Gender-dependent drop of cardiac function driven by chronic geriatric-associated RAGE overexpression

An overexpression 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 binding partners affect the clinical outcome of heart failure and may play an important role by accelerating cardiovascular age-decline. Therefore, hearts of wild type (WT) C57black6/N and cardiac-specific RAGE-overexpressing transgenic (TR) mice were investigated for function by ultrasound at young (4 5 months) and old (22 23 months) ages. Omics were performed to detect molecular candidates contributing to the encountered elderly-like phenotype, followed by target validation of ATP production and protein expression. Transgenic mice exhibit significantly increased systolic (LVD sy) as well as diastolic (LVD di) diameters. The left ventricular ejection fraction (EF) is significantly reduced in young TR male mice. Overexpression of RAGE did not result in activation of inflammation but altered energy-associated pathways in transcriptomics and proteomics. Indeed, the mitochondrial energy allocation was diminished in TR animals. Gender differences might be influenced by an altered expression of the four and a half LIM domains protein 2 (FHL2). Geriatric associated RAGE-overexpression contribute to cardiac EF decrease by energy reduction and may help to understand sex differences in the development of cardiovascular diseases.