**3. Atherothrombosis stabilization and regression mechanism**

Atherosclerotic plaque lesions are generally asymptomatic for years with slowly evolving in restricting blood flow around lesion [51]. The transition between stable and unstable is decided by the development of a large necrotic core resulting from cell death within the plaque and failure to clearing dead cells. Macrophages are key players in the transition from stable to unstable lesions [52].

Primarily, autophagy is recognized as a survival mechanism and not as one of the cell death pathways. This renders the role of autophagy in atherosclerosis to be equivocal [53]. Successful autophagy generally contributes to cellular survival by acting anti-apoptosis and cellular recovery by supplying biomaterials. Autophagy serves as safeguards for atherosclerotic plaque cells against cellular oxidative stress by polarizing mitochondria not to release cytochrome c [54]. In this reason, autophagy of VSMCs of the fibrous cap in advanced atherosclerotic lesion is important to plaque stabilization. Autophagic death in VSMCs results from excessively stimulated autophagy, and results in plaque destabilization [53]. Autophagic death in endothelial cells affects to maintain the structure of the thrombotic plaques. In view of stabilizing plaque on the rupture-prone lesion, induction of autophagic macrophages might be a promising strategic role in plaque which is not obstructive into lumen but prone to rupture [55]. Dysfunctional autophagy stimulates accumulation of damaged mitochondria, ROS over-expression, and ceroid in human plaque. Continuously and excessively stimulated autophagy can initiate autophagic VSMCs death resulting in plaque destabilization because collagen synthesis in reduced and also the fibrous plaque cap gets thinning. Of course, autophagic cell death is triggered in endothelial cells, which is detrimental role in the sustaining structure of the atherosclerotic plaque. It is an acute clinical event promoting thrombosis on the atherosclerotic lesion.

cells. These inflammatory cells further modulate the endothelial cells into a pro-inflammatory phenotype, and have the endothelial cells work on structural instability of the plaque by mod-

Because of the above-mentioned characteristics, exogenous NO has been implicated as a therapeutic target. NO has benefits in vascular inflammatory diseases, and some researchers have tried to ameliorate atherosclerosis and other vascular diseases with NO donor therapy [41]. The therapeutic use of NO therapy has been reported to ameliorate atherosclerosis [48]. It is an important aspect of therapy whether atherogenesis initiates the formation of endothelial dysfunction or activation. Although it is unclear how endothelial cells recruit inflammatory cells, it is clear that inflammatory cytokines secretion of endothelial cells is tightly linked to eNOS expression. This relationship gives us hints for therapy. Also, vascular endotheliumderived NO has a protective role extending to endothelial-leukocyte interactions, leukocyte trafficking to hinder platelet activation, and smooth muscle contraction and proliferation. Statins (HMG-CoA reductase inhibitors) restore endothelial function, and protect vessels by boosting endothelium-derived NO. Endostatin has been reported to induce autophagic cell death in human endothelial cells (EA.hy926) [49]. When human endothelial cells are exposed to oxLDL, autophagy in the cells is increased to deal with plaque components. It is accepted that endostatin induces damaged endothelial cells by overloaded lipid through autophagic

ifying the proteolytic activity of extracellular matrix components [47].

**3. Atherothrombosis stabilization and regression mechanism**

Atherosclerotic plaque lesions are generally asymptomatic for years with slowly evolving in restricting blood flow around lesion [51]. The transition between stable and unstable is decided by the development of a large necrotic core resulting from cell death within the plaque and failure to clearing dead cells. Macrophages are key players in the transition from

Primarily, autophagy is recognized as a survival mechanism and not as one of the cell death pathways. This renders the role of autophagy in atherosclerosis to be equivocal [53]. Successful autophagy generally contributes to cellular survival by acting anti-apoptosis and cellular recovery by supplying biomaterials. Autophagy serves as safeguards for atherosclerotic plaque cells against cellular oxidative stress by polarizing mitochondria not to release cytochrome c [54]. In this reason, autophagy of VSMCs of the fibrous cap in advanced atherosclerotic lesion is important to plaque stabilization. Autophagic death in VSMCs results from excessively stimulated autophagy, and results in plaque destabilization [53]. Autophagic death in endothelial cells affects to maintain the structure of the thrombotic plaques. In view of stabilizing plaque on the rupture-prone lesion, induction of autophagic macrophages might be a promising strategic role in plaque which is not obstructive into lumen but prone to rupture [55]. Dysfunctional autophagy stimulates accumulation of damaged mitochondria, ROS over-expression, and ceroid in human plaque. Continuously and excessively stimulated autophagy can initiate autophagic VSMCs death resulting in plaque destabilization because

cell death pathways [50].

