Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide

Abstract

Endothelial dysfunction (ED) is an early feature of cardiovascular risk and diabetes. Hyperglycemia and hyperlipidemia are causative factors. Excessive endothelial mitochondrial superoxide (ROS) production with hyperglycemia and hyperlipidemia is a key mechanism. Inositol components of an insulin inositol glycan mediator, D-chiro-inositol (DCI) and 3-O-methyl DCI (pinitol), decrease hyperglycemia and hyperlipidemia. We tested whether these, myoinositol and dibutyryl DCI (db-DCI), would prevent or reverse ED in diabetic rats and rabbits. Oral inositols reduced hyperglycemia and hypertriglyceridemia with different potencies and prevented ED in rat aortic rings and mesenteric beds. Inositols added in vitro to five diabetic tissues reversed ED. Relaxation by Ach, NO, and electrical field stimulation was potentiated by inositols in vitro in rabbit penile corpus cavernosa. Inositols in vitro restored impaired contraction by the eNOS inhibitor L-NAME and increased NO effectiveness. DCI and db-DCI decreased elevated ROS in endothelial cells in high glucose and db-DCI reduced PKC activation, hexosamine pathway activity, and advanced glycation end products to basal levels. Xanthine͞xanthine oxidase generated superoxide was reduced by superoxide dismutase or inositols, with db-DCI efficacious in a mechanism requiring chelated Fe 3؉ . Histochemical examination of rat aortic rings for protein SNO demonstrated a decrease in diabetic rings with restoration by inositols. In summary, inositols prevented and reversed ED in rat and rabbit vessels, reduced elevated ROS in endothelial cells, potentiated nitrergic or vasculo-myogenic relaxations, and preserved NO signaling. These effects are related to their metabolic actions, direct superoxide scavenging, and enhancing and protecting NO signaling. Of the inositols tested, db-DCI was most effective.I nositol phosphoglycans (IPGs) are potentially important putative intracellular mediators of insulin action (1, 2). Separate classes have been identified (3), one containing D-chiro-inositol (DCI) and galactosamine (4) and a second containing myo-inositol (myo-INS) and glucosamine (1-5). Generated rapidly from lipid and͞or protein precursors in response to insulin, they have insulin-like effects in vitro and in vivo (1, 2, 4, 6, 7). Myo-INS phospho-glycans have been prepared by enzymatic cleavage of protein precursors and chemically synthesized (7-9). They have dose-dependent insulinlike effects on isolated adipocytes, cardiomyocytes, and diaphragms including increased glucose transport (7-9). One DCI containing IPG has been isolated from liver, and its structure has been determined and chemically synthesized (10). It is active in vivo; lowering elevated blood glucose when administered intravenously to diabetic rats (10-12). In vitro, it enhances insulin to stimulate [ 14 C]glucose incorporation into glycogen in H4IIE hepatoma cells (10). It activates pyruvate dehydrogenase (PDH) phosphatase (10), phosphoprotein phosphatase PP2C directly (13), and PP1 indirectly (4,14). Both PDH and glyco...

Glycated Albumin Modulates Endothelial Cell Thrombogenic and Inflammatory Responses

“…These findings are in agreement with previous work that has shown that the metabolic activity of endothelial cells within a diabetic vasculature is reduced and that this can be reversed through the application of pharmacological agents. 24 Combined, our data suggest that there is an overall impairment of endothelial cell culture in response to albumin exposed to glucose for longer durations.…”

Protective mechanisms of resveratrol against ischemia-reperfusion-induced damage in hearts obtained from Zucker obese rats: the role of GLUT-4 and endothelin

“…The underlying mechanisms responsible for the development of diabetes are a complex interplay of various and potential factors, such as increased thrombotic potential (29), endothelial dysfunction (19), and increased oxidative stress (1). In experimental studies, feeding a carbohydrate-enriched diet to normal or obese Zucker rats has been shown to induce insulin resistance and hyperinsulinemia, associated with an elevation in blood pressure (22), and development of vascular endothelial cell damages (35). It has also been shown that resveratrol improves vascular endothelial and postischemic cardiac function in various experimental models (11,23,27,34), which suggests that this agent may change the outcome of myocardial infarction in the diabetic state.…”

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…[94] D-chiro-Inositol is able to prevent and reverse endothelial dysfunction in rat and rabbit blood vessels. [95] Some bone-related diseases are caused by excessive bone resorption by osteoclasts that are multinucleated giant cells formed by cell-cell fusion. D-chiro-Inositol has been shown to inhibit cell-cell fusion and the expression of several osteoclastogenic genes by downregulating nuclear factor of activated T cells c1.…”