AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation

Abstract

AMP-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy. Here, we show that submaximal AMPK activation blocks cardiomyocyte hypertrophy without affecting downstream targets previously suggested to be involved, such as p70 ribosomal S6 protein kinase, calcineurin/nuclear factor of activated T cells (NFAT) and extracellular signal-regulated kinases. Instead, cardiomyocyte hypertrophy is accompanied by increased protein O-GlcNAcylation, which is reversed by AMPK activation. Decreasing O-GlcNAcylation by inhibitors of the glutamine:fructose-6-phosphate aminotransferase (GFAT), blocks cardiomyocyte hypertrophy, mimicking AMPK activation. Conversely, O-GlcNAcylation-inducing agents counteract the anti-hypertrophic effect of AMPK. In vivo, AMPK activation prevents myocardial hypertrophy and the concomitant rise of O-GlcNAcylation in wild-type but not in AMPKα2-deficient mice. Treatment of wild-type mice with O-GlcNAcylation-inducing agents reverses AMPK action. Finally, we demonstrate that AMPK inhibits O-GlcNAcylation by mainly controlling GFAT phosphorylation, thereby reducing O-GlcNAcylation of proteins such as troponin T. We conclude that AMPK activation prevents cardiac hypertrophy predominantly by inhibiting O-GlcNAcylation.

Modeling the Transition From Decompensated to Pathological Hypertrophy

“…Instead, we observed an increase in alternative downstream uses of glucose; in addition to energy production, both our global gene expression and metabolomics analyses suggest that the excess imported glucose may be partially directed toward hexosamine and ECM biosynthesis, protein O‐/N‐GlcNAcylation, and the pentose phosphate shunt (Figure 8). Given that other studies have also observed changes in hexosamine biosynthesis and protein O‐GlcNAcylation in response to alterations in cardiac metabolism36 and hypertrophy,37 further study of these changes is warranted. In addition to the observed diversion of glucose toward alternative downstream fates, glucose metabolism correlated negatively with heart size.…”

Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling

“…Under conditions of chronic stress, however, this prolonged response may lead to adverse consequences. Recently, AMPK was shown to phosphorylate Gfat1 and suppress its enzymatic activity under pressure overload 25 . Indeed, glucose infusion in the heart leads to stimulation of the HBP, which is associated with pathological remodeling 27 .…”

“…Moreover, O-GlcNAc protein modification in hearts is increased in various models of cardiac hypertrophic growth 24 . More recently, Gelinas et al 25 showed that 5′-adenosine monophosphate-activated protein kinase (AMPK) prevents pathological cardiac hypertrophy by promoting Gfat1 phosphorylation and thereby decreasing O-GlcNAc modification in the heart. Despite these findings, it remains to be answered whether the upregulation of HBP by pressure overload plays a causal role in pathological cardiac remodeling.…”

Pharmacological basis and new insights of resveratrol action in the cardiovascular system

“…For instance, both resveratrol and metformin share analogous beneficial effects in counteracting oxidative stress in endothelial cells by activating AMPK (Cheang et al, ). They both can attenuate cardiac hypertrophy by activating AMPK (Gélinas et al, ). In a previous study, resveratrol and metformin may synergistically lower hepatic lipid contents and systolic blood pressure in Type 2 diabetes patients (Timmers et al, ).…”