Intimal redox stress: accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus. Atheroscleropathy

Abstract

Metabolic syndrome, insulin resistance, prediabetes, and overt type 2 diabetes mellitus are associated with an accelerated atherosclerosis (atheroscleropathy). This quartet is also associated with multiple metabolic toxicities resulting in the production of reactive oxygen species. The redox stress associated with these reactive oxygen species contribute to the development, progression, and the final fate of the arterial vessel wall in prediabetic and diabetic atheroscleropathy. The prevention of morbidity and mortality of these intersecting metabolic diseases can be approached through comprehensive global risk reduction.

Figure 1

An anatomical pull out image of each layer of the arterial vessel wall. The intima colored light blue is the location of the primary remodeling including the positive outward and later in time the negative inward remodeling with encroachment of the lumen. The inward negative remodeling is associated more with stable angina and stable plaques. The positive outward remodeling is associated more with unstable coronary syndromes and unstable VPs and has a much higher level of MMP-3 (stromelysin-ase) activity which may be increased as is MMP-9 in the diabetic patients. It is the MMPs which allow the tearing down (remodeling) in order for the outward remodeling to occur. See section on Redox Stress and MMP activity.

Figure 2

This image portrays the anatomical relationships of the endothelium, intima, media, and adventitia. Each of these layers play an important role in the development of atheroscleropathy. Since the discovery of the essential role of an intact endothelium for the vasomotor control of musculo-elastic arteries by Furchgott and Zawadski in 1980, and the discovery of the NOSs in 1989, the endothelium has been found to play a central role in the maintenance of healthy arteries and found to be placed in a central role for the development and progression of atherogenesis and subsequent atheroscleropathy. The endothelium is five times the weight of the heart and equal to the weight of the liver. This organ is placed at a critical location as an interface with nutrients and toxic products not only at its luminal side of musculo-eleastic arteries but also at the endothelial extracellular matrix interface at the site of capillaries. This exciting monolayer of unique cells is responsible for the production of a gas NO that acts to modulate blood flow and is a naturally occurring interfacing antioxidant capable of scavenging ROS. The intima, sandwiched between the internal elastic lamina of the medial smooth muscle cell layer and the endothelium is the site of atherosclerosis, intimopathy, and the atheroscleropathy associated with MS, IR, PD, and T2DM. The injurious stimuli depicted on the luminal side of the endothelial cell (including redox and oxidative stress with ROS) result in the adaptive changes in which we are familiar: Remodeling of the arterial vessel wall: From Atheroma to Atherosclerosis, to Atheroscleropathy: A MALIGNANT TRANSFORMATION.

Figure 3

The cluster of multiple abnormalities are associated with the metabolic syndrome and insulin resistance is central to the development of ATHEROSCLEROPATHY, cardiovascular disease, and events in the patient with MS, IR, PD, and overt T2DM.

Figure 4

The various subunits of the plasma membrane bound reaction responsible for the production of eNOS derived nitric oxide (NO). This reaction can uncouple and be a net producer of [O2']. In diabetes there are several reasons for uncoupling. Decreased or dysfunctional eNOS enzyme, substrate L-arginine, deficient or dysfunctional cofactor BH4. Increased ROS, RNS, glucose, native LDL-C and oxidized mmLDL-C, ADMA, Hcy, and CRP. Each of these factors can contribute to making the endothelium of the patient with MS, IR, PD and overt T2DM a net producer of [O2']. The above dysfunctional endothelium with a decreased ratio of NO / ROS. RNS can further contribute to the overall increase in intimal redox stress and atheroscleropathy.

Figure 5

Vulnerable plaques are proinflammatory, profibrotic, prothrombotic, proangiogenic, lipid ladened and recently found to be acidic. The activated endothelium is associated with endothelial dysfunction due to eNOS dysfunction and eNOS uncoupling with resultant overproduction of superoxide [O2']. Diabetes is associated with a dysfunctional endothelium not only at sites of vulnerable plaque but have been shown to be a systemic net producer of [O2']. The inflammatory cells and intimal remodeling are depicted in this image as well as an intraplaque hemorrhage (IPH) from the angiogenic vasavasorum vessels originating from the adventitia of this lipid ladened vulnerable plaque. Redox stress and ROS play a prominent role within the intima. The profibrotic arm of the unstable VP is responsible for the positive outward and negative inward remodeling.

Figure 6

Venn diagrams revealing the multiple intersects of this quartet of MS, IR, PD, and overt T2DM. The morbid – mortal intersection of T2DM and Accelerated Atherosclerosis (ATHEROSCLEROPATHY) are a result of the interweaving threads that weave this complicated mosaic fabric.

Figure 7

Glucotoxicity and intimal redox stress injury to the arterial vessel wall in atheroscleropathy initially associated with glucose elevations post prandial then fasting as in prediabetes (PD). Stages III and IV. Transitioning to overt T2DM on the continuum. (table 8)