An Ethanolic Extract of Lindera obtusiloba Stems, YJP-14, Improves Endothelial Dysfunction, Metabolic Parameters and Physical Performance in Diabetic db/db Mice

Abstract

Lindera obtusiloba is a medicinal herb traditionally used in Asia for improvement of blood circulation, treatment of inflammation, and prevention of liver damage. A previous study has shown that an ethanolic extract of Lindera obtusiloba stems (LOE) has vasoprotective and antihypertensive effects. The possibility that Lindera obtusiloba improves endothelial function and metabolic parameters in type 2 diabetes mellitus (T2DM) remains to be examined. Therefore, the aim of the present study was to determine the potential of LOE to prevent the development of an endothelial dysfunction, and improve metabolic parameters including hyperglycemia, albuminuria and physical exercise capacity in db/db mice, an experimental model of T2DM. The effect of LOE (100 mg/kg/day by gavage for 8 weeks) on these parameters was compared to that of an oral antidiabetic drug, pioglitazone (30 mg/kg/day by gavage). Reduced blood glucose level, body weight and albumin-creatinine ratio were observed in the group receiving LOE compared to the control db/db group. The LOE treatment improved endothelium-dependent relaxations, abolished endothelium-dependent contractions to acetylcholine in the aorta, and normalized the increased vascular oxidative stress and expression of NADPH oxidase, cyclooxygenases, angiotensin II, angiotensin type 1 receptors and peroxynitrite and the decreased expression of endothelial NO synthase in db/db mice. The angiotensin-converting enzyme (ACE) activity was reduced in the LOE group compared to that in the control db/db group. LOE also inhibited the activity of purified ACE, COX-1 and COX-2 in a dose-dependent manner. In addition, LOE improved physical exercise capacity. Thus, the present findings indicate that LOE has a beneficial effect on the vascular system in db/db mice by improving endothelium-dependent relaxations and vascular oxidative stress most likely by normalizing the angiotensin system, and also on metabolic parameters, and these effects are associated with an enhanced physical exercise capacity.

Angiotensin II-induced upregulation of SGLT1 and 2 contributes to human microparticle‐stimulated endothelial senescence and dysfunction: protective effect of gliflozins

“…Indeed, exposure of endothelial cells (ECs) to circulating MPs from acute coronary syndrome patients induced premature endothelial senescence and thrombogenicity through activation of the Ang II/AT1R/NADPH oxidase pathway [ 13 ]. Such findings are in good agreement with observations indicating that the angiotensin system contributes to the induction of endothelial dysfunction in the inner curvature of the aortic arch [ 14 ], in experimental models of atherosclerosis and aging, hypertension, diabetes and in patients at high cardiovascular risk [ 15 – 17 ]. ECs express angiotensin-converting enzyme (ACE) that stimulates the conversion of angiotensin I (Ang I) into the biologically active Ang II [ 18 ], which, in turn, causes NADPH oxidase-mediated oxidative stress and promotes vasoconstriction, endothelial senescence and dysfunction, and vascular and cardiac remodeling [ 19 , 20 ].…”

“…The angiotensin system is a major contributor to endothelial dysfunction observed prematurely at atheroprone arterial sites at risk, and also in aging- and major cardiovascular disease-related endothelial dysfunction such as coronary artery disease [ 14 – 17 ]. The angiotensin system promotes vascular pro-oxidant, pro-atherothrombotic and pro-senescence responses, and contributes to MPs shedding [ 7 , 8 , 53 ].…”

Intake of omega-3 formulation EPA:DHA 6:1 by old rats for 2 weeks improved endothelium-dependent relaxations and normalized the expression level of ACE/AT1R/NADPH oxidase and the formation of ROS in the mesenteric artery

“…Previous studies have shown a pivotal role of both circulating and local angiotensin systems in the induction of endothelial dysfunction in several experimental models of hypertension, atherosclerosis, diabetes, and aging [4,6,[8][9][10] and also in humans [11]. Angiotensin II (Ang II)-induced endothelial dysfunction is characterized by the vascular formation of ROS subsequent to the upregulation of the expression level of NADPH oxidase [12,13], thereby promoting eNOS uncoupling to further generate ROS [14], alteration of calcium-dependent K + channels involved in EDH responses [15], and increased expression of COXs, promoting EDCF responses [16,17].…”

Effects of metformin on endothelial function in type 2 diabetes

“…The pathogenesis of DM vascular lesions is relative to vascular endothelial cell injury, platelet activation and the abnormality of coagulation and fibrinolysis ( 1 ). Endothelial cell injury is a vital early manifestation of DM vascular disease and is the initiating factor in the development of atherosclerosis ( 2 , 3 ). Therefore, the improvement of vascular endothelial function is crucial for the treatment of DM.…”