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Targeting the Pentose Phosphate Pathway in Syndrome X-related Cardiovascular Complications.

ABSTRACT: Syndrome X is a combination or co-occurrence of several known cardiovascular risk factors (including central obesity, dyslipidemias, fatty liver disease, hyperinsulinemia, insulin resistance, and hypertension) that affects at least one in five people in developed countries. Syndrome X shortens life and increases morbidity by contributing to the development of both diabetes and cardiovascular disease. Type 1 or 2 diabetes affects approximately 170 million people globally and these numbers are rapidly rising. In patients with diabetes, vascular diseases develop early and progress at an accelerated rate. It has recently become evident that glucose-6-phosphate dehydrogenase (G6PD), the rate limiting enzyme in the pentose-phosphate pathway and its reaction products play key roles in regulating vascular function. Epidemiological studies have also shown that G6PD deficiency markedly reduces retinopathy and mortality due to cardiovascular diseases in males from certain Mediterranean regions. Conversely, G6PD expression and activity are upregulated in rat and mouse models of obesity, hyperglycemia and hyperinsulinemia, and a role for G6PD in the development of insulin resistance in type 2 diabetes has been proposed. Unfortunately, there are no selective drugs available to validate the hypothesis that G6PD and its products are involved in the development of Syndrome X in humans. This review discusses the potential mechanisms by which G6PD could be implicated in vascular diseases in Syndrome X and the need to develop new approaches, including new drugs and molecular tools, to ameliorate diabetes-induced vascular dysfunction and vasculopathies.

SUBMITTER: Gupte SA

PROVIDER: S-EPMC2918918 | biostudies-other | 2010 May

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:Metabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson's disease (PD). The pentose phosphate pathway (PPP, a metabolic pathway parallel to glycolysis) converts glucose-6-phosphate into pentoses and generates ribose-5-phosphate and NADPH thereby governing anabolic biosynthesis and redox homeostasis. Brains and immune cells display high activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP. A postmortem study reveals dysregulation of G6PD enzyme in brains of PD patients. However, spatial and temporal changes in activity/expression of G6PD in PD remain undetermined. More importantly, it is unclear how dysfunction of G6PD and the PPP affects neuroinflammation and neurodegeneration in PD. METHODS:We examined expression/activity of G6PD and its association with microglial activation and dopaminergic neurodegeneration in multiple chronic PD models generated by an intranigral/intraperitoneal injection of LPS, daily subcutaneous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 6?days, or transgenic expression of A53T ?-synuclein. Primary microglia were transfected with G6PD siRNAs and treated with lipopolysaccharide (LPS) to examine effects of G6PD knockdown on microglial activation and death of co-cultured neurons. LPS alone or with G6PD inhibitor(s) was administrated to mouse substantia nigra or midbrain neuron-glia cultures. While histological and biochemical analyses were conducted to examine microglial activation and dopaminergic neurodegeneration in vitro and in vivo, rotarod behavior test was performed to evaluate locomotor impairment in mice. RESULTS:Expression and activity of G6PD were elevated in LPS-treated midbrain neuron-glia cultures (an in vitro PD model) and the substantia nigra of four in vivo PD models. Such elevation was positively associated with microglial activation and dopaminergic neurodegeneration. Furthermore, inhibition of G6PD by 6-aminonicotinamide and dehydroepiandrosterone and knockdown of microglial G6PD attenuated LPS-elicited chronic dopaminergic neurodegeneration. Mechanistically, microglia with elevated G6PD activity/expression produced excessive NADPH and provided abundant substrate to over-activated NADPH oxidase (NOX2) leading to production of excessive reactive oxygen species (ROS). Knockdown and inhibition of G6PD ameliorated LPS-triggered production of ROS and activation of NF-?B thereby dampening microglial activation. CONCLUSIONS:Our findings indicated that G6PD-mediated PPP dysfunction and neuroinflammation exacerbated each other mediating chronic dopaminergic neurodegeneration and locomotor impairment. Insight into metabolic-inflammatory interface suggests that G6PD and NOX2 are potential therapeutic targets for PD.

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Targeting the Pentose Phosphate Pathway in Syndrome X-related Cardiovascular Complications.

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