**2. Atherogenesis and cardiovascular diseases**

Decades ago, the endothelium was considered just a barrier non thrombogenic, vascular control which was attributed primarily to the sympathetic nervous system and circulating vasoactive hormones. The discovery that the endothelium synthesizes important vasodila‐

tors such as nitric oxide and prostacyclin, and vasoconstrictors such as endothelin, aroused great interestin endothelial function and role of vascular control, both in physiological proc‐ esses and in pathological conditions. The model 'response to injury' of the endothelium ex‐ plains more precisely this complex pathophysiological mechanism. In this model the endothelium is injured by hemodynamic stimulus, such as hypertension, or bychemical at‐ tack, such as in smoking, begins to operate in a manner dysfunctional. This endothelial dys‐ function leads to compensatory responses that alter the normal homeostatic properties of the endothelium to a reduction in nitric oxide synthesis and an increase inpermeability of the endothelium which binds to LDL cholesterol in the vessel wall[6]. Adhesion molecules begin to be expressed on the surface of the endothelium will lead to attraction of monocytes and lymphocytes to the arterial wall[7].

Apart from traditional risk factors, numerous evidences have shown an association between atherosclerosis and genetic variants which should allow in the future, a new understanding

Atherogenesis: Diseases that May Affect the Natural History "Schistosomiasis and HIV Infection"

http://dx.doi.org/10.5772/54018

83

**3. Schistosomiasis mansoni infection may affect the natural history of**

Infections of Schistosoma mansoni, the adult worms significantly reduced atherogenesis in apolipoprotein E gene knockout (apoE(-/-)) mice. These effects occurred in tandem with a lowering of serum total cholesterol levels in both apoE(-/-) and random-bred laboratory mice and a beneficial increase in the proportion of HDL to LDL cholesterol. The serum cho‐ lesterol-lowering effect is mediated by factors released from S. mansoni eggs, while the pres‐ ence of adult worms seemed to have little or no effect. High levels of lipids, particularly triacylglycerols and cholesterol esters, present in the uninfected livers of both random-bred and apoE(-/-)mice fed a high-fat diet were not present in livers of the schistosome-infected mice[16].ApoE-deficient mice chronically exposed to the eggs of Schistosomamansoni over a period of 16 weeks showed thattotal serum cholesterol and low-density lipoprotein (LDL) were reduced in egg-exposed ApoE-deficient mice fed a diet high in cholesterol compared to unexposed controls. However, exposure to eggs has no effect on atherosclerotic lesion size or progression in these animals. Macrophages isolated from egg-exposed mice had an enhanced ability to take up LDL but not acetylated LDL (acLDL). This suggests that schisto‐ some eggs alone may alter serum lipid profiles through enhancing LDL uptake by macro‐ phages, but these changes do not ultimately affect atherosclerotic lesion development[17].

Previous studies have shown that people infected with schistosomiasis have lower levels of serum cholesterol than uninfected controls. In human beings the first manifestations of car‐ diovascular disease from atherogenesis arise at an advanced stage of atherosclerosis. How‐ ever, patients with hepatosplenic schistosomiasis mansoni have abnormal lipid peroxidation, with elevated erythrocyte-conjugated dienes implying dysfunctional cell membranes, and also imply that this may be attenuated by the redox capacity of antioxidant agents, which prevent accumulation of plasma malondialdehyde (MDA)[18]. These lipid metabolism changes affect the natural history of atherogenesis including the risk factors.

The alterations in the arterial wall occur during the subclinical period of atherogenesis, char‐ acterized by progressive thickening of the endothelium. This endocrine organ is responsible

When risk factors exist, endothelial thickening can be detected already in childhood, and can be predictive of cardiovascular events in adults[20]-[22]. Since the first anatomopatho‐ logical description, several articles have been published associating ultrasound measure‐ ments (intima-media thickening – the identifiable portion of the endothelium) with

for physiological processes that are vital to vascular homeostasis[19].

cardiovascular diseases[23].

of the molecular mechanisms of cardiovascular disease[15].

**atherogenesis**

LDL modified by oxidation is a major cause of injury to the endothelium. Many au‐ thors believe that LDL oxidation does not take place in the circulation, and therefore it must occur in the subendothelial space of the arterial wall. After being trapped in the artery wall, it is internalized by macrophages via the scavenger receptor surfaces of these cells which leads to the formation of foam cells. Inflammation mediators such as tumor necrosis factor α, interleukin-1 and macrophage colony-stimulating factor further increase the binding of LDL to the endothelium and smooth muscle and increase the transcription of the LDL receptor gene. Experimental studies in mice show that oxi‐ dized LDL (oxLDL) promotes atherosclerosis, however, clinical trials of antioxidants were not effective in reducing cardiovascular events[8],[9].Increased levels of oxLDL are presentin human gingival crevicular fluid compared to plasma of healthy individuals, indicating that oxLDL could be generated in inflamed extra-arterial tissues, transferred to the circulation, rapidly taken up into the arterial wall, and contribute to the perpetu‐ ation ofatherosclerosis[10].

