Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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ROS [ 84 ]. In addition, activation of the polyol pathway has been reported to predis-

pose the cardiac tissue to ischemic insult. This notion has been supported by the

study of Ramasamy et al. [ 85 ] where inhibition of aldose reductase protected iso-

lated type 1 diabetic hearts from ischemia reperfusion injury. The impact of exercise

on hyperglycemia-induced activation of the polyol pathway in the diabetic myocar-

dium hasn’t been investigated yet. Therefore, studies are required to uncover any

possible effect of exercise on myocardial aldose reductase.

5.3 AGE/RAGE Axis

In hyperglycemia, intracellular and extracellular proteins and lipids are exposed to

high concentrations of glucose and glycolytic intermediates. Proteins, lipids and

nucleic acids undergo a non-enzymatic reaction with sugars to produce AGEs [ 86 ].

AGEs can alter the elastic properties of blood vessels and modify the extracellular

matrix, rendering the tissues less compliant and consequently induce myocardial

stiffness [ 86 ]. Binding of AGEs to their receptors (RAGEs) on smooth muscle cells,

macrophages and endothelium contributes to increased vascular permeability, vaso-

constriction, atherogenesis, production of ROS and pro-inflammatory cytokines

[ 87 – 90 ], and reduced NO bioavailability [ 91 ].

Studies have introduced evidences on the role of AGEs in the development of

cardiomyopathy in diabetes [ 86 , 92 ]. In this context, treatment of STZ-induced dia-

betic rodents with ALT-711, an AGE cross-link breaker, reduced levels of AGE in

the myocardium, improved Ca2+ handling, normalize collagen III deposition and

attenuated myocardial structural changes [ 86 , 92 ]. High levels of circulating AGEs

have been positively correlated with type 2 diabetes [ 93 ] and heart failure [ 94 ]. In

addition, type 2 diabetic patients exhibited inverse correlation between glycated

hemoglobin (HbA1c) and soluble RAGEs (sRAGEs) [ 95 ]. This soluble form

RAGEs are known to work as scavengers for AGEs [ 96 ].

Few studies have demonstrated the effects of exercise on the AGEs/RAGEs axis.

Exercise has been reported to increase circulating levels of sRAGEs and reduced

cardiometabolic risk factors in type 2 diabetic patients [ 97 ]. In aged rats, exercise

produced a significant decline in the ventricular AGE levels [ 98 ]. In addition,

reduction in obesity-induced inflammatory responses and transcription factors in

the myocardium [ 30 , 99 ]. On the contrary, exercise decreased plasma AGEs in

obese Zucker rats, whereas exerted no effect on the inflammatory markers [ 100 ].

5.4 Hexosamine Pathway

In the hexosamine pathway, the enzyme glutamine:fructose-6-phosphate

amidotransferase (GFAT) converts fructose-6-phosphate to glucosamine-

6-phosphate (GlcN-6-P). GlcN-6-P is metabolized to produce uridine diphosphate

A.M. Mahmoud