Not All Hypertrophy Is Created Equal

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See related article, pages 1164–1174 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-3β (GSK-3β) is an important negative regulator of cardiomyocyte hypertrophy, yet inhibition of GSK-3β 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-3β 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, α and β. 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-3β has been implicated in the pathogenesis of many human diseases including Alzheimer disease, diabetes, and tumorgenesis.4–8 GSK-3α (51 kDa) is the larger of the two and has a glycine-rich N terminus of unknown function. GSK-3β (47 kDa) and α share significant sequence homology (97%) in their kinase domains, however the homology between the …