosolic components to elevated cal- to prevent the deleterious consequences heart failure (16) or in rare familial ar- cium. It is also possible that increased in- of ischemia͞reperfusion injury. rhythmias associated with RyR missense activation of the L-type calcium current in mutations (17). Early afterdepolarizations the setting of the increased SR calcium Calcium Cycling and Normal Cardiac (EADs) are another source of arrhyth- load due to SERCA overexpression may Function mias, caused by prolonged action poten- reduce the likelihood of action potential Carefully regulated calcium cycling is criti- tials (due to failure of inward Naϩ alternans, and thus reduce the propensity cal for cardiac function, which depends on currents to inactivate or failure of outward for reentry. The potential benefits of the calcium concentration surrounding the Kϩ currents to activate) caused by drugs improving SR calcium uptake are also myofilaments rising and falling in a cyclic or mutation-induced dysfunction of Naϩ supported by a string of recent successes manner in response to membrane depo- or Kϩ channels (18), thus allowing exces- targeting the same machinery. Inactivation larization. Insufficient calcium delivery sive calcium entry through L-type calcium to the myofilaments results in a weak channels (19, 20). Finally, abnormal See companion article on page 5622 in issue 15 of vol- contraction, whereas excessive calcium de- calcium cycling by the SR has been impli- ume 101. livery carries the risk of contracture, cated in the pathogenesis of action poten- ‡To whom correspondence may be addressed. activation of proteases and other maladap- tial alternans (21) and spiral wave E-mail: [email protected] or jgoldhaber@ tive calcium-sensitive pathways that lead break-up leading to the development of mednet.ucla.edu. to cell death, and generation of pathologi- ventricular fibrillation (22). SERCA dys- © 2004 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0401518101 PNAS ͉ April 20, 2004 ͉ vol. 101 ͉ no. 16 ͉ 5697–5698 Downloaded by guest on October 2, 2021 of phospholamban (PLB), an endogenous inhibitor of SERCA, has been shown to prevent or ‘‘rescue’’ the pathological phe- notype in some (25–28), but not all, models of heart failure (6). Risks of SERCA Overexpression Despite the significant promises brought by the success of the gene therapy approach described in this report, it is wise to take a cautionary note when we at- tempt to translate the observation made in rodents into human clinics. Significant differences do exist between them in terms of the regulatory mechanisms of calcium cycling, the relative contribution of SR calcium vs. L-type calcium channel mediated calcium entry to total intracellular calcium, and the triggering factors for ventricular arrhythmia. These differences make it difficult to predict the outcome of SR calcium manipulation perceived from small animal models. Indeed, PLB inacti- Fig. 1. Major control points for calcium in cardiac myocytes. A small amount of calcium enters cells through the L-type calcium channel (LTCC), triggering release of a much larger amount of calcium from vation, although apparently beneficial in the sarcoplasmic reticulum (SR) through ryanodine receptors (RyR). Most of the calcium is pumped back rodent models of heart failure, appears to into the SR by SERCA2a, and the rest is extruded from the cell by the NCX. Calcium uptake by SERCA is be deleterious in humans with a familial regulated by the inhibitory protein phospholamban (PLB), which is dependent on signaling pathways form of heart failure characterized by de- involving PKC␣, PP1, and PKA. At the end of the cardiac cycle, calcium efﬂux must balance calcium inﬂux. fective PLB (5). There are also potential del Monte et al. (7) show that in the setting of ischemia͞reperfusion injury, overexpression of SERCA2a inherent risks to SERCA overexpression, hastens removal of calcium from the cytosol and reduces cell death, contractile dysfunction, and arrhyth- particularly the risk of SR calcium over- mias. load. SR calcium overload, as in the case of digitalis toxicity, is clearly proarrhyth- reperfusion, apoptosis, and remodeling. mic. In addition, when using genetic ap- assessed. A better gene delivery system Nevertheless, we can view this as yet an- proaches to arrhythmia management one with efficient and prolonged expression is

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