Arginase inhibition prevents the development of hypertension and improves insulin resistance in obese rats
- 174 Downloads
This study investigated the temporal activation of arginase in obese Zucker rats (ZR) and determined if arginase inhibition prevents the development of hypertension and improves insulin resistance in these animals. Arginase activity, plasma arginine and nitric oxide (NO) concentration, blood pressure, and insulin resistance were measured in lean and obese animals. There was a chronological increase in vascular and plasma arginase activity in obese ZR beginning at 8 weeks of age. The increase in arginase activity in obese animals was associated with a decrease in insulin sensitivity and circulating levels of arginine and NO. The rise in arginase activity also preceded the increase in blood pressure in obese ZR detected at 12 weeks of age. Chronic treatment of 8-week-old obese animals with an arginase inhibitor or l-arginine for 4 weeks prevented the development of hypertension and improved plasma concentrations of arginine and NO. Arginase inhibition also improved insulin sensitivity in obese ZR while l-arginine supplementation had no effect. In conclusion, arginase inhibition prevents the development of hypertension and improves insulin sensitivity while l-arginine administration only mitigates hypertension in obese animals. Arginase represents a promising therapeutic target in ameliorating obesity-associated vascular and metabolic dysfunction.
KeywordsArginine Arginase Obesity Hypertension
This study was supported by the National Institutes of Health National Heart, Lung, and Blood Institute Grant R01-HL074966 (WD) and the American Heart Association Grant 17IRG33370074 (WD).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. The article does not contain any studies with human participants performed by any of the authors, thus no informed consent was required in the study.
- El Assar M, Angulo J, Santos-Ruiz M, Ruiz de Adana JC, Pindado ML, Sanchez-Ferrer A et al (2016) Asymmetric dimethylarginine (ADMA) elevation and arginase upregulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans. J Physiol 594:3045–3060CrossRefPubMedPubMedCentralGoogle Scholar
- Erdely A, Kepka-Lenhart D, Salmen-Muniz R, Chapman R, Hulderman T, Kashen M, Simeonova PP, Morris JM Jr (2010) Arginase activities and global arginine bioavailability in wild-type and ApoE-deficient mice: responses to high fat and high cholesterol diets. PLoS One 5:e15253CrossRefPubMedPubMedCentralGoogle Scholar
- Ming X-F, Rajapakse AG, Yepuri G, Xiong Y, Carvas JM, Ruffieux J et al (2012) Arginase II promotes macrophage inflammatory responses through mitochondrial reactive oxygen species, contributing to insulin resistance and atherogenesis. J Am Heart Assoc 1:e000992CrossRefPubMedPubMedCentralGoogle Scholar
- Moon J, Do HJ, Cho Y, Shin MJ (2014) Arginase inhibition ameliorates hepatic metabolic abnormalities in obese mice. PLoS One 9:7Google Scholar
- Quitter F, Figulla HR, Ferrari M, Pernow J, Jung C (2013) Increased arginase levels in heart failure represent a therapeutic target to rescue microvascular perfusion. Clin Hemorrheol Microcirc 54:75–85Google Scholar