Abstract 16822: Endothelial c-Myc Protects the Heart From Pro-Inflammatory Changes During Aging and Atherogenic Stress

Background: Inflammation plays an important role in cardiac remodeling and occurs in response to risk factors such as aging and high-fat diet (HFD). We have recently reported that c-Myc knockdown in endothelial cells triggers a senescence-associated pro-inflammatory phenotype. We found that c-Myc expression declines in human coronary artery endothelial cells (HCAECs) during replicative senescence and aging. These findings suggest that threshold levels of c-Myc in endothelial cells are required to protect the heart. Here we investigated the impact of endothelial c-Myc in the heart during aging and exposure to HFD using a transgenic mouse model with endothelial-specific c-Myc overexpression. Methods and Results: Gene expression profiling and pathway analysis of young (2-month) and old (10-month) mice showed that endothelial c-Myc overexpression has a protective effect, increasing the expression of genes that prevent cardiac hypertrophy such as Rgs2, Braf and Ppargc1a and reducing inflammatory mediators such as S100a9 and Ptx3. We validated the expression of inflammatory markers IL-1β, Cxcl1 and TGF-β2 by qPCR and found that in aged group, their expression was downregulated in transgenic mice by 2.46 (p<0.002), 2.92 (p<0.001) and 1.85 (p<0.001) fold, respectively, relative to control mice. We further explored this novel protective role of c-Myc in the context of HFD using pre-designed Taqman stress array. Results showed significant downregulation of genes involved in oxidative stress (Noxo1, -1.72-fold, p<0.01), autophagy (Tfeb, -1.72-fold, p=0.03) and DNA repair (Bub1b, -1.37-fold, p=0.02) in transgenic mice under control diet. In response to HFD, most stress genes were downregulated in control mice while a specific group was upregulated in transgenic animals, including genes involved in autophagy (Tfeb, 1.39-fold, p=0.06) and antioxidant pathways (Txnrd2, 1.58-fold, p=0.03; Msra, 1.72-fold, p=0.04 and Msrb3, 1.47-fold, p=0.05). Conclusion: Our c-Myc overexpression mouse model exhibits a distinct gene expression pattern that is potentially cardiac protective in response to aging and HFD. Endothelial c-Myc may be essential to protect cardiac tissues under stress conditions.