The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target.

Thioredoxin interacting protein (TXNIP) is a metabolism- oxidative- and inflammation-related marker induced in cardiovascular diseases and is believed to represent a possible link between metabolism and cellular redox status. TXNIP is a potential biomarker in cardiovascular and ischemic diseases but also a novel identified target for preventive and curative medicine. The goal of this review is to focus on the novelties concerning TXNIP. After an overview in TXNIP involvement in oxidative stress, inflammation and metabolism, the remainder of this review presents the clues used to define TXNIP as a new marker at the genetic, blood, or ischemic site level in the context of cardiovascular and ischemic diseases.

Targeting endothelial thioredoxin-interacting protein (TXNIP) protects from metabolic disorder-related impairment of vascular function and post-ischemic revascularisation.

INTRODUCTION: Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biological functions, the contribution of endothelial TXNIP has not been well-defined in regards to endothelial and vascular function or in post-ischemic revascularisation. We postulated that inhibition of endothelial TXNIP with siRNA or in a Cre-LoxP system could be involved in protection from high fat, high protein, low carbohydrate (HFHPLC) diet-induced oxidative stress and endothelial dysfunction, leading to vascular damage and impaired revascularisation in vivo. METHODS AND RESULTS: To investigate the role of endothelial TXNIP, the TXNIP gene was deleted in endothelial cells using anti-TXNIP siRNA treatment or the Cre-LoxP system. Murine models were fed a HFHPLC diet, known to induce metabolic disorders. Endothelial TXNIP targeting resulted in protection against metabolic disorder-related endothelial oxidative stress and endothelial dysfunction. This protective effect mitigates media cell loss induced by metabolic disorders and hampered metabolic disorder-related vascular dysfunction assessed by aortic reactivity and distensibility. In aortic ring cultures, metabolic disorders impaired vessel sprouting and this alteration was alleviated by deletion of endothelial TXNIP. When subjected to ischemia, mice fed a HFHPLC diet exhibited defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia. However, reducing endothelial TXNIP rescued metabolic disorder-related impairment of ischemia-induced revascularisation. CONCLUSION: Collectively, these results show that targeting endothelial TXNIP in metabolic disorders is essential to maintaining endothelial function, vascular function and improving ischemia-induced revascularisation, making TXNIP a potential therapeutic target for therapy of vascular complications related to metabolic disorders.

Combined effect of citrulline and lactoserum on amino acid availability in aged rats.

OBJECTIVE: Age-associated sarcopenia is due to anabolic resistance to feeding. Muscle protein synthesis is improved by fast proteins (e.g., lactoserum), which increase peripheral amino acid (AA) bioavailability more rapidly than slow proteins (e.g., casein), and by citrulline. Citrulline, which limits splanchnic sequestration of AA, may more effectively increase peripheral AA bioavailability when combined with lactoserum than with casein when administered as an oral nutritional protein supplement. METHODS: In this study, 25 fasted aged rats received a single gavage administration of lactoserum or casein 0.4 g/kg, alone or with citrulline 0.4 g/kg, and AA pharmacokinetics, glucose, insulin, triglycerides, and insulin-like growth factor 1 (IGF1) were monitored for 4 h. At 4 h, muscle protein and AA contents and protein synthesis activation were measured. RESULTS: While lactoserum was associated with higher AA availability, citrulline exerts only limited effects on the plasma profile of AAs from the two proteins. Maximum plasma citrulline was reached earlier with casein (T90 min) than with lactoserum (T120 min). A protein x citrulline interaction was observed for some plasma and muscle AA levels with a significant activation of mechanistic target of rapamycin complex 1 (mTORC1) signaling suggesting higher anabolism with the combination of citrulline and lactoserum. Lower plasma and muscle AA levels with citrulline and lactoserum compared to lactoserum alone suggest a greater AA utilization in a context of muscle anabolic signaling activation. CONCLUSION: Provision of a citrulline-lactoserum combination as a nutritional supplement could therefore be beneficial in terms of muscle protein balance and prevention of sarcopenia. Further studies are warranted to evaluate the efficacy of this combination.

Mitochondrial Aging and Physical Decline: Insights From Three Generations of Women.

Decline in mitochondrial DNA (mtDNA) copy number, function, and accumulation of mutations and deletions have been proposed to contribute to age-related physical decline, based on cross sectional studies in genetically unrelated individuals. There is wide variability of mtDNA and functional measurements in many population studies and therefore we assessed mitochondrial function and physical function in 18 families of grandmothers, mothers, and daughters who share the same maternally inherited mtDNA sequence. A significant age-related decline in mtDNA copy number, mitochondrial protein expression, citrate synthase activity, cytochrome c oxidase content, and VO2 peak were observed. Also, a lower abundance of SIRT3, accompanied by an increase in acetylated skeletal muscle proteins, was observed in grandmothers. Muscle tissue-based full sequencing of mtDNA showed greater than 5% change in minor allele frequency over a lifetime in two locations, position 189 and 408 in the noncoding D-loop region but no changes were noted in blood cells mtDNA. The decline in oxidative capacity and muscle function with age in three generations of women who share the same mtDNA sequence are associated with a decline in muscle mtDNA copy number and reduced protein deacetylase activity of SIRT3.

Citrulline diet supplementation improves specific age-related raft changes in wild-type rodent hippocampus.

The levels of molecules crucial for signal transduction processing change in the brain with aging. Lipid rafts are membrane microdomains involved in cell signaling. We describe here substantial biophysical and biochemical changes occurring within the rafts in hippocampus neurons from aging wild-type rats and mice. Using continuous sucrose density gradients, we observed light-, medium-, and heavy raft subpopulations in young adult rodent hippocampus neurons containing very low levels of amyloid precursor protein (APP) and almost no caveolin-1 (CAV-1). By contrast, old rodents had a homogeneous age-specific high-density caveolar raft subpopulation containing significantly more cholesterol (CHOL), CAV-1, and APP. C99-APP-Cter fragment detection demonstrates that the first step of amyloidogenic APP processing takes place in this caveolar structure during physiological aging of the rat brain. In this age-specific caveolar raft subpopulation, levels of the C99-APP-Cter fragment are exponentially correlated with those of APP, suggesting that high APP concentrations may be associated with a risk of large increases in beta-amyloid peptide levels. Citrulline (an intermediate amino acid of the urea cycle) supplementation in the diet of aged rats for 3 months reduced these age-related hippocampus raft changes, resulting in raft patterns tightly close to those in young animals: CHOL, CAV-1, and APP concentrations were significantly lower and the C99-APP-Cter fragment was less abundant in the heavy raft subpopulation than in controls. Thus, we report substantial changes in raft structures during the aging of rodent hippocampus and describe new and promising areas of investigation concerning the possible protective effect of citrulline on brain function during aging.