Impairment of nitrergic system and delayed gastric emptying in low density lipoprotein receptor deficient female mice

Abstract

In the current study, we have investigated whether low density lipoprotein receptor knockout mice (LDLR-KO), moderate oxidative stress model and cholesteremia burden display gastroparesis and if so whether nitrergic system is involved in this setting. In addition, we have investigated if sepiapterin (SEP) supplementation attenuated impaired nitrergic system and delayed gastric emptying. Gastric emptying and nitrergic relaxation were measured in overnight fasting mice. nNOSα dimerization, anti-oxidant markers such as Nrf2, GCLM, GCLC, HO-1, catalase (CAT), and superoxide dismutase (SOD1) were measured using standard methods. Biopterin levels and intestinal transit time were measured using HPLC and dye migration assay, respectively. Wild type (WT) and LDLR-KO were supplemented with SEP. In LDLR null stomachs: (i) significant reduction in rate of gastric emptying, gastric pyloric and fundus nitrergic relaxation and nNOSα dimerization, (ii) elevated oxidized biopterins and reduced ratio of BH(4) /BH(2) + B, (iii) reduced Nrf2 and GCLC protein expression and no change in GCLM, HO-1, CAT, SOD1, and (iv) accelerated small intestinal motility were noticed. Supplementation of SEP restored delayed gastric emptying, impaired pyloric and fundus nitrergic relaxation with restoration of nNOS dimerization and nNOS expression. This novel data suggests that hyperlipidemia and/or suppression of selective antioxidants may be a potential cause of developing gastroparesis in diabetic patients.