Table1_Altered Glycosylation in the Aging Heart.XLSX

Cardiovascular disease is one of the leading causes of death in developed countries. Because the incidence increases exponentially in the aging population, aging is a major risk factor for cardiovascular disease. Cardiac hypertrophy, fibrosis and inflammation are typical hallmarks of the aged heart. The molecular mechanisms, however, are poorly understood. Because glycosylation is one of the most common post-translational protein modifications and can affect biological properties and functions of proteins, we here provide the first analysis of the cardiac glycoproteome of mice at different ages. Western blot as well as MALDI-TOF based glycome analysis suggest that high-mannose N-glycans increase with age. In agreement, we found an age-related regulation of GMPPB, the enzyme, which facilitates the supply of the sugar-donor GDP-mannose. Glycoprotein pull-downs from heart lysates of young, middle-aged and old mice in combination with quantitative mass spectrometry bolster widespread alterations of the cardiac glycoproteome. Major hits are glycoproteins related to the extracellular matrix and Ca2+-binding proteins of the endoplasmic reticulum. We propose that changes in the heart glycoproteome likely contribute to the age-related functional decline of the cardiovascular system.

心血管疾病是发达国家中导致死亡的主要原因之一。鉴于其在老龄化人口中的发病率呈指数级增长，衰老已成为心血管疾病的主要风险因素。心脏肥大、纤维化和炎症是老年心脏的典型特征。然而，其分子机制却鲜为人知。鉴于糖基化是蛋白质翻译后最常见的修饰方式之一，并能影响蛋白质的生物特性和功能，本研究首次对不同年龄小鼠的心脏糖蛋白组进行了分析。Western blot以及基于MALDI-TOF的糖组分析表明，高甘露糖N-聚糖的浓度随年龄增长而增加。与此一致，我们发现GMPPB酶（一种促进糖供体GDP-甘露糖供应的酶）的表达受到年龄相关调控。结合年轻、中年和老年小鼠心脏裂解物的糖蛋白沉淀以及定量质谱分析，我们证实了心脏糖蛋白组的广泛变化。主要影响的是与细胞外基质相关的糖蛋白以及内质网Ca2+结合蛋白。我们提出，心脏糖蛋白组的变化可能导致了心血管系统随着年龄增长而出现的功能衰退。