Elevated expression of the receptor for advanced-glycation endproducts (RAGE) in cardiac tissue is well-known in the elderly, in diabetes mellitus, and after acute cardiac infarction or ischemia/reperfusion injuries. RAGE and its binding partners affect the clinical outcome of heart failure and may play an essential role in accelerating the functional decline in cardiovascular aging. Therefore, hearts of wild-type (WT) C57black6/N and cardiac-specific RAGE-overexpressing transgenic (TR) mice were analyzed for their function by ultrasound at young (4–5 months) and old (22–23 months) ages. Transgenic mice exhibit significantly increased systolic (LVD-sy) and diastolic (LVD-di) diameters of their left ventricles. The left ventricular ejection fraction (EF) was significantly reduced in young male TR mice. Omics of the heart did not reveal direct activation of cytokine-induced inflammation. Instead, energy metabolism-associated genes were enriched in downregulated transcripts and proteins of TR animals, causing decreased ATP production. In a sex-specific manner, there was a reduced expression of the four-and-a-half LIM-domains protein 2 (FHL2). In conclusion, transgene-induced RAGE overexpression, as a model for age- and disease-associated RAGE alteration, leads to a sex-dependent EF decline, in which FHL2 and energy depletion might play crucial roles.

心脏组织中晚期糖基化终产物受体 (RAGE) 的表达升高在老年人、糖尿病和急性心肌梗死或缺血/再灌注损伤后是众所周知的。RAGE 及其结合伙伴影响心力衰竭的临床结果，并可能在加速心血管衰老的功能衰退中发挥重要作用。因此，通过超声分析了野生型 (WT) C57black6/N 和心脏特异性 RAGE 过表达转基因 (TR) 小鼠的心脏在年轻（4-5 个月）和老年（22-23 个月）年龄时的功能。转基因小鼠的左心室收缩 (LVD-sy) 和舒张 (LVD-di) 直径显着增加。年轻雄性 TR 小鼠的左心室射血分数 (EF) 显着降低。心脏组学没有揭示细胞因子诱导的炎症的直接激活。相反，能量代谢相关基因在 TR 动物的下调转录物和蛋白质中富集，导致 ATP 产生减少。以特定性别的方式，四个半 LIM 结构域蛋白 2 (FHL2) 的表达降低。总之，转基因诱导的 RAGE 过表达，作为与年龄和疾病相关的 RAGE 改变的模型，导致性别依赖性 EF 下降，其中 FHL2 和能量消耗可能起关键作用。