Not all hypertrophy is created equal.

Cardiac hypertrophy is the natural response of myocardium to various stressors, including neurohormonal stimuli, hemodynamic overload, and injury. In the face of continued stress, pathological hypertrophy progresses to a loss of cardiomyocytes, the development of fibrosis, and, ultimately, heart failure. Emerging evidence has shown that glycogen synthase kinase-3 (GSK-3 ) is an important negative regulator of cardiomyocyte hypertrophy, yet inhibition of GSK-3 has been shown to reduce cell death after ischemia reperfusion. Therefore, it has been difficult to predict what the consequences of chronic inhibition of GSK-3 in the heart would be because it might be a balance between the potential for the aggravation of cardiac hypertrophy versus antiapoptotic effects. In this issue of Circulation Research, Hirotani and colleagues report that sustained inhibition of GSK-3 in postneonatal hearts results in well-compensated “physiologic” cardiac hypertrophy and, most intriguingly, exerts protective effects against the development of “pathological” hypertrophy and heart failure with pressure overload.1 Although there are a number of concerns that need to be addressed before targeting GSK-3 for the treatment of heart failure, this “best of both worlds” outcome provides an interesting and favorable rationale for such intervention. The GSK-3 family of protein kinases is encoded by 2 genes, and . They are highly conserved throughout evolution and are critical to the regulation of diverse biological processes ranging from organ development to cell death, including cell growth, cell cycling, cytoskeletal organization, and metabolism.2,3 Furthermore, dysregulation of GSK-3 has been implicated in the pathogenesis of many human diseases including Alzheimer disease, diabetes, and tumorgenesis.4–8 GSK-3 (51 kDa) is the larger of the two and has a glycine-rich N terminus of unknown function. GSK-3 (47 kDa) and share significant sequence homology (97%) in their kinase domains, however the homology between the last 76 C-terminal resides is rather low (36%).3 Both isoforms are widely expressed, but the majority of prior investigations have focused on the role of GSK-3 . This bias likely arose from studies in Drosophila that may have erroneously identified GSK-3 as the dominant isoform.9 Although these two isoforms typically share substrates, the pattern of their expression, substrate preference, and biological function are not always the same.9,10 For example, embryonic lethality, attributable to marked hepatic apoptosis, occurred in mice lacking GSK-3 , suggesting that GSK-3 plays a dominant role during liver development.11 In contrast, and appear to be completely redundant in the regulation of -catenin, the downstream effector of the canonical Wnt pathway, because deletion of both alleles or both alleles had no effect on -catenin expression or function.9 Unlike most kinases, under unstimulated conditions, GSK-3s are active and phosphorylate downstream targets, including -catenin, NF-AT family members, c-Jun, cyclin D1, c-myc, and the protein translation factor, eIF2B , with subsequent repression of activity of these targets. On phosphorylation (at serine 21 for and serine 9 for ) by its upstream kinases including Akt, PKC, and PKA, GSK-3 is inactived and the repression is relieved (Figure, A). The other important mechanism of GSK-3 regulation, recruited by Wnt signaling, likely does not involve phosphorylation of Ser 9/21 because mice with knock-ins of GSK-3 with mutations at Ser 9 and 21, preventing phosphorylation, demonstrated normal inhibition of GSK-3 as evidenced by normal activation of -catenin signaling. This mechanism is not well-defined but involves modulation of GSK-3 activity by the scaffolding protein Axin and by Disheveled (Figure, B). In brief, this mechanism leads to disruption of the Axin complex by Disheveled-mediated displacement of GSK-3, thereby limiting the accessibility of GSK-3 to -catenin.12 On the other hand, the protein interactions among PKA, GSK-3 , and AKAP 220 (A-kinase anchoring protein) regulate the ability of PKA to phosphorylate GSK-3 .13 Of note the PKA-mediated inhibition of GSK-3 may be critical to the response to -adrenergic stimulation in cardiomyocytes. Among the diverse upstream kinases, Akt seems to be the major kinase regulating inhibition of GSK-3 in response to various hypertrophic stimuli, including IGF-1, angiotensin II, endothelin-1, and -adrenergic stimulation (For review, see14). The role of GSK-3 in regulating cardiac hypertrophy has been extensively investigated both in vitro and in animal models by several groups (for review, see15–17). It had been demonstrated some years ago that hypertrophic stimuli led to phosphorylation and inhibition of GSK-3 both in vitro and in vivo.18,19 Overexpression of mutant GSK-3 (GSK-3 S9A) that is resistant to inhibitory phosphorylation has been shown to attenuate the development of aortic banding-induced hypertrophy, suggesting that the inhibition of GSK-3 is necessary for the development of pathologic stress-induced cardiomyocyte hypertrophy.18–20 Furthermore, inhibition of GSK-3 is also necessary for normal cardiomyocyte The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Cardiac Muscle Research Laboratory (R.L.), Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and the Center for Translational Medicine (T.F.), Jefferson Medical College, Philadelphia, Pa. Correspondence to Dr Ronglih Liao, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 431, Boston, MA 02115. E-mail [email protected]; and Dr Thomas Force, Center for Translational Medicine, Jefferson Medical College, 1025 Walnut St, room 316, Philadelphia, PA 19107. E-mail [email protected] (Circ Res. 2007;101:1069-1072.) © 2007 American Heart Association, Inc.