Transcriptomic analysis of cardiac gene expression associated to RAGE deletion and aging

Cardiac aging is characterized by increased cardiomyocyte hypertrophy, myocardial stiffness and fibrosis, which enhance the cardiovascular risk. The receptor for advanced glycation end-products (RAGE) is involved in several age-related diseases. Rage knockout (Rage-/-) mice show an acceleration of cardiac dimensions changes and interstitial fibrosis with aging. This study identifies the age-associated cardiac gene expression signature induced by RAGE deletion. We analyzed the left ventricle transcriptome of 2.5- (Young), 12- (Middle age, MA) and 21- (Old) month-old female Rage-/- and C57BL/6 (WT) mice. By comparing Young, MA and Old Rage-/- versus age-matched WT mice, we identified 122, 192 and 11 differently expressed genes, respectively. Functional inference analysis showed that RAGE deletion is associated with: (i) a down-regulation of genes involved in antigen processing and presentation of exogenous antigen, adaptive immune response, cytokine and type I- and gamma-interferon mediated pathway in Young animals; (ii) an up-regulation of genes related to fatty acid oxidation, cardiac structure remodeling and impaired response to hypoxia in MA mice; (iii) an up-regulation of few genes belonging to complement activation and triglyceride biosynthetic process in Old animals. Our findings show that the age-dependent cardiac phenotype of Rage-/- mice is mainly associated to alterations of genes related to adaptive immunity and cardiac stress pathways. A total of 29 mice of different ages (i.e. ten-week-old, twelve-month-old or twenty-one-month-old (Young, MA and Old, respectively)), and genotypes (i.e. Wild type and Rage-/-) were used. RNA was extracted from left ventricle of frozen mouse hearts and used for microarray assays. An additive linear model for a multilevel experiment, which includes mouse age and genotype factors, was designed.