Role of Advanced Glycation End Products in Hypertension and Atherosclerosis: Therapeutic Implications

Abstract

The vascular diseases, hypertension and atherosclerosis, affect millions of individuals worldwide, and account for a large number of deaths globally. A better understanding of the mechanism of these conditions will lead to more specific and effective therapies. Hypertension and atherosclerosis are both characterized by insulin resistance, and we suggest that this plays a major role in their etiology. The cause of insulin resistance is not known, but may be a result of a combination of genetic and lifestyle factors. In insulin resistance, alterations in glucose and lipid metabolism lead to the production of excess aldehydes including glyoxal and methylglyoxal. These aldehydes react non-enzymatically with free amino and sulfhydryl groups of amino acids of proteins to form stable conjugates called advanced glycation end products (AGEs). AGEs act directly, as well as via receptors to alter the function of many intra- and extracellular proteins including antioxidant and metabolic enzymes, calcium channels, lipoproteins, and transcriptional and structural proteins. This results in endothelial dysfunction, inflammation and oxidative stress. All these changes are characteristic of hypertension and atherosclerosis. Human and animal studies have demonstrated that increased AGEs are also associated with these conditions. A pathological role for AGEs is substantiated by studies showing that therapies that attenuate insulin resistance and/or lower AGEs, are effective in decreasing oxidative stress, lowering blood pressure, and attenuating atherosclerotic vascular changes. These interventions include lipoic acid and other antioxidants, AGE breakers or soluble receptors of AGEs, and aldehyde-binding agents like cysteine. Such therapies may offer alternative specific means to treat hypertension and atherosclerosis. An adjunct therapy may be to implement lifestyle changes such as weight reduction, regular exercise, smoking cessation, and increasing dietary intake of fruits and vegetables that also decrease insulin resistance as well as oxidative stress.

Disease-modifying treatments for Alzheimer’s disease

“…It is closely associated with atherosclerosis and vascular function, and in the brain results in hypoperfusion and ischemic conditions of the nucleus basalis of Meynert. The use of targeted molecular mechanisms and dietary methods and therapies is grounded in reducing free radicals and associated oxidative stress-related damage initiating hypertension [Vasdev et al 2007]. …”

Maillard Reaction Products in Processed Food: Pros and Cons

“…Indeed, AGE form crosslinks with low-density lipoprotein (LDL), which become more atherogenic and less susceptible to absorption and subsequent clearance. In addition, LDL modified by AGEs is more easily captured by receptors located on macrophages, generating foam cells (cells with fat droplets and cholesterol) (Hartog et al, 2007;Vasdev et al, 2007) (Figure 7). It has also been suggested that AGEs are involved in neurodegenerative diseases, such as Alzheimer and Parkinson (Grillo & Colombato, 2008;Sato et al, 2006b), arthritis (Vytásek et al, 2010), loss of bone mass (Ding et al, 2006) and promotion of changes in the function and/or structure of DNA and RNA molecules .…”

Glycemic and cardiovascular parameters improved in type 2 diabetes with the high nutrient density (HND) diet

“…The high nutrient density (HND) diet emphasizes micronutrients (phytochemicals and antioxidants) from greens, fruits, nuts/seeds and beans/legumes, the latter containing high amounts of viscous fiber and resistant starches. The HND diet incorporates features of other dietary interventions, but is designed to create advantages from multiple mechanisms, including the effect that high micronutrient food has in reducing cravings and overeating, and on lowering oxidative stress [8] and deposition of advanced glycation end products [9,10].…”