Inhibition of Glycogen Synthase Kinase 3β During Heart Failure Is Protective

Abstract

Abstract-Glycogen synthase kinase (GSK)-3, a negative regulator of cardiac hypertrophy, is inactivated in failing hearts. To examine the histopathological and functional consequence of the persistent inhibition of GSK-3␤ in the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of dominant negative GSK-3␤ (Tg-GSK-3␤-DN) and tetracycline-regulatable wild-type GSK-3␤. GSK-3␤-DN significantly reduced the kinase activity of endogenous GSK-3␤, inhibited phosphorylation of eukaryotic translation initiation factor 2B, and induced accumulation of ␤-catenin and myeloid cell leukemia-1, confirming that GSK-3␤-DN acts as a dominant negative in vivo. Tg-GSK-3␤-DN exhibited concentric hypertrophy at baseline, accompanied by upregulation of the ␣-myosin heavy chain gene and increases in cardiac function, as evidenced by a significantly greater E max after dobutamine infusion and percentage of contraction in isolated cardiac myocytes, indicating that inhibition of GSK-3␤ induces well-compensated hypertrophy. Although transverse aortic constriction induced a similar increase in hypertrophy in both Tg-GSK-3␤-DN and nontransgenic mice, Tg-GSK-3␤-DN exhibited better left ventricular function and less fibrosis and apoptosis than nontransgenic mice. Induction of the GSK-3␤ transgene in tetracycline-regulatable wild-type GSK-3␤ mice induced left ventricular dysfunction and premature death, accompanied by increases in apoptosis and fibrosis. Overexpression of GSK-3␤-DN in cardiac myocytes inhibited tumor necrosis factor-␣-induced apoptosis, and the antiapoptotic effect of GSK-3␤-DN was abrogated in the absence of myeloid cell leukemia-1. These results suggest that persistent inhibition of GSK-3␤ induces compensatory hypertrophy, inhibits apoptosis and fibrosis, and increases cardiac contractility and that the antiapoptotic effect of GSK-3␤ inhibition is mediated by myeloid cell leukemia-1. Thus, downregulation of GSK-3␤ during heart failure could be compensatory. Key Words: GSK-3␤ Ⅲ heart failure Ⅲ cardiac hypertrophy Ⅲ apoptosis G SK-3␤ is a ubiquitously expressed serine/threonine kinase that has versatile biological functions in cells, including regulation of metabolism, cell growth/death, and protein translation and transcription. 1,2 Unlike most protein kinases, GSK-3␤ remains active in the resting state and is inactivated when cells are stimulated by mitogens, by other protein kinases, such as Akt, or by the Wnt pathway. In cardiac myocytes, GSK-3␤ phosphorylates ␤-catenin, 3 eukaryotic translation initiation factor (eIF)2B, 4 NFAT, 5 GATA4, 6 myocardin, 7 and other proteins, thereby negatively regulating protein synthesis and gene expression. GSK-3␤ downregulates SERCA2a 8 and enhances mitochondrial permeability transition, 9 thereby leading to an inability to normalize cytosolic Ca 2ϩ in diastole and reduced cell survival, respectively.GSK-3␤ is an important negative regulator of cardiac hypertrophy. 10 GSK-3␤ negatively regulates ␤-adrenergic and endothelin-induced cardiac hypertrophy in cultured ...

GSK-3 protein and the heart: friend or foe?

“…In addition, mitochondrial affinity for the anti-apoptotic protein Bcl-2 increased, with more Bcl-2 associated with mitochondria in the presence of GSK-3 inhibition, inferring a pro-apoptotic role for GSK-3. This conclusion is substantiated by the work of Hirotani et al, (83) On the other hand, Nishino et al, (86) using a mouse line lacking the critical N-terminal serine within myocardial GSK-3β (Ser9) as well as Ser21 in GSK-3β, still found protection via preconditioning in the isolated, perfused heart subjected to ischaemia, excluding a role for inhibition of GSK-3 in this phenomenon in the mouse heart as opposed to the findings of Juhaszova in the rat heart. (81) GSK-3 inhibition in the heArt -A tuG-of-WAr?…”

GSK-3α directly regulates β-adrenergic signaling and the response of the heart to hemodynamic stress in mice

“…The role of GSK-3β in cardiac hypertrophy has been examined extensively by several groups, and the vast majority of studies have found that expression of either WT or a constitutively active S9A mutant repressed hypertrophy (8)(9)(10)(11)(12)(13)(14). However, based on studies with overexpression of a dominant inhibitory mutant of GSK-3β, which showed no enhancement of hypertrophy following TAC, it was not clear what role, if any, inhibition of GSK-3β played in the response (12). Findings with GSK-3α have been even less clear.…”

“…This is due to the fact that all studies to date have used transgenesis, knockin of activated mutants, or nonselective small molecule inhibitors (e.g., BIO) (8)(9)(10)(11)(12)(13)(14). None of these strategies allow one to define the true biology of GSK-3s or an understanding of isoform-specific effects.…”

GSK-3.BETA., a Therapeutic Target for Cardiomyocyte Protection

“…99 Apoptosis by these insults was suppressed by overexpression of the adrenomedullin gene 95 or kallikrein gene 96 or treatment with statins, 97 all of which induced phosphorylation of GSK-3β. Furthermore, this protection from apoptosis was inhibited by dominant-negative Akt or active GSK-3β mutant and mimicked by pharmacological inhibitors of GSK-3β.…”