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

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Being able to regulate the activity of cytokines may contribute to the protective

effect of physical exercise [ 32 , 33 ]. TNF-α levels are found to be increased in

patients with atherosclerosis [ 34 – 36 ]. It activates and accelerates atherogenesis pro-

cess by promoting thrombosis, vascular remodeling, inflammation, endothelium

apoptosis, oxidative stress and impairing NO bioavailability [ 35 , 37 , 38 ]. Apart

from that, TNF-α precipitates in the secretion of adhesive molecules, thus encourag-

ing recruitment of inflammatory cells [ 36 ]. Overexpression of TNF-α is implicated

in damaged arterial wall and unstable plaque [ 39 ]. The reduction of TNF-α could be

achieved by lipopolysaccharide-stimulated monocytes in whole blood from healthy

subjects [ 40 ]. Further study looking into physical exercise and TNF-α found that

physical exercise could prevent the elevation of circulating TNF-α [ 41 ]. Other stud-

ies also showed that physical exercise decreases cytokines, in particular TNF-α

[ 42 – 44 ], which is a crucial risk actor in atherosclerosis development and vascular

function. TNF-α plays a central role in vascular inflammation, involved in oxidative

stress, apoptosis and also thrombogenesis [ 45 – 47 ].

IL-6 has received increasing attention as it interprets the anti-inflammatory effect

of physical exercise in patients with CVD [ 48 , 49 ]. In contrast to TNF-α, IL-6 inhib-

its the endotoxin-induced increase of TNF-α [ 41 ], induces concentrations of two

other anti-inflammatory cytokines: IL-1Ra (IL-1 receptor antagonist) and IL-10,

and has a central role in exercise-induced leukocyte trafficking [ 50 ]. Furthermore,

IL-6 has vital effect on atherosclerosis by producing CRP. CRP can increase the

levels of reactive oxygen species (ROS) and NF-κB. Both of them can precipitate

inflammation [ 32 , 51 ]. Also, CRP is associated with higher cardiovascular risks [ 32 ,

52 ]. A recent review has summarized that physical exercise could lower the effects

of CRP on inflammation of atherosclerosis [ 53 ]. Increasing evidence has clarified

that physical activity ameliorated activation of inflammation, by decreasing level of

TNF-α, IL-1β, and IL-6. In addition, it activates matrix metalloproteinase 9, thus in

turn attenuates fibrosis, in an MI animal model [ 50 , 54 ].

IL-18 is another pleiotropic inflammatory cytokine, which was found to be

increased in the serum of type II diabetes patients. It revealed itself a predictor of

cardiovascular death and future CVD [ 55 ]. Besides, it worsens the plaque burden

and is related to left ventricular myocardial dysfunction [ 56 ]. IL-18 can be reduced

by an exercise intervention without weight change [ 57 , 58 ].

In summary, physical exercise is an effective way to decrease the key inflamma-

tory factors like TNF-α, CRP, IL-6 and IL-18, suppressing atherosclerosis from a

molecular level.

2.3 Physical Exercise Exerts Antioxidant Effects

Oxidative stress is another important pathology change in atherosclerosis. It has

been well established that physical exercise has a strong negative effect on oxidative

stress [ 59 – 62 ]. Oxidative stress is defined as an imbalance between the excessive

production of oxidant compounds plus the insufficient anti-oxidant defense

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