Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking.
Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking.
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DOI：
10.1093/eurheartj/ehab412
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发表时间：
2021-11-14
影响因子：
39.3
通讯作者：
Levin MC
中科院分区：
文献类型：
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作者：
Andersson L;Cinato M;Mardani I;Miljanovic A;Arif M;Koh A;Lindbom M;Laudette M;Bollano E;Omerovic E;Klevstig M;Henricsson M;Fogelstrand P;Swärd K;Ekstrand M;Levin M;Wikström J;Doran S;Hyötyläinen T;Sinisalu L;Orešič M;Tivesten Å;Adiels M;Bergo MO;Proia R;Mardinoglu A;Jeppsson A;Borén J;Levin MC
心脏损伤和重塑与心脏脂质重排有关。鞘糖脂是对细胞结构和功能重要的膜脂质，并且心功能不全是具有鞘糖脂合成和周转缺陷的罕见单基因疾病的特征。然而，目前尚不清楚心脏鞘糖脂如何调节心脏中的细胞过程。本研究的目的是确定心脏鞘糖脂在心脏功能中的作用。使用人类心肌活检，我们发现，鞘糖脂葡萄糖神经酰胺和乳糖神经酰胺是目前在非常低的水平，在非缺血的人类心脏功能正常，并在重塑过程中升高。在心脏重塑的小鼠模型中观察到类似的结果。我们还产生了心肌细胞特异性缺乏Ugcg（编码葡萄糖神经酰胺合酶的基因）的小鼠（hUgcg -/-小鼠）。在9至10周龄的hUgcg -/-小鼠中，响应多巴酚丁胺应激的收缩能力降低。年龄较大的hUgcg -/-小鼠即使在基线条件下也发生严重的心力衰竭和左心室扩张，并过早死亡。使用RNA-seq和细胞培养模型，我们在Ugcg缺陷的心肌细胞中显示了有缺陷的内溶酶体逆行运输和自噬。我们还发现，在hUgcg -/-小鼠的心肌细胞中，对β-肾上腺素能刺激的反应性降低，并且Ugcg敲低抑制β1-肾上腺素能受体的内化和运输。我们的研究结果表明，心脏鞘糖脂是维持β-肾上腺素能信号传导和心肌细胞收缩能力以及维持正常心脏功能所必需的。 心脏鞘糖脂是维持β-肾上腺素能信号传导和心肌细胞收缩能力以及维持正常心脏功能所必需的。
Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function. Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg –/– mice). In 9- to 10-week-old hUgcg –/– mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg –/– mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg –/– mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors. Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function. Cardiac glycosphingolipids are required to maintain β-adrenergic signaling and contractile capacity in cardiomyocytes and to preserve normal heart function.
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影响因子：
4.5
作者：
Hicks AA;Pramstaller PP;Johansson A;Vitart V;Rudan I;Ugocsai P;Aulchenko Y;Franklin CS;Liebisch G;Erdmann J;Jonasson I;Zorkoltseva IV;Pattaro C;Hayward C;Isaacs A;Hengstenberg C;Campbell S;Gnewuch C;Janssens AC;Kirichenko AV;König IR;Marroni F;Polasek O;Demirkan A;Kolcic I;Schwienbacher C;Igl W;Biloglav Z;Witteman JC;Pichler I;Zaboli G;Axenovich TI;Peters A;Schreiber S;Wichmann HE;Schunkert H;Hastie N;Oostra BA;Wild SH;Meitinger T;Gyllensten U;van Duijn CM;Wilson JF;Wright A;Schmitz G;Campbell H
通讯作者：
Campbell H
影响因子：
20.1
作者：
Curran J;Makara MA;Little SC;Musa H;Liu B;Wu X;Polina I;Alecusan JS;Wright P;Li J;Billman GE;Boyden PA;Gyorke S;Band H;Hund TJ;Mohler PJ
通讯作者：
Mohler PJ
影响因子：
8
作者：
Jean-Charles, Pierre-Yves;Yu, Samuel Mon-Wei;Shenoy, Sudha K.
通讯作者：
Shenoy, Sudha K.
影响因子：
37.8
作者：
Burchfield JS;Xie M;Hill JA
通讯作者：
Hill JA
影响因子：
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作者：
Akhtar, M M;Elliott, P M
通讯作者：
Elliott, P M