Sex-dependent deterioration of cardiac function and molecular alterations in age- and disease-associated RAGE overexpression

Abstract

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.