Are AGEs Implicated in Atherosclerosis?

By Nieske Zabriskie, ND

Arterial stiffening occurs as early atherosclerosis is developing and is associated with increased risk of cardiovascular events, dementia, and death. Atherosclerosis is an inflammatory disease in which fatty substances, cholesterol, platelets, cellular waste products, and calcium accumulate on the inner lining (endothelium) of arteries. These plaques grow in size and may occlude the artery causing diminished blood flow and oxygen transport or may rupture and induce heart attacks or strokes. In the United States, it is estimated that atherosclerosis affects one in four Americans, causing approximately 42 percent of all deaths. Approximately half of these deaths are due to atherosclerotic coronary heart disease (CHD).¹

Heart-Harming Compounds

Although it is common to focus on many aspects of arterial stiffening, one potential factor involved in this damaging process is often overlooked. That potential cause is known as Advanced glycosylation end products, or AGEs for short. AGEs are formed by the attachment of sugars (glycosylation) onto biological proteins or lipids. This reaction is irreversible causing glycated proteins and lipids to accumulate over time. AGE formation and accumulation is greatly accelerated with high levels of circulating sugars and oxidative stress.² Hyperglycemia (elevated blood sugar) increases reactive oxygen species and carbonyl intermediates, such as glyoxal and methylglyoxal, which increases glycosylation.³ AGEs react with molecules such as proteins and lipids creating cross-linkages, causing them to become less elastic and less degradable by enzymes. Glycosylated hemoglobin (HbA1c) is an example of AGEs and is measured to evaluate blood sugar control in diabetics.

AGEs interact with specific cell receptors such as RAGE. RAGE activation may lead to an increase in inflammatory responses and cellular injury.⁴ The interaction between AGEs and RAGE modulate numerous physiological functions, such as gene expression, intracellular signaling, and the release of pro-inflammatory molecules and free radicals that contribute towards the pathology of numerous diseases.⁵

In this article, I will discuss the role that AGEs play in the health of the cardiovascular system.

Cross-linking and the Heart

AGE accumulation is associated with cardiovascular dysfunction including atherosclerotic plaque formation, decreased vascular and myocardial (heart muscle) elasticity, endothelial dysfunction, and hypertension.⁶

Arterial stiffness is caused by inflammatory molecules, endothelial cell dysfunction, and reactive oxygen species.⁷ In addition, AGEs alter structural proteins causing cross-linking of collagen and elastin in the myocardium and arterial wall leading to age-related increase in cardiovascular stiffness. Researchers have also shown that plasma levels of AGEs are significantly higher in hypertensive patients compared to subjects with normal blood pressure. Additionally, they found that plasma AGE levels correlate to aortic stiffness independent of age and blood pressure.⁸ Even among healthy adults, AGE levels are associated with increased arterial stiffness.⁹

In blood vessels, cross-linkages trap other proteins, such as LDL cholesterol, leading to a cascade of events that result in accelerated atherosclerotic formation. Data suggests that AGEs act through receptor-independent and dependent mechanisms increasing vascular damage, fibrosis, and inflammation associated with accelerated atherogenesis.¹⁰ In addition, AGE accumulation is associated with atherosclerotic plaque formation independent of hyperglycemia.¹¹ AGEs act directly, as well as through receptors, to alter the function of many proteins including antioxidant and metabolic enzymes, calcium channels, lipoproteins, and transcriptional and structural proteins. This results in endothelial dysfunction, inflammation, and oxidative stress, which are characteristic of hypertension and atherosclerosis. Also, researchers have found that AGEs quench nitric oxide (NO), which is an endothelium-derived relaxing factor in smooth muscle. Decreasing levels of NO by AGEs results in impaired relaxation which is associated with hypertension, atherosclerosis, and diabetes.¹²

RAGES and Blood Vessels

The AGE receptors are also important in the development of atherosclerosis. By engaging the RAGEs, AGEs induce the expression of pro-inflammatory mediators in various vascular cell types and are involved in a variety of microvascular and macrovascular complications. Studies indicate that low levels of circulating endogenous secretory RAGE (esRAGE) and total soluble RAGE (sRAGE) induce the progression of carotid intima-media thickness, a marker of atherosclerosis, independently of conventional cardiovascular risk factors.¹³ Researchers have found that fasting insulin, the pro-inflammatory cytokine interleukin-6, glucose levels, and insulin resistance are major factors determining circulating esRAGE levels. Pulse wave velocity, another measure of arterial stiffness, was found to be associated with esRAGE levels, indicating that low esRAGE levels correlate with inflammation and arterial stiffness and may play an important role on RAGE interaction-induced atherosclerosis.¹⁴