102 Atherosclerosis - Yesterday, Today and Tomorrow

stable to unstable lesions [52].

Lipid modification such as LDL oxidation brings about a range of modifications with various physiological and biochemical properties [8]. Modified lipids in macrophage cells are able to induce lysosomal dysfunction which can result in the accumulation of intra-lysosomal cholesteryl esters [56]. A number studies have shown that uptake of modified lipids induces a lysosomal lipid storage disease-like condition [5]. Accumulated lipids in lysosomes cause lysosomal dysfunction and affects the intracellular transport machinery. When macrophages are exposed to oxLDL and cholesterol, so-called atherogenic or modified lipids, lysosomal dysfunction occurs [16]. The oxLDL-derived cholesteryl esters form cholesterol crystal when oxLDLderived cholesteryl esters are inefficiently hydrolyzed and transported in lysosomes [57]. Through CD36-dependent mechanisms, oxLDL is moved to macrophage lysosomes; cholesterol crystals accumulate in the lysosomes. Cholesterol crystals beyond the dealing range initiate lysosomal damage and result in leaking lysosomes [57]. As an example, phagocytosis of apoptotic cells (efferocytosis) is detected in plaque progression and is regarded as a critical feature of increasing plaque complexity [5]. PRPs, cell surface receptors and also scavenger receptors, recognize modified lipids (oxLDL) and pathogens. Plasma levels of soluble CD36, one of scavenger receptors, are higher in the context of risk factors for the development of atherosclerosis such as diabetes [58]. The altered "eat-me" signals can also affect efferocytosis and the targets of apoptotic cells. For example, mice lacking complement factor C1q exhibited efferocytosis dysfunction and atherosclerotic plaque burden [59]. In human atherosclerotic plaques, efferocytosis is impaired and also shaded phagocytic receptors, which impedes phagocytic capacity of macrophages and involves activation of the inflammatory response [60]. The LDLR-related protein 1 (LRP1) is one of the important receptors interacting with C1q for opsonizing.

Prolonged oxidative damage induces protein misfolding and the accumulation of dysfunctional proteins to be degraded [61]. Large protein aggregates are ubiquitinated, and the poly-ubiquitinated protein aggregates are shuttled to the autophagosome. This is generally performed via chaperone proteins such as p62/SQSTM1 [11]. The reason for inflammasome activation in the plaque is not currently unclear, but two mechanisms have been suggested. One is that inefficient mitophagy clearing of damaged mitochondria results in increasing reactive oxygen species (ROS), which induces inflammasome activation. However, the level of protein oxidation and superoxides are augmented in autophagy-deficient macrophages and atherosclerotic plaques [12]. The other mechanism is that overloaded oxLDLs and cholesterol crystals destabilize the lysosomal membrane, resulting in inflammasome activation by producing IL-1β [7]. In the atherosclerotic context, it has been shown that aggregated proteins activate inflammasomes and aggravate atherosclerosis in autophagy-deficient systems [12].

Atherosclerosis progression presents the features of impaired autophagy. Autophagy is sequential events called as autophagic flux (autophagosome formation, cargo sequestration, and autolysosomal fusion), and unfortunately, hard to assess the flux in vivo. When p62/SQSTM1, a chaperone shuttling protein aggregates from cytosol to autophagosomes, is combined to protein aggregates and degraded, increased level of p62/SQSTM1 indicate defective in autophagic flux autophagy [62]. Correspondingly, deficient autophagy of macrophage can facilitate atherosclerotic plaque progression. *Atg*5 knock-out mice with ApoE-null background showed that western diet for 2 months increased the level of p62/SQSTM1 in the vessel with similar level of control mice whereas atherosclerotic lesion was bigger than control both in aortic root and whole aorta [62]. Using animals with experimental atherosclerosis, ApoE-null mice, recent study proposed that plaque formation expands when macrophagic autophagy is completely disrupted and not partially disrupted. Partially disrupted autophagic condition induces rather macrophagy inflammation and excess IL-1beta, because cholesterol crystal of atherosclerotic plaques is potent stimuli to activate inflammasome [62].

