As this transporter is regulated by redox reaction we invest

As this transporter is regulated by redox reaction, we investigated whether there was any change in SVCT2 pak4 with age. Our study shows that there is an age dependent decrease in SVCT2 transcript number in old mice femur along with other bone marker such as Collagen type 1, BMP-2, and RUNX2 (data not shown). Similar results were reported in rat liver showing down regulation of SVCT with age (Michels et al., 2003). Liver express both sub-types, SVCT1 and SVCT2, and only SVCT1 significantly down regulated (Michels et al., 2003). Aging is a complicated process and is associated with a number of systemic changes in the body. The changes in SVCT2 expression with age in bone could be a consequence of systemic changes such as an increasingly pro-oxidant environment, redox active metal accumulation, and change in growth hormone and growth factors expression in aged tissues. In aged bone, there is a decrease in osteoblast activity and an increase in osteoclast activity. Oxidative stress increased osteoblast apoptosis and compromises osteoblast differentiation (Wauquier et al., 2009; Almeida et al., 2010). The changes in SVCT2 expression that we observed with age suggest that it could play an important role in bone formation. Thus, future studies should explore the regulation of SVCT2 transporter by redox reaction and age-associated changes in various growth factors and sex steroids.
Acknowledgments Funding for this research was provided in part by the AO Foundation (S-11-12F) and National Institute on Aging (P01AG036675).
Introduction It was recognized some 15years ago that drug-induced block of human Ether-à-go-go Related Gene (hERG) potassium channel, which conducts the rapid component of the delayed rectifier potassium current (IKr), can induce ventricular tachyarrhythmias in the heart known as Torsade de Pointes (TdP). As a result, electrophysiological assays that measure IKr block have since then become standard tools for assessing cardiac hazard (Fermini and Fossa, 2003). Although these adverse drug effects occur only rarely, the impact can be high, with some patients undergoing arrhythmias that are lethal and the drugs responsible being withdrawn from the market. It is therefore of key interest to assess these risks accurately during the early stages of drug development. Regulatory guidelines intended to manage TdP risk through assessing the extent of hERG block and QT prolongation both pre-clinically (ICH S7B) and clinically (ICH E14), turned out to have several shortcomings. For example, not only QT-prolonging drugs but also QT-shortening drugs can have pro-arrhythmic effects (Shah, 2010). In addition, hERG block alone does not capture all compounds that can induce delayed repolarization and TdP (Lu et al., 2008b). These issues can be explained by the fact that repolarization of the cardiac action potential is not only dependent on IKr, but also depends on other potassium currents, including the slow component of the delayed rectifier potassium current, IKs (Li et al., 1996). This is exemplified by the fact that mutations in KCNQ1, the gene that encodes for the channel conducting IKs, can cause the pro-arrhythmic long QT syndrome type 1 (LQTS1) (Moss et al., 2007; Roden and Viswanathan, 2005). Although IKs by itself does not have a major effect on the action potential duration (APD) or QT interval under base-line conditions (Jost et al., 2005; Lengyel et al., 2001; Varró et al., 2000; Volders et al., 2003), accumulating evidence indicates that IKs blocking drugs can be highly torsadogenic (Guérard et al., 2008; Towart et al., 2009). This can be explained by the concept of “repolarization reserve” (Varro and Baczkó, 2011). The idea of repolarization reserve is that the complexity of repolarization, that returns the action potential to its resting state, includes some redundancy. Reduction of one component (such as IKs) ordinarily will not lead to failure of repolarization (i.e. marked action potential prolongation) but individuals with lesions in other components of the system, say IKr, may be sensitized and react strongly (Roden, 1998, 2008). However, IKs function in human cardiac repolarization is still incompletely understood. It is therefore of significant concern that there are several drugs on the market, or in development, which block IKs in addition to IKr and/or INa. Examples of such drugs include the diuretic indapamide (Letsas et al., 2006), the class III anti-arrhythmic azimilide (Davies et al., 1996) (Carlson, 2005) and the anti-arrhythmic vernakalant (Camm and Savelieva, 2008). Furthermore, in addition to direct interaction with outward repolarization currents, compounds can also delay repolarization through other mechanisms. For example, an increase in peak and late sodium current (Lacerda et al., 2008) or in calcium currents can also prolong the action potential/QT interval (Lu et al., 2008a). Taken together, it is clear that the less frequent effects on other ion channels are much more complex and difficult to capture than hERG risks.