CATEGORÍA ALTERIDAD

Diabetes mellitus is a group of diseases in which the blood glucose level is too high over a prolonged period. There are two main types of diabetes. Type I diabetes results from the failure

of sufficient insulin production. Type II diabetes relates to unhealthy lifestyle, and is caused by insulin resistance with obesity and insufficient exercise. Cardiovascular diseases are the principal cause of morbidity and mortality in patients with diabetes. Hyperglycemia is a major contributor of the development of micro- and macro-vascular complications in diabetes through different

mechanisms 148,149. The microvascular complications in the retina is one major cause leading to

blindness and visual disability in diabetes. While, atherosclerosis and medial calcification are the common macrovascular diseases in diabetes. High blood sugar level in diabetes generates

oxidative stress, accelerate inflammation, activate protein kinase C (PKC) pathway and increase formation of advanced glycation end products (AGEs) contributing to the damages of the vasculature.

2.3.3.1 Oxidative stress in diabetic vascular lesion

Oxidative stress refers to an elevated intracellular level of reactive oxygen species (ROS),

such as hydrogen peroxide (H2O2), hydroxyl radical (OH•), superoxide anion (O2• ‾), and

hypochlorous acid (HOCl) 150-152. ROS are generated as byproduct of cellular metabolism. There

is considerable evidences indicating that hyperglycemia-induced endoplasmic reticulum stress and mitochondrial dysfunction promote the accumulation of ROS. ROS can also be generated by endothelial NAD(P)H oxidase, a membrane-associated enzyme catalyzing the production of

superoxide, and endothelial uncoupled eNOS, a mechanism leading to excessive superoxide 153-

155_{. Without appropriate compensation by the antioxidant defense network, excessive ROS}

contributes to the development and progression of cardiovascular disorders in diabetes. Hyperglycemia-caused oxidative stress induces dysfunction of the vascular endothelium, the primary defense against thrombosis and other vascular injury. The overproduced ROS results in

channel on the membrane of VSMCs, thus leading to impairment of vasodilation 156,157.

Oxidative stress may also promote the expression of pro-coagulant and pro-inflammatory factors

as well as induce cell apoptosis 155. Besides, it also potentially involve in atherosclerotic

instability and subsequent rupture through promoting both VSMC apoptosis and its proliferation

158,159_.

2.3.3.2 Inflammatory status in diabetes vascular lesion

Accumulating evidence suggests that hyperglycemia is associated with inflammatory state characterized by increased level of pro-inflammatory cytokines and markers which raise the

risks of diabetic cardiovascular disorders 160. For example, atherosclerotic cardiovascular disease

is one of the most common inflammatory diseases in diabetes. Evidence indicates that

hyperglycemia may play a role in atherosclerosis by promoting pro-inflammatory responses of myeloid cells, such as monocytes, macrophages and T lymphocytes, which are rapidly

accumulated at the site of inflammation in vessel 161-163. In addition, the differentiation and

maturation of dendritic cells from type II diabetic patients are impaired with high glucose

exposure 164_{. The hypoglycemic stress caused by overdose insulin, excessive exercise or fasting}

in diabetes patients also contributes to elevation of the pro-inflammatory leukocytosis and cytokines 165.

Oxidative stress and inflammation state usually interact with each other. ROS whose production is enhanced in diabetes by increased dysfunctional mitochondrial can act as a mediator of inflammation, aggravating the tissue injury thus progressing the inflammatory

disorders 166. Activated polymorphonuclear neutrophils at the inflammatory site, in turn, increase

2.3.3.3 Activation of PKC pathway in diabetic vascular lesion

PKC pathway can be stimulated by hyperglycemia, having a big impact on ROS and NO generation. PKC activated by glucose may be implicated in the activation of NAD(P)H oxidase and the consequent production of superoxide. Indeed, increased activity of this enzyme is found

in internal mammary arteries and saphenous veins of diabetes patients 168_{. In addition, activation}

of PKC inhibits the activity of the phosphatidylinositol 3 kinase (PI3K) pathway, an important pathway to generate vasodilator NO in endothelium in response to insulin stimulation in order to

maintain glucose homeostasis 169. Inhibition of PKC pathway can restore the abnormal

endothelium-dependent relaxation of animal aorta caused by hyperglycemia 170. In addition,

hyperglycemia activated PKC signaling may contribute to the hypercoagulable state and the formation of thrombus as well, by activation of platelets and clotting factors and impairing fibrinolytic capacity 171,172.

2.3.3.4 Advanced glycation end products (AGEs) in diabetic vascular lesion

AGEs are glycated proteins or lipids as a result of exposure to glucose 173. AGEs, such as

glyoxal, 3-deoxyglucosone and MGO, can be generated from many processes 174_{. Mitochondrial}

superoxide also increases the production of AGEs 175. Increased AGEs induced by

hyperglycemia is found in diabetic retinal vessels and renal glomeruli 176,177. AGEs can induce

crosslinking of collagen fibers in the artery walls, leading to vascular stiffening and entrapment of low-density lipoprotein particles (LDL). Both of these events are associated with arterial

complications, such as arteriosclerosis 178_{. AGEs can also lead to the glycation of LDL which}

promotes its oxidation as one of the major contributors in development of atherosclerosis 179.

Furthermore, AGEs adversely affect cellular function by activation of the AGEs receptors

to macromolecules 173,180. AGEs also contribute to production of ROS and diminished NO

activity 173_{. Oxidative stress caused by hyperglycemia in patients with diabetes facilitates the}

formation of AGEs. In sum, AGEs affect many of molecules and cells, and interact with other hyperglycemia-induced mechanisms of vessel lesion.