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LE Magazine August 2001


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Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats.

High levels of tissue advanced glycation end products (AGEs) that result from the spontaneous modification of proteins by glucose occur in diabetes and aging. To address the potential pathogenic role of AGEs in the glomerulosclerosis of diabetes or nephrosclerosis of aging, doses of AGE-modified rat albumin (25 mg per kg per day, i.v.) sufficient to elevate circulating AGE levels to the range of diabetic serum were administered daily to healthy rats alone or in combination with the AGE inhibitor aminoguanidine. After 5 months, the AGE content of renal tissues in AGE-treated rats rose to 50% above controls (P < 0.025), whereas serum contained 2.8-fold greater AGE levels (P < 0.025). Light and electron microscopy of kidneys from AGE-treated rats revealed a more than 50% increase in glomerular volume compared to controls (P < 0.001), significant periodic acid/Schiff reagent-positive deposits, basement membrane widening, and mesangial extracellular matrix increase and indicated significant glomerulosclerosis compared to untreated (P < 0.002) or albumin-treated controls (P < 0.002). These changes were associated with significant loss of protein (P < 0.005) and albumin (P < 0.002) in the urine of AGE-treated rats compared to controls. Cotreatment with aminoguanidine markedly limited both the structural and functional defects. These in vivo data demonstrate that AGEs influence glomerular structure and function in a manner leading to glomerulosclerosis. The effects are AGE-specific, as they are ameliorated by a pharmacological AGE inhibitor, aminoguanidine.

Proc Natl Acad Sci U S A 1994 Nov 22;91(24):11704-8

An agent cleaving glucose-derived protein crosslinks in vitro and in vivo.

Glucose and other reducing sugars react with proteins by a nonenzymatic, post-translational modification process called nonenzymatic glycosylation or glycation. The sugar-derived carbonyl group adds to a free amine, forming a reversible adduct which over time rearranges to produce a class of products termed advanced-glycation end-products (AGEs). These remain irreversibly bound to macromolecules and can covalently crosslink proximate amino groups. The formation of AGEs on long-lived connective tissue and matrix components accounts largely for the increase in collagen crosslinking that accompanies normal ageing and which occurs at an accelerated rate in diabetes. AGEs can activate cellular receptors and initiate a variety of pathophysiological responses. They modify an appreciable fraction of circulating low-density lipoproteins preventing uptake of these particles by their high-affinity tissue receptors. Advanced glycation has also been implicated in the pathology of Alzheimer's disease. Because AGEs may form by a pathway involving reactive alpha-dicarbonyl intermediates, we investigated a potential pharmacological strategy for selectively cleaving the resultant glucose-derived protein crosslinks. We now describe a prototypic AGE crosslink "breaker", N-phenacylthiazolium bromide (PTB), which reacts with and cleaves covalent, AGE-derived protein crosslinks. The ability of PTB to break AGE crosslinks in vivo points to the importance of an alpha-dicarbonyl intermediate in the advanced glycation pathway and offers a potential therapeutic approach for the removal of established AGE crosslinks.

Nature 1996 Jul 18;382(6588):275-8

Pharmaceutical intervention of advanced glycation endproducts.

Recent studies have revealed that reducing sugars, such as glucose, react with proteins through non-enzymatic glycosylation to form irreversible, covalently cross-linked proteins known as advanced glycation endproducts (AGEs). Furthermore, it has been demonstrated that this naturally occurring process, accelerated in diabetics due to hyperglycaemia, impairs biological functions leading to cardiovascular disorders, as well as diabetic and age-related complications. Pharmaceutical intervention to prevent or reverse these complications have focused on inhibiting the formation of AGEs by compounds such as dimethyl-3-phenacylthiazolium chloride or breaking the glucose derived cross-links by selective cleavage. Intervention targeted at AGE cross-links in vivo offers a way to interfere with age-related changes of tissues.

