Abstract P281: A Novel Mutation in Adiponectin Receptor 1 Contributes to Cardiac Hypertrophy and Cardiometabolic Dysregulation

Abstract

Adiponectin, an adipocyte-derived cytokine, is known to influence cardiac remodeling and to suppress pathological cardiac growth and diabetes-induced disorders. Disruption of adiponectin or its receptor AdipoR1 has significant effects on cardiomyocyte hypertrophy and myocardial metabolism signal transduction. We recently identified a novel mutation in the AdipoR1 gene among 126 hypertrophic cardiomyopathy patients, including two family members with diabetes. Our screening identified a G>A transition at 146th position that replaced the amino acid valine (GUG) into methionine (AUG) (V146M). The consequences of this mutation on cardiac function and metabolism are not known. Here, using adenoviral gene delivery system, we found that Ad.V146M increased cell size, protein synthesis, induced expression of hypertrophic gene markers and increased serine phosphorylation of insulin receptor substrate 1 (IRS1) compared to control Ad.βGal or wild type AdipoR1 (Ad.AR1) in cultured cardiomyocytes. We also discovered that p38 and mTOR were activated by AdipoR1 mutant, but not wild-type. Pharmacological inhibition of p38 (SB203580) and mTOR (rapamycin) reversed the Ad.V146M-induced hypertrophic responses. Adiponectin is also known to promote the uptake and oxidation of fatty acid and glucose through AR1 in cultured myocytes. Recent studies suggest that p38 acts as an essential mediator in regulating adiponectin-induced glucose uptake and fatty acid oxidation in C2C12 myocytes, and the serine phosphorylation of IRS1 at S636/639 is known to be mediated by mTOR pathway. AdipoR1 mutant significantly deceased glucose uptake, facilitated palmitate uptake and repressed insulin responses. Interestingly, inhibition of p38 and mTOR pathways significantly attenuated the effects of Ad.V146M on the expression of genes involved in lipid oxidation (peroxisome proliferator-activated receptor α, PPARα; carnitine palmitoyltransferase 1, CPT1) or glucose utilization (phosphofructokinase, muscle, PFK-M), respectively. Intriguingly, these findings were confirmed in vivo in cardiac-specific transgenic mice overexpressing AdipoR1 mutant. Taken together, these results suggest that a mutation in the AdipoR1 may contribute to the development of cardiomyopathy via alterations in mTOR/p38 pathways and cardiac metabolism.