Nelson 2015 Master Thesis

Nelson MB (2015) The role of receptors for advanced glycation end-products (RAGE) and ceramide in cardiovascular disease. Master Thesis 1-53.

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Nelson MB (2015) Master Thesis

Abstract: Type 2 diabetes and cigarette smoke exposure are associated with an increased risk of cardiovascular complications. The role of advanced glycation end-products (AGEs) is already well-established in numerous comorbidities including cardiomyopathy. Given the role of AGEs and their receptor, RAGE, in activating inflammatory pathways, we sought to determine whether ceramides could be a mediator of RAGE-induced altered heart mitochondrial function. Using an in vitro model, we treated H9C2 cardiomyocytes with carboxy-methyl lysine-BSA, followed by mitochondrial respiration assessment. We found that mitochondrial respiration was significantly impaired in AGE-treated cells, but not when co-treated with myriocin, an inhibitor of de novo ceramide biosynthesis. Moreover, we exposed WT and RAGE KO mice to side-stream cigarette smoke and found reduced mitochondrial respiration in the left ventricle myocardium from WT mice, but the RAGE KO mice were protected from this effect. Finally, conditional over-expression of RAGE in the lungs of mice also elicited a robust increase in left ventricular ceramides. Altogether, these findings suggest a RAGE-ceramide axis as an important contributor to cardiomyopathy. • Keywords: Rat H9C2 cardiomyocyte

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cardiovascular, Diabetes 

Organism: Mouse, Rat  Tissue;cell: Heart, Other cell lines  Preparation: Permeabilized cells, Permeabilized tissue 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS  HRR: Oxygraph-2k