Gélinas Roselle, Mailleux Florence, Dontaine Justine, Bultot Laurent, Demeulder Bénédicte, Ginion Audrey, Daskalopoulos Evangelos P, Esfahani Hrag, Dubois-Deruy Emilie, Lauzier Benjamin, Gauthier Chantal, Olson Aaron K, Bouchard Bertrand, Des Rosiers Christine, Viollet Benoit, Sakamoto Kei, Balligand Jean-Luc, Vanoverschelde Jean-Louis, Beauloye Christophe, Horman Sandrine, Bertrand Luc
Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium.
Pole of Pharmacotherapy, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium.
Nat Commun. 2018 Jan 25;9(1):374. doi: 10.1038/s41467-017-02795-4.
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.
已有研究表明，AMP激活的蛋白激酶（AMPK）可抑制心肌肥大。在此，我们发现亚最大程度的AMPK激活可阻断心肌细胞肥大，而不影响先前认为与之相关的下游靶点，如p70核糖体S6蛋白激酶、钙调神经磷酸酶/活化T细胞核因子（NFAT）和细胞外信号调节激酶。相反，心肌细胞肥大伴随着蛋白质O-连接的N-乙酰葡糖胺化（O-GlcNAcylation）增加，而AMPK激活可使其逆转。用谷氨酰胺：6-磷酸果糖氨基转移酶（GFAT）抑制剂降低O-GlcNAcylation可阻断心肌细胞肥大，模拟AMPK激活。相反，诱导O-GlcNAcylation的试剂可抵消AMPK的抗肥大作用。在体内，AMPK激活可预防野生型小鼠的心肌肥大以及随之而来的O-GlcNAcylation升高，但在AMPKα2缺陷小鼠中则不然。用诱导O-GlcNAcylation的试剂处理野生型小鼠可逆转AMPK的作用。最后，我们证明AMPK主要通过控制GFAT磷酸化来抑制O-GlcNAcylation，从而减少肌钙蛋白T等蛋白质的O-GlcNAcylation。我们得出结论，AMPK激活主要通过抑制O-GlcNAcylation来预防心肌肥大。