such, little is known regarding the potential role of circulating adhesion molecules in patients

Cerebrovascular Atherosclerosis: Cognitive Dysfunction Progress and Autophagic Regression

http://dx.doi.org/10.5772/intechopen.72296

105

Many definitions have been proposed for the transition point when healthy aging with a slight cognitive decline progresses to dementia [70]. Mild cognitive impairment (MCI), which was first proposed by a group of investigators from the Mayo Clinic in the late 1990s [70], was defined to be based on a memory problem. This section provides our results about assessing the relationship between changes in blood factors and ultrasound findings in patients with

Carotid atherosclerosis severity is assessed by considering the plaque number, proportions, and location as well as the presence of carotid stenosis that is caused by plaques. Additionally, the severity of carotid stenosis is determined according to the blood flow velocities, residual rumen diameter, and carotid artery flow velocities ratio to internal carotid artery versus the common carotid artery [71]. For AD, it is generally accepted that vascular risk factors have an epidemiological effect on dementia [72]. It has been reported that a narrowed carotid lumen is a risk factor for cognitive impairment in steno-occlusive carotid artery disease patients [72]. Revascularization procedures may have some benefit in the alleviation of dementia, but not for all of these patients [72]. In cases of mild AD with severe asymptomatic intra-carotid artery (ICA) stenosis, cognitive decline progressed even though they have not experienced cerebral ischemia [72]. One possible explanation of this relationship is that insufficient cerebrovascular flow causes cerebral atrophy. Another one is vascular factors that are promoting

The available studies have identified factors associated with aging and vascular dysfunction that exhibit a cross-sectional relationship with mental status based on the Mini-Mental State Examination (MMSE) score. Recent studies have reported that carotid artery atherosclerosis is associated with a subsequent risk of new or recurrent cerebrovascular diseases, such as stroke, post-stroke vascular dementia, and MCI [66, 73, 74]. Furthermore, chronic hypoperfusion caused by carotid stenosis has been reported to play a role in cognitive decline [75]. Dementia represents a major public health concern [68], as accumulating evidence has demonstrated that the incidence and prevalence of dementia increases rapidly with advancing age. Although it has been difficult to investigate changes in the incidence and prevalence of dementia due to variations in diagnostic criteria and methods, a recent epidemiological study indicated that the dementia prevalence and incidence have decreased in some countries. Moreover, the number of patients with dementia has remained stable in the aging population of these countries [76]. Some evidence has suggested that vascular risk factors are associated with the onset and progression of AD [77]. There are increasing concerns that microvascular disease and tau deposition are found concomitantly and it is thought that treating vascular risk factors is as important as preventing cognitive decline [66]. Although the association between anterior cerebral artery (ACA) plaques and dementia has not been fully determined for the number and the location of plaques, it can be used as a better indicator of disease pro-

with vascular diseases during the early and later stages of cognitive dysfunction.

MCI and dementia who were also exhibiting signs of atherosclerosis.

**4.1. Atherosclerosis and dementia**

the degenerative changes of AD [72].

gression and severity.

Cholesterol efflux is induced to balance the level of macrophage storing lipid by transferring increased cholesterol from peripheral tissues to the liver. The primary cholesterol efflux mechanism has been thought that cholesterols are hydrolyzed cholesteryl esters cytosolic hydrolases; free cholesterols are moved to the plasma membrane; finally free cholesterols are delivered to the periphery by ATP-binding cassette transporters (ABCA1 or ABCG1) [63]. Autophagic malfunction of macrophages abrogates this cholesterol efflux when macrophages are faced to hinder autophage by chemically (chloroquine) or genetically (*Atg*5 deficiency). Furthermore, inhibitors of lysosomal acid lipase also diminish cholesterol efflux. These showed that cholesterol hydrolysis as well as autophagic delivery is a critical step in atherosclerotic plaque progression and regression. Although lipid-laden macrophages induce lipophagy and also trigger a counter regulatory mechanism are unclear, it is clear that lipophagy-mediated efflux plays an important role in cholesterol transport in vivo [7]. Therefore, efficient cholesterol metabolism and efflux considered athero-protective mechanisms against accumulated lipid-laden atherogenic condition [64].
