High Fat-High Sucrose diet induced vascular endothelial dysfunction, fibrosis and stiffness involve elevated arginase activity

Prevalence of obesity and hyperglycemia is a global health epidemic. Metabolic syndrome, a cluster of hyperglycemia, hypertension, and obesity, is associated with vascular dysfunctions such as impaired endothelial-dependent vasorelaxation and arterial stiffening. Mechanisms involved in these pathogenesis are not well understood. Elevated arginase activity, implicated in many cardiovascular diseases, has been identified to promote endothelial dysfunction by reducing nitric oxide production. Less of a focus has been given to the other side of arginine metabolism where ornithine, product of arginase, can potentially promote vascular proliferation and collagen formation through elevated proline and polyamines. We hypothesized that elevated arginase activity is involved in vascular dysfunction and fibrosis/stiffening associated with obesity-related diabetes. In our study, we fed wild-type (WT) or endothelial-specific arginase 1 knockout (EC-A1−/−) mice (C57BL/6J) a high fat-high sucrose (HFHS) diet for 6 months with or without oral administration of an arginase inhibitor ABH (amino-2-borono-6-hexanoic acid, 10 mg/kg/day)le. HFHS diet increased body weight and fasting glucose level. Also observed were elevated vascular arginase activity/expression, collagen content and oxidative stress, impaired endothelial-dependent vasorelaxation, and increased arterial stiffening. These changes were not observed in EC-A1−/− mice or ABH-treated mice fed with HFHS diet. Furthermore, increase in vascular inflammation observed with HFHS diet was prevented in EC-A1−/− mice or those treated with ABH. In conclusion, vascular dysfunctions observed in our model of obesity-induced diabetes are prevented by inhibition of arginase or lack of endothelial arginase 1. Therapeutic intervention to prevent arginase upregulation may hold promise as a therapy to ameliorate vascular dysfunction related to obesity. (A) Relaxation responses in isolated aortic rings from wild type (WT) mice with or without arginase inhibitor ABH. (C) Responses for mice lacking endothelial arginase 1 (EC-A1−/−) and littermate mice with intact endothelial A1 (A1loxp/loxp ). (B) and (D) Endothelium-independent vasorelaxation to NO donor sodium nitropruside (SNP). n=6–8 mice/group. * P< 0.05, vs. ND-WT or A1loxp/loxp groups.