Induction of hypoxic response despite normoxic conditions associated with vascular mitochondrial dysfunction in diet induced metabolic syndrome

Abstract

Reduced mitochondrial function is one of the various cellular pathologies in cardio-metabolic syndrome. Elevated asymmetric dimethyl arginine (ADMA) levels is known to induce hypoxia driven mitochondrial dysfunction in the lungs, despite normoxic conditions. This alteration is known to be caused by interleukin-4 (IL-4). In addition to asthma, IL-4 and ADMA are also known to be elevated in metabolic syndrome (MetS), but the existence of hypoxic response in arterial tissue remains elusive. Since, MetS and asthma are correlated; we explored whether hypoxia exists in vascular tissue and is associated with IL-4 and ADMA levels. To induce MetS, C57BL/6 mice were fed chow, high-fat or high-fructose diets for six months. Interestingly, MetS was associated with the induction of the hypoxic response in aortic tissue. Further, IL-4 and ADMA, which induce aberrant hypoxic response despite normoxia in the lungs, were elevated in the aorta of mice with MetS. Additionally, significant reductions in the levels of mitochondrial biogenesis factors (TFAM, PGC1) and respiratory chain complexes (Complex I and Complex IV) activities were observed in MetS mice. Mitochondrial dysfunction in the aorta of mice with MetS perturbed mitochondrial inner membrane integrity and was associated with the leakage of cytochrome c in the cytosol. These results collectively suggest that elevated levels of IL-4 and ADMA in the aorta of mice with MetS correlates with induced vascular mitochondrial dysfunction and hypoxic response.