Early 'fatty-streak' lesions consist of T cells and monocyte-derived macrophage-like foam cells loaded with lipids and after successive accumulation of apoptotic cells, de‐ bris and cholesterol crystals forms a necrotic core. Initial lesions most commonly devel‐ opin places where laminar blood flow is altered, as in the bifurcations of the vessels, which interferes with the shear stress and adequate production of nitric oxide[11]. In these places, substances are produced by the endothelium that promote adhesion, mi‐ gration and accumulation of monocytes and T cells. The flow changes, leading to a re‐ duced shear stress, modifies the expression of genes such as intercellular adhesion molecule, platelet derived growth factor B chain[12],[13].

The mature atherosclerotic plaque shows in addition to cells, two distinct structural compo‐ nents: a lipid core, very dense, and fibrous cap that is its fibrotic component. The higher the fibrotic component less prone to disruption (less unstable) is the atherosclerotic plaque. The lipid core is highly thrombogenic. When it makes contact with the blood stream by rupture of the fibrous cap or endothelial erosion, occurring phenomena of platelet adhesion and ag‐ gregation, thrombin generation and fibrin, with underlying thrombus formation, which rep‐ resents the common starting point of acute coronary syndromes[14].

Apart from traditional risk factors, numerous evidences have shown an association between atherosclerosis and genetic variants which should allow in the future, a new understanding of the molecular mechanisms of cardiovascular disease[15].

tors such as nitric oxide and prostacyclin, and vasoconstrictors such as endothelin, aroused great interestin endothelial function and role of vascular control, both in physiological proc‐ esses and in pathological conditions. The model 'response to injury' of the endothelium ex‐ plains more precisely this complex pathophysiological mechanism. In this model the endothelium is injured by hemodynamic stimulus, such as hypertension, or bychemical at‐ tack, such as in smoking, begins to operate in a manner dysfunctional. This endothelial dys‐ function leads to compensatory responses that alter the normal homeostatic properties of the endothelium to a reduction in nitric oxide synthesis and an increase inpermeability of the endothelium which binds to LDL cholesterol in the vessel wall[6]. Adhesion molecules begin to be expressed on the surface of the endothelium will lead to attraction of monocytes

LDL modified by oxidation is a major cause of injury to the endothelium. Many au‐ thors believe that LDL oxidation does not take place in the circulation, and therefore it must occur in the subendothelial space of the arterial wall. After being trapped in the artery wall, it is internalized by macrophages via the scavenger receptor surfaces of these cells which leads to the formation of foam cells. Inflammation mediators such as tumor necrosis factor α, interleukin-1 and macrophage colony-stimulating factor further increase the binding of LDL to the endothelium and smooth muscle and increase the transcription of the LDL receptor gene. Experimental studies in mice show that oxi‐ dized LDL (oxLDL) promotes atherosclerosis, however, clinical trials of antioxidants were not effective in reducing cardiovascular events[8],[9].Increased levels of oxLDL are presentin human gingival crevicular fluid compared to plasma of healthy individuals, indicating that oxLDL could be generated in inflamed extra-arterial tissues, transferred to the circulation, rapidly taken up into the arterial wall, and contribute to the perpetu‐

Early 'fatty-streak' lesions consist of T cells and monocyte-derived macrophage-like foam cells loaded with lipids and after successive accumulation of apoptotic cells, de‐ bris and cholesterol crystals forms a necrotic core. Initial lesions most commonly devel‐ opin places where laminar blood flow is altered, as in the bifurcations of the vessels, which interferes with the shear stress and adequate production of nitric oxide[11]. In these places, substances are produced by the endothelium that promote adhesion, mi‐ gration and accumulation of monocytes and T cells. The flow changes, leading to a re‐ duced shear stress, modifies the expression of genes such as intercellular adhesion

The mature atherosclerotic plaque shows in addition to cells, two distinct structural compo‐ nents: a lipid core, very dense, and fibrous cap that is its fibrotic component. The higher the fibrotic component less prone to disruption (less unstable) is the atherosclerotic plaque. The lipid core is highly thrombogenic. When it makes contact with the blood stream by rupture of the fibrous cap or endothelial erosion, occurring phenomena of platelet adhesion and ag‐ gregation, thrombin generation and fibrin, with underlying thrombus formation, which rep‐

molecule, platelet derived growth factor B chain[12],[13].

resents the common starting point of acute coronary syndromes[14].

and lymphocytes to the arterial wall[7].

82 Current Trends in Atherogenesis

ation ofatherosclerosis[10].