Novartis Found Symp 2001;235:202-12; discussion 212-6, 217-20

A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys.

Nonenzymatic glycosylation and cross-linking of proteins by glucose contributes to an age-associated increase in vascular and myocardial stiffness. Some recently sythesized thiazolium compounds selectively break these protein cross-links, reducing collagen stiffness. We investigated the effects of 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711) on arterial and left ventricular (LV) properties and their coupling in old, healthy, nondiabetic Macaca mulatta primates (age 21 +/- 3.6 years). Serial measurements of arterial stiffness indices [i.e., aortic pulse wave velocity (PWV) and augmentation (AGI) of carotid arterial pressure waveform] as well as echocardiographic determinations of LV structure and function were made before and for 39 weeks after 11 intramuscular injections of ALT-711 at 1.0 mg/kg body weight every other day. Heart rate, brachial blood pressure, and body weight were unchanged by the drug. PWV and AGI decreased to a nadir at 6 weeks [PWV to 74.2 +/- 4.4% of baseline (B), P = 0.007; AGI to 41 +/- 7.3% of B, P = 0.046], and thereafter gradually returned to baseline. Concomitant increases in LV end diastolic diameter to 116.7 +/- 2.7% of B, P = 0.02; stroke volume index (SV(index)) to 173.1 +/- 40.1% of B, P = 0.01; and systolic fractional shortening to 180 +/- 29.7% of B, P = 0.01 occurred after drug treatment. The LV end systolic pressure/SV(index), an estimate of total LV vascular load, decreased to 60 +/- 12.1% of B (P = 0.02). The LV end systolic diameter/SV(index), an estimate of arterio-ventricular coupling, was improved (decreased to 54.3 +/- 11% of B, P < 0.002). Thus, in healthy older primates without diabetes, ALT-711 improved both arterial and ventricular function and optimized ventriculo-vascular coupling. This previously unidentified cross-link breaker may be an effective pharmacological therapy to improve impaired cardiovascular function that occurs in the context of heart failure associated with aging, diabetes, or hypertension, conditions in which arterial and ventricular stiffness are increased.

Proc Natl Acad Sci U S A 2001 Jan 30;98(3):1171-5

B vitamins

Hyperhomocysteinaemia and atherothrombosis.

Homocysteine (Hcy) is a sulfhydryl amino acid derived from the metabolic conversion of methionine that is dependent on vitamins (folic acid, B12 and B6) as cofactors or cosubstrates. In 1969, McCully first reported the presence of severe atherosclerotic lesions in patients with severe hyperhomocysteinaemia and hypothesized the existence of a pathogenic link between hyperhomocysteinaemia and atherogenesis. Several case-control and cross-sectional studies confirmed the initial hypothesis of McCully, showing that also moderate hyperhomocysteinaemia is associated with a heightened risk of occlusive arterial disease. Less consistent results have been reported by prospective cohort studies of subjects who were healthy at the time of their enrollment, whereas prospective cohort studies of patients with overt coronary artery disease or other risk conditions consistently confirmed the association between moderate hyperhomocysteinaemia and the risk of cardiovascular morbidity and mortality. More recently, an association between moderate hyperhomocysteinaemia and heightened risk of venous thromboembolism has been documented, suggesting that hyperhomocysteinaemia might be involved not only in atherogenesis, but also in thrombogenesis. The mechanisms by which hyperhomocysteinaemia might contribute to atherogenesis and thrombogenesis are incompletely understood. The mainstay of treatment of hyperhomocysteinaemia is folic acid, alone or in combination with vitamins B12 and B6. Although it is quite clear that vitamins effectively reduce the plasma levels of total Hcy, we do not yet know whether they will decrease the risk of vascular disease. The results of ongoing randomized, placebo-controlled, double-blinded trials on the effects of vitamins on thrombotic risk will help in defining whether the relationship between hyperhomocysteinaemia and thrombosis is causal, and will potentially have a dramatic impact on the prevention of thromboembolic events.

