Myocardial hypertrophy is a common precursor of many diseases, and it can lead to myocardial ischemia and weaken cardiac contractility. High-sugar diets and diabetes are high risk factors for cardiac hypertrophy. O-GlcNAcylation, a dynamic and ubiquitous post-translational glycosylation of proteins on serine/threonine residues, has been usually considered as a nutrient sensor. Hyperglycemia, hyperlipidemia, and hyperinsulinemia lead to an enhancement of protein O-GlcNAcylation; however, whether excessive O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation of proteins in cardiomyocytes causes cardiac hypertrophy remains unclear. In this study, we treated cultured primary cardiomyocytes or mice with streptozotocin (STZ) or PUGNAc, two inhibitors of O-GlcNAcase (OGA) to elevate cellular O-GlcNAcylation. We found that increased O-GlcNAcylation induced hypertrophy-like changes by detecting cardiomyocyte morphology or measuring the thickness of mice left ventricular wall with HE staining. The mRNA levels of cardiac hypertrophy–related genes, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC), are increased in drug treatment groups. We further found that the increase of O-GlcNAcylation upregulated the activity of cAMP response element-binding protein (CREB) in cultured primary cells and in vivo by detecting the phosphorylation level of CREB by Western blot and the mRNA levels of CREB downstream targets C-fos and C-jun by RT-qPCR. These results suggest that the increased O-GlcNAcylation in cardiomyocytes is associated with cardiac hypertrophy both in cultured cells and in vivo, which provides possible intervention targets and approaches for the clinical treatment of myocardial hypertrophy triggered by high carbohydrate diets.

心肌肥厚是许多疾病的常见前兆，可导致心肌缺血，减弱心肌收缩力。高糖饮食和糖尿病是心脏肥大的高危因素。O-GlcNAcylation 是一种动态且普遍存在的蛋白质在丝氨酸/苏氨酸残基上的翻译后糖基化，通常被认为是一种营养传感器。高血糖、高脂血症和高胰岛素血症导致蛋白 O-GlcNAcylation 增强；然而，心肌细胞中蛋白质的过度 O-连接 β-N-乙酰氨基葡萄糖 (O-GlcNAc) 糖基化是否会导致心脏肥大仍不清楚。在这项研究中，我们用链脲佐菌素 (STZ) 或 PUGNAc（两种 O-GlcNAcase (OGA) 抑制剂）处理培养的原代心肌细胞或小鼠，以提高细胞 O-GlcNAcylation。我们发现通过检测心肌细胞形态或用 HE 染色测量小鼠左心室壁的厚度，增加的 O-GlcNAcylation 诱导了肥大样变化。在药物治疗组中，心脏肥大相关基因、心房利钠肽 (ANP) 和 β-肌球蛋白重链 (β-MHC) 的 mRNA 水平增加。我们进一步发现O-GlcNAcylation的增加通过Western blot检测CREB的磷酸化水平和CREB下游靶标C- fos 和 C-jun 通过 RT-qPCR。这些结果表明，心肌细胞中 O-GlcNAcylation 的增加与培养细胞和体内的心脏肥大有关，