taurochenodeoxycholic-acid and Diabetic-Angiopathies

Endoplasmic reticulum (ER) stress has emerged as a potential mechanism contributing to diabetes and its comorbidities. However, the importance of ER stress in diabetic vascular dysfunction is unclear. The purpose of this study was to examine the effects of the ER stress inhibitor, tauroursodeoxycholic acid (TUDCA), on arterial stiffness and endothelial dysfunction in type 2 diabetic mice.. Carotid and mesenteric artery endothelial function were assessed via ex vivo pressure myography, and arterial stiffness was measured by aortic pulse wave velocity. The effects of TUDCA were examined both acutely (ex vivo) and chronically (250 mg/kg/day; i.p., 4 weeks).. Compared to control C57BL/6J mice, db/db (DB) mice did not display carotid artery endothelial dysfunction; however, mesenteric artery endothelial function was markedly impaired. Acute incubation and chronic administration of TUDCA improved endothelium-dependent dilation in DB mesenteric arteries, without affecting endothelium-independent dilation. Chronic TUDCA administration also reduced arterial stiffness and was associated with reductions in ER stress markers in aortic and perivascular adipose tissue.. These results suggest that ER stress may represent a novel cause of, and therapeutic target for, diabetic vascular dysfunction.

Topics: Animals; Carotid Arteries; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Endothelium, Vascular; Male; Mesenteric Arteries; Mice, Inbred C57BL; Myography; Pulse Wave Analysis; Taurochenodeoxycholic Acid; Vascular Stiffness; Vasodilation; Vasodilator Agents

Physical activity has profound benefits on health, especially on cardiometabolic wellness. Experiments in rodents with trained exercise have shown that exercise improves vascular function and reduces vascular inflammation by modulating the balance between nitric oxide (NO) and oxidative stress. However, the upstream regulator of exercise-induced vascular benefits is unclear. We aimed to investigate the involvement of peroxisome proliferator-activated receptor δ (PPARδ) in exercise-induced vascular functional improvement. We show that PPARδ is a crucial mediator for exercise to exert a beneficial effect on the vascular endothelium in diabetic mice. In db/db mice and high-fat diet-induced obese mice, 4 weeks of treadmill exercise restored endothelium-dependent vasodilation of aortas and flow-mediated vasodilation in mesenteric resistance arteries, whereas genetic ablation of Ppard abolished such improvements. Exercise induces AMPK activation and subsequent PPARδ activation, which help to reduce endoplasmic reticulum (ER) and oxidative stress, thus increasing NO bioavailability in endothelial cells and vascular tissues. Chemical chaperones 4-phenylbutyric acid and tauroursodeoxycholic acid decrease ER stress and protect against endothelial dysfunction in diabetic mice. The results demonstrate that PPARδ-mediated inhibition of ER stress contributes to the vascular benefits of exercise and provides potentially effective targets for treating diabetic vasculopathy.

Topics: Animals; Aorta; Blood Pressure; Diabetes Mellitus; Diabetic Angiopathies; Diet, High-Fat; Endoplasmic Reticulum Stress; Endothelium, Vascular; Male; Mesenteric Arteries; Mice; Mice, Knockout; Myography; Nitric Oxide; Obesity; Organ Culture Techniques; Oxidative Stress; Phenylbutyrates; Physical Conditioning, Animal; Receptors, Cytoplasmic and Nuclear; Taurochenodeoxycholic Acid; Vasodilation

Endoplasmic reticulum (ER) stress and inflammation are important mechanisms that underlie many of the serious consequences of type II diabetes. However, the role of ER stress and inflammation in impaired ischaemia-induced neovascularization in type II diabetes is unknown. We studied ischaemia-induced neovascularization in the hind-limb of 4-week-old db - /db- mice and their controls treated with or without the ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) and interleukin-1 receptor antagonist (anakinra, 0.5 µg/mouse per day) for 4 weeks. Blood pressure was similar in all groups of mice. Blood glucose, insulin levels, and body weight were reduced in db - /db- mice treated with TUDCA. Increased cholesterol and reduced adiponectin in db - /db- mice were restored by TUDCA and anakinra treatment. ER stress and inflammation in the ischaemic hind-limb in db - /db- mice were attenuated by TUDCA and anakinra treatment. Ischaemia-induced neovascularization and blood flow recovery were significantly reduced in db - /db- mice compared to control. Interestingly, neovascularization and blood flow recovery were restored in db - /db- mice treated with TUDCA or anakinra compared to non-treated db - /db- mice. TUDCA and anakinra enhanced eNOS-cGMP, VEGFR2, and reduced ERK1/2 MAP-kinase signalling, while endothelial progenitor cell number was similar in all groups of mice. Our findings demonstrate that the inhibition of ER stress and inflammation prevents impaired ischaemia-induced neovascularization in type II diabetic mice. Thus, ER stress and inflammation could be potential targets for a novel therapeutic approach to prevent impaired ischaemia-induced vascular pathology in type II diabetes.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Blood Vessels; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Hindlimb; Interleukin 1 Receptor Antagonist Protein; Ischemia; Macrophages; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Neovascularization, Physiologic; Recovery of Function; Regional Blood Flow; Signal Transduction; Taurochenodeoxycholic Acid; Time Factors