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

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systems, which may cause tissue injury. It can produce endothelial dysfunction and

accelerate atherosclerosis in patients with CVD.

Oxidized LDL (OxLDL), formed under oxidative stimulation, can enhance local

inflammatory response. Lots of factors contributing to the formation of

OxLDL. Systemic diseases like diabetes, chronic kidney disease are well known to

induce OxLDL [ 63 ]. Air pollution, which is usually neglected, is also a strong

inducer for systemic oxidative stress [ 64 ]. Physical exercise has been proven to

ameliorate systemic inflammation and oxidative burden via acting on NO [ 65 , 66 ].

It has been well studied that NO is involved in the oxidation of LDL-cholesterol

[ 67 , 68 ]. Decreased endothelial NO bioavailability may be the earliest indication of

atherosclerosis [ 69 ]. Reduction of endothelial NO bioavailability is closely related

to vasoconstriction, platelet adherence and aggregation, leukocytes adherence, and

increased proliferation of SMC [ 70 ]. These effects all contribute to the pathogenesis

of atherosclerosis. Decreased expression of endothelial NO synthase (eNOS), loss

of eNOS activity, and accelerated NO degradation by ROS are associated with sup-

pressed NO bioactivity [ 71 , 72 ]. Exercise readjusts the balance between NO genera-

tion and NO inactivation [ 73 ]. Among many enzymatic systems that are able to

produce ROS, NADPH oxidase appears to be the most significant one [ 74 , 75 ].

Physical inactivity increases the activity of NADPH oxidase, followed by enhanced

O2− and ROS production. It finally will lead to endothelial dysfunction and athero-

sclerotic lesion progression [ 76 ]. To sum up, the mechanism of exercise modulating

oxidative stress are as follows: (1) increases eNOS expression and/or eNOS Ser1177

phosphorylation [mediated by an increase in Akt expression and/or phosphoryla-

tion]; (2) increases antioxidant superoxide dismutase (SOD) expression; (3)

decreases NADPH oxidase activity and expression of its subunits (gp91phox,

p22phox and nox4), leading to reduced ROS generation [ 77 – 82 ].

Last but not the least, hyperhomocysteinemia(HHcy) is an unneglectable risk

factor for atherosclerosis and oxidative stress. HHcy also involved in vascular

responses and endothelial injury [ 83 ]. It could enhance propensity for plaque rup-

ture and promote vascular SMCs proliferation [ 84 – 87 ]. Studies have elucidated that

HHcy induces oxidative stress/ROS through induction of thrombin and activation of

PAR-4 and NADPH oxidase 1, or oxidation of reactive sulfhydryl groups in the

presence of molecular oxygen [ 83 , 88 , 89 ]. Exercise is found to be effective in sup-

pressing HHcy induced destruction. Firstly, exercise can reduce HHcy-mediated

oxidative stress and atherogenesis, either directly by reducing Hcy levels or indi-

rectly by enhancing PON1 levels. PON1 is a calcium-dependent esterase belonging

to the PON family of proteins and is strongly associated with HDL level. PON1 can

reduce cellular oxidative stress as well as the rate of cholesterol biosynthesis after

entry into the macrophages [ 90 – 92 ]. Secondly, exercise can upregulate kidney beta-

ine homocysteine S-methyltransferase level, which removes Hcy through the non-

classical remethylation pathway [ 93 ]. In turn, HHcy can also restrict the physical

activity capacity. Therefore, it is inevitable to correct the HHcy before the exercise

regimen to exert its full potential [ 94 – 96 ].

Physical Exercise Regulates Endothelial Function

15 Physical Exercise Is a Potential “Medicine” for Atherosclerosis