Evanka Chopra
Institute of Genomics and Integrative Biology (IGIB), India
Title: Cardiovascular disease in metabolic syndrome associated with metabolic induction of a hypoxic response
Biography
Biography: Evanka Chopra
Abstract
Statement of the Problem: The risk of cardiovascular disease (CVD), asthma, non-alcoholic fatty liver disease (NAFLD) as well as common cancers is increased in subjects with metabolic syndrome (MetS). Interleukin-4 (IL-4), a marker of Th2 immune response, is often upregulated in these contexts and may potentiate aberrant arginine metabolism. Altered arginine/nitric oxide metabolism and mitochondrial dysfunction represent putative common molecular pathways that may connect these diseases, possibly via oxidative-stress driven induction of the cellular hypoxic response. The importance of this pathway is not well studied in MetS associated vascular dysfunction.
The purpose of this study is to investigate how altered arginine/methyl arginine balance, oxo-nitrative stress, hypoxic response, and mitochondrial dysfunction may cause vascular dysfunction in metabolic syndrome.
dysfunction in metabolic syndrome.
Methodology & Theoretical Orientation: MetS mice (C57BL/6) were fed chow-diet (CN), high-fat-diet (HFA), or high-fructose-diet (HFR) for 6 months. HFR and HFA diets induce MetS. Arginine/methyl arginine balance and oxo-nitrative stress were determined in aortic tissue by measuring the levels of ADMA, iNOS and 3-nitrotyrosine. Estimation of hypoxic response done by checking levels of HIF1α and resultant mitochondrial dysfunction by measuring levels of cytochrome c, TFAM, mitochondrial membrane potential and Mitochondrial Complex I and IV activity.
Conclusion & Significance: IL-4 and ADMA were increased in HFA and HFR mice with MetS, compared to normal controls (CN). Vascular endothelial cells of both these groups also showed an increase in oxo-nitrative stress. IL-4 and ADMA led to potent induction of the cellular hypoxic response (HIF1α), despite normoxic conditions. The hypoxic response was associated with increased levels of the hypoxamir-210 that targets mitochondria, reduced mitochondrial membrane potential, Complex I and Complex IV activities, decreased TFAM and PGC1α levels, and leak of cytochrome-c to cytosol.
In conclusion, IL-4 and ADMA are increased in MetS, leading to mitochondrial dysfunction through oxo-nitrative stress and hypoxic response. This has broad applicability to multiple diseases influenced by the hypoxic response, including cancer.