In one study, investigators examined the relationship between the levels sRAGE and endothelial dysfunction in non-diabetic subjects with suspected coronary artery disease. Plasma levels of sRAGE were evaluated and endothelial function was measured by endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery. The subjects were followed for 48 months to assess the occurrence of major cardiovascular events. The results showed that plasma sRAGE level was an independent predictor of endothelium-dependent FMD, and decreased levels of sRAGE were associated with significantly higher number of adverse cardiovascular events. The study authors concluded that this data suggests that sRAGE plays a pivotal role in atherothrombosis (rupture of atherosclerotic plaque).¹⁵

Pharmaceutical agents that prevent AGE formation, break cross-links, or block AGE receptors reduce vascular and myocardial stiffness, inhibit atherosclerotic plaque formation, and improve endothelial function. They have also been shown to improve arterial compliance in elderly patients with vascular stiffening thus improving cardiac function and blood pressure.^16-17 This suggests that therapeutics that positively affect AGE formation and activity, such as some natural options, may greatly impact the progression of cardiovascular diseases.

Natural AGE-Reduction Strategies

Numerous nutrients and botanicals (found in the formula AGEBlock^®) are effective inhibitors of AGE formation. B vitamins have been shown to inhibit both AGE formation and associated free radical damage. Several studies have found that pyridoxal-5-phosphate (the active form of vitamin B6) significantly inhibits AGE formation. In fact, one study showed that P5P inhibited platelet aggregation (the clumping together of platelets) in rats injected with AGEs.¹⁸

Additional research indicates that pyridoxal-5-phosphate, thiamine, and thiamine pyrophosphate can protect DNA from damage by inhibiting production of hydroxyl and superoxide radicals due to methylglyoxal-induced AGE formation.¹⁹ Studies also show that benfotiamine, the lipid-soluble derivative of thiamine, inhibits AGE formation and pro-inflammatory nuclear factor (NF)kb activation, as well decreases diabetic complications.²⁰

Given the link between glycation and oxidation, it is not surprising that several antioxidants have been shown to inhibit AGE formation. Carnosine is a dipeptide (beta-alanyl-L-histidine) normally present in many vital tissues.²¹ Carnosine exhibits antioxidant properties as well as the ability to prevent the formation of AGEs, cross-linking reactions, glycation, and protein carbonyl group formation.^22-23 Carnosine has been shown to scavenge aldehyde byproducts from lipid peroxidation preventing DNA-protein and protein-protein cross-linking reactions²⁴ and inhibits protein modification induced by methylgloxal, a puruvate aldehyde metabolite implicated in AGE formation.²⁵ Methylglyoxal (MG) (pyruvaldehyde) is an endogenous metabolite which is present in increased concentrations in diabetics and implicated in formation of advanced glycosylation end-products (AGEs) and secondary diabetic complications. In addition, research shows that carnosine decreases oxidative stress and formation of reactive oxygen species and reactive nitrogen species, protects membranes from free radical damage, regulates macrophage function, and chelates reactive metals. Muscle carnosine levels decrease significantly with age, as one study found a 63 percent decrease from age 10 to age 70.²⁶

The antioxidants N-acetyl cysteine and lipoic acid have been shown to decrease cell death induced by AGEs.²⁷ In addition, numerous studies indicate that alpha-lipoic acid reduces oxidative stress and prevents the formation AGEs.^28-29 One study found that the combination of benfotiamine plus alpha-lipoic acid completely normalized increased AGE formation and reduced increased monocyte hexosamine-modified proteins by 40 percent in type 1 diabetic subjects.³⁰ The hexosamine pathway has been implicated in the pathogenesis of diabetic complications. Elevated blood sugars increase hexosamine synthesis and contribute to the pathogenesis of diabetic complications.

The antioxidant botanicals Psidium guajava L. (Guava) and Ilex paraguariensis (Yerba Maté) also inhibit glycation. Studies have shown that Psidium guajava L. aqueous extract significantly inhibits low density lipoprotein (LDL) glycation in a dose-dependent manner suggesting that this herb has potential therapeutic uses in the prevention of cardiovascular and neurodegenerative diseases associated with glycation.³¹ Ilex paraguariensis, rich in polyphenols, has been shown to exert significant dose-dependent inhibition of AGE formation comparable to the standard antiglycation agent aminoguanidine.³² Research indicates that the active constituents chlorogenic acid and caffeic acid are the main substances responsible for the antiglycation effect of this herb.³³ In addition, Ilex paraguariensis extract has been shown to inhibit the progression of atherosclerosis in animal models.³⁴

Conclusion

AGE formation has detrimental effects on the cardiovascular system including the induction of arterial stiffening and atherosclerosis. A number of natural substances, all found in AGEBlock, are effective AGE inhibitors and may help decrease the accumulation and damaging effects of AGEs, possibly slowing the progression of atherosclerosis and cardiovascular disease.

References

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