Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.
Cell Mol Biol Lett. 2023 Sep 1;28(1):71. doi: 10.1186/s11658-023-00484-3.
Mechanical pressure overload and other stimuli often contribute to heart hypertrophy, a significant factor in the induction of heart failure. The UDP-glucose ceramide glycosyltransferase (UGCG) enzyme plays a crucial role in the metabolism of sphingolipids through the production of glucosylceramide. However, its role in heart hypertrophy remains unknown. In this study, UGCG was induced in response to pressure overload in vivo and phenylephrine stimulation in vitro. Additionally, UGCG downregulation ameliorated cardiomyocyte hypertrophy, improved cardiomyocyte mitochondrial oxidative stress, and reduced the ERK signaling pathway. Conversely, UGCG overexpression in cardiomyocytes promoted heart hypertrophy development, aggravated mitochondrial oxidative stress, and stimulated ERK signaling. Furthermore, the interaction between beta-1,4-galactosyltransferase 5 (B4GalT5), which catalyses the synthesis of lactosylceramide, and UGCG was identified, which also functions as a synergistic molecule of UGCG. Notably, limiting the expression of B4GalT5 impaired the capacity of UGCG to promote myocardial hypertrophy, suggesting that B4GalT5 acts as an intermediary for UGCG. Overall, this study highlights the potential of UGCG as a modulator of heart hypertrophy, rendering it a potential target for combating heart hypertrophy.
机械压力过载和其他刺激因素常常导致心肌肥厚，这是心力衰竭发生的一个重要因素。UDP-葡萄糖神经酰胺糖基转移酶（UGCG）酶通过产生葡萄糖神经酰胺在神经鞘脂代谢中发挥关键作用。然而，其在心肌肥厚中的作用尚不清楚。在这项研究中，UGCG 在内源性压力过载和苯肾上腺素刺激的体外模型中被诱导。此外，UGCG 的下调改善了心肌细胞肥大，减轻了心肌细胞线粒体氧化应激，并减少了 ERK 信号通路。相反，心肌细胞中 UGCG 的过表达促进了心脏肥大的发展，加重了线粒体氧化应激，并刺激了 ERK 信号。此外，还鉴定出了β-1,4-半乳糖基转移酶 5（B4GalT5）与 UGCG 的相互作用，B4GalT5 催化乳糖神经酰胺的合成，同时也是 UGCG 的协同分子。值得注意的是，限制 B4GalT5 的表达削弱了 UGCG 促进心肌肥大的能力，表明 B4GalT5 作为 UGCG 的中介发挥作用。总的来说，这项研究强调了 UGCG 作为心肌肥厚调节剂的潜力，使其成为对抗心肌肥厚的潜在靶点。
