fps-zm1 and Fibrosis

Topics: Animals; Benzamides; Collagen; Diabetes Mellitus, Experimental; Drug Interactions; Epithelial Cells; Fibrosis; Glycation End Products, Advanced; Kidney Tubules; Male; Oxidative Stress; Rats; Rats, Wistar; Valsartan

Heart failure is the consequence of sustained, abnormal neurohormonal and mechanical stress and remains a leading cause of death worldwide. The aim of this work was to identify whether blockade of receptor for advanced glycation end products (RAGE) protected against systolic overload-induced heart failure and investigate the possible underlying mechanism. It was found that RAGE mRNA and protein expression was up-regulated in cardiac tissues from mice subjected to pressure overload by transverse aortic constriction (TAC). Importantly, inhibition of RAGE by treatment with soluble RAGE (sRAGE) or FPS-ZM1 (a high-affinity RAGE-specific inhibitor) for 8 weeks attenuated cardiac remodeling (including cardiac hypertrophy and fibrosis), and dysfunction in mice exposed to TAC. Furthermore, treatment of TAC mice with sRAGE or FPS-ZM1 enhanced phosphorylation of AMPK and reduced phosphorylation of mTOR and protein expression of NFκB p65 in cardiac tissues. In addition, treatment of TAC mice with sRAGE or FPS-ZM1 abated oxidative stress, attenuated endoplasmic reticulum stress, and suppressed inflammation in cardiac tissues. These data demonstrated the benefits of blocking RAGE on the progression of systolic overload-induced heart failure in mice, which was possibly through modulating AMPK/mTOR and NFκB pathways.

Topics: Animals; Aorta; Benzamides; Endoplasmic Reticulum Stress; Fibrosis; Glycation End Products, Advanced; Heart Failure; Hypertrophy; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Pressure; Receptor for Advanced Glycation End Products; Signal Transduction; Solubility; Systole; TOR Serine-Threonine Kinases; Vasoconstriction