Effects of RAGE Overexpression on Heart Function in Mice Depend on Age and Sex

Objectives: The upregulation of the receptor for advanced-glycation end products (RAGE) in cardiac tissue is a well-known effect observed after injuries, in diabetic situation as well as in elderly patients. RAGE and binding partners affect the clinical outcome for heart failure (HF) in several ways and may play an important role while accelerating cardiovascular disease.

Methods: Female and male wild-type (WT) C57black6/N mice were compared with cardiac specific RAGE overexpressing transgenic (TR) animals in a genetic wild-type background by ultrasound at young (4–5 months) and old (22–23 months) age. Transcriptomics as well as proteomics of young WT and TR mice were performed to investigate the biological targets of the phenotypical clinical outcome. To avoid systematical errors a third group of age and litter independent animals was evaluated for the target validation by ATP-production and immunoblot.

Result: Our functional studies revealed that excessive RAGE levels lead to an increased heart dilatation like phenotype comparable to old animals in a gender-determined manner. RAGE abates the oxidative phosphorylation and reduces FHL2 protein expression male specific. Further, chanced FHL2 expression and variants in patients correlated with cardiac hypertrophy. Taken together our results might provide a new insight into gender specific differences in cardiac disease.

Conclusion: The permanent expression and presumably enhanced activation of RAGE correlate with dilated cardiomyopathy associated with heritable cardiomyopathies and aging. Targets like FHL2 and the energy metabolism and might help to address future therapies and might be beneficial to overcome gender specific differences in clinical cardiac outcome. However, it remains to be elucidated whether a RAGE- or gender-mediated treatment could help to prevent harmful heart functions.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
19 February 2021