Ann Med 2000 Dec;32 Suppl 1:46-52

Distribution of and factors associated with serum homocysteine levels in children: child and adolescent trial for cardiovascular health.

CONTEXT: Although evidence suggests that homocysteine is a risk factor for cardiovascular disease in adults, little information exists on homocysteine levels in children. OBJECTIVES: To describe the distribution of serum homocysteine concentrations among children and to examine the association between homocysteine levels and several characteristics, including serum levels of folic acid and vitamins B12 and B6. DESIGN: Cross-sectional analysis. SETTING: School-based cohort from California, Louisiana, Minnesota, and Texas. PARTICIPANTS: A total of 3524 US schoolchildren, aged 13 and 14 years, from the Child and Adolescent Trial for Cardiovascular Health (completed in 1994). Measurement was conducted in 1997. MAIN OUTCOME MEASURE: Nonfasting serum total homocysteine concentration. RESULTS: The distribution of homocysteine values ranged from 0.1 to 25.7 micromol/L (median, 4.9 micromol/L). Geometric mean homocysteine concentration was significantly higher in boys (5.22 micromol/L) than girls (4.84 micromol/L); blacks (5.51 micromol/L) than whites (4.96 micromol/L) or Hispanics (4.93 micromol/L); nonusers of multivitamins (5.09 micromol/L) than users (4.82 micromol/L); and smokers (5.19 micromol/L) than nonsmokers (5.00 micromol/ L). Serum homocysteine was significantly inversely correlated with serum levels of folic acid (r= -0.36; P = .001), vitamin B12 (r = -0.21; P = .001), and vitamin B6 (r = -0.18; P = .001). Serum homocysteine was not significantly associated with serum lipid levels or family history of cardiovascular disease and was only weakly related to body mass index and systolic blood pressure. After multivariate adjustment, homocysteine remained independently associated with sex, race, serum folic acid and vitamin B12 levels, and systolic blood pressure. CONCLUSIONS: The distribution of homocysteine levels in children is substantially lower than that observed for adults; however, a small percentage of children are still potentially at elevated risk for future cardiovascular disease. Serum folic acid may be an important determinant of homocysteine levels in children.

JAMA 1999 Apr 7;281(13):1189-96

Effects of folic acid and combinations of folic acid and vitamin B12 on plasma homocysteine concentrations in healthy, young women.

BACKGROUND: Elevated plasma homocysteine concentrations are considered to be a risk factor for vascular disease and fetal malformations such as neural tube defects. Recent studies have shown that plasma homocysteine can be lowered by folic acid in amounts corresponding to 1 to 2 times the recommended dietary allowance. Preliminary evidence indicates that vitamin B12 may be beneficial when included in supplements or in a food-fortification regimen together with folic acid. OBJECTIVE: We aimed to compare the homocysteine-lowering potential of a folic acid supplement with that of 2 supplements containing different doses of vitamin B12 in addition to folic acid. DESIGN: Female volunteers of childbearing age (n = 150) received a placebo for 4 wk followed by a 4 wk treatment with either 400 microg folic acid, 400 microg folic acid + 6 microg vitamin B12, or 400 microg folic acid + 400 microg vitamin B12. RESULTS: Significant reductions (P < 0.001) in plasma homocysteine were observed in all groups receiving vitamin treatment. The effect observed with the combination of folic acid + 400 microg vitamin B12 (total homocysteine, -18%) was significantly larger than that with a supplement containing folic acid alone (total homocysteine, -11%) (P < 0.05). Folic acid in combination with a low vitamin B12 dose (6 microg) affected homocysteine as well (-15%). CONCLUSIONS: These results suggest that the addition of vitamin B12 to folic acid supplements or enriched foods maximizes the reduction of homocysteine and may thus increase the benefits of the proposed measures in the prevention of vascular disease and neural tube defects.

Am J Clin Nutr 1998 Nov;68(5):1104-10

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