|
 
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| REVIEW ARTICLE |
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| Year : 2016 | Volume
: 1
| Issue : 3 | Page : 90-94 |
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Fat, diet, and intracranial atherosclerosis
Jiamei Shen1, Xiaokun Geng2, James Stevenson3, Longfei Guan4, Yuchuan Ding1
1 China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
2 China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA; Department of Neurology, Beijing Luhe Hospital, Capital Medical University, China
3 Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
4 China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China
| Date of Submission | 06-Sep-2016 |
| Date of Acceptance | 13-Sep-2016 |
| Date of Web Publication | 12-Oct-2016 |
Correspondence Address:
Xiaokun Geng
Department of Neurology, Beijing Luhe Hospital, Capital Medical University, No. 82 Xinhua South Road, Tongzhou District, Beijing 101149, China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2468-5690.191978
Atherosclerosis in the cerebral vasculature is a major risk factor for death and disability. However, atherosclerosis has been primarily studied in the coronary vasculature despite the distinct characteristics of the brain's vessel morphometry and biochemistry. Recent preclinical work has established a rat model for studying intracranial atherosclerosis to optimize pharmacologic and lifestyle changes to prevent or reverse this disease. One such preventative strategy utilizes dietary omega-3 fatty acids (O3FAs), which have gained public interest due to its potential application in various diseases. A large number of studies of O3FA have examined the basic scientific framework, and this article examines its role as a dietary supplement to prevent the development of intracranial atherosclerotic stenosis. Keywords: Basilar artery, CD68, high cholesterol diet, internal carotid artery, intracranial atherosclerotic stenosis, middle cerebral artery, NG-nitro-L-arginine methyl ester, stroke
How to cite this article:
Shen J, Geng X, Stevenson J, Guan L, Ding Y. Fat, diet, and intracranial atherosclerosis. Environ Dis 2016;1:90-4 |
| Introduction | |  |
Atherosclerosis is a chronic complex disease that affects half of women and two-thirds of men after the age of 40. [1] The pathophysiologic changes that occur have been extensively studied in reference to lifestyle factors and pharmacologic therapies, but these have primarily focused on the coronary vasculature. Notably, intracranial atherosclerotic stenosis (ICAS) involving the major cerebral arteries (intracranial internal carotid artery, middle cerebral artery [MCA], vertebral artery, and basilar artery) is a disease state that has been implicated as a leading cause of recurrent ischemic stroke and transient ischemic attacks. [2],[3] There are several mechanisms by which ICAS can induce or contribute to cognitive deficits. These include in situ thrombosis, arterial emboli, hemodynamic compromise, and atherosclerotic occlusion of small arterial branch origins. [4] Functional impairment due to ICAS extends beyond the traditional presentation of stroke and according to the Baltimore Longitudinal Study of Aging, was a causal factor in 34% of dementia cases. [5] Of note, the Baltimore study demonstrated that increasing intracranial atherosclerosis significantly elevated the odds of dementia independent of the degree of cardiac or aortic atherosclerosis. Given the presence of cognitive impairment due to ICAS in which there is a lack of correlation to cardiac/aortic disease, it is pertinent to study this process intracranially and develop strategies to effectively prevent or reverse it. This is especially true because an optimal preventative therapy for symptomatic ICAS has not been established. [6] While statins are a common treatment for atherosclerosis, their efficacy has not been confirmed intracranially. A recent double-blind placebo-controlled study in humans demonstrated that simvastatin had no apparent effect on MCA stenosis over 2 years of treatment. [7]
Preclinical studies of atherosclerosis using animal models have mainly focused on the vasculature around the heart. [8],[9],[10],[11] Since there have been few studies investigating ICAS specifically, it is crucial to investigate the similarities and differences of intracranial atherosclerosis to its cardiac counterpart. Previous research from other vascular beds demonstrated that atherogenesis can be induced in rats by inhibiting nitric oxide synthase (NOS) with NG-nitro-L-arginine methyl ester (L-NAME). [12],[13] While this particular strategy has been primarily utilized for the study of heart disease, there has been a recent adaptation of this model centering around pelvic vessels for the study of erectile dysfunction. [14] A model developed by Park et al.[14] utilizes both L-NAME and high cholesterol (CHO) diet to rapidly induce atherosclerosis in the pelvic vasculature. Because rats are normally resistant to atherogenesis with increased dietary CHO, [15] 6 months is required to develop atherosclerosis in rats on a high CHO diet alone. The addition of L-NAME is necessary to induce endothelial dysfunction and allow the dyslipidemic rats to develop intimal changes.
Our recent study built off of this strategy to establish a model for intracranial atherosclerosis since this has not been effectively induced in rat cerebral vessels. [16] We demonstrated that temporary systemic inhibition of NOS combined with a CHO diet can also generate a reliable ICAS model in rats. The model of intracranial atherosclerosis that we developed consistently alters the morphometry of the major cerebral arteries in as soon as 6 weeks. This protocol induces atherogenic changes, which are characterized by CHO buildup and macrophage infiltration into the tunica media. The levels of low-density lipoprotein (LDL), CHO, and triglycerides (TGs) were elevated, and the high-density lipoprotein (HDL) was decreased by the high-CHO diet. These changes in lipid levels are consistent with proatherogenic conditions that directly contribute to vessel impairment. [10],[17] Another critical factor in the development of atherosclerosis is the induction of endothelial injury, which exposes the underlying cells to increased oxidative stress. Normally, the production of nitric oxide by NOS isoforms within endothelial cells provides vascular protection through several biological responses such as vasorelaxation, the inhibition of cell proliferation and migration, and extracellular matrix production. [18] The inhibition of NOS with L-NAME eliminates the protective property of nitric oxide and generates early atherosclerotic changes to the vasculature. [19] The disruption of the endothelium also increases the tendency of circulating LDL particles to enter the vessel wall where they are much more likely to become oxidized, triggering inflammation. This process is associated with and further exacerbated by, the recruitment of leukocytes into the arterial wall. [10],[20] The influx of monocytes happens in the early stage of atherosclerosis and results in their differentiation into macrophages. These activated macrophages are the main players in vascular damage as they absorb and retain the accumulated oxidized LDL. Unable to digest these lipids, they contribute to a destructive cycle of inflammation and further leukocyte recruitment. These infiltrating leukocytes can be identified early on through immunohistochemical staining of CD68, a membrane glycoprotein Type 1 that is found in endosomes and lysosomes and is strongly expressed by blood monocytes and tissue macrophages. [21],[22]
Among the therapeutic modalities for cardiovascular atherosclerosis, the effects of dietary omega-3 fatty acids (O3FAs) have received considerable attention but their efficacy for secondary prevention remains controversial. [19],[23],[24] Despite these mixed results, the effects of O3FAs such as α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have continued to be studied for various applications. [25],[26],[27],[28] Furthermore, studies of Mediterranean populations showed that regular consumption of dietary O3FA is associated with a lower incidence of cardiovascular disease. [29] Previous animal studies have shown improvement of several diseases by O3FA through a number of mechanisms. [23],[27],[30] Polyunsaturated fatty acids (500 µg/kg/day) have been shown to prevent chemically induced diabetes in experimental animals. [31] Barbosa et al. found beneficial effects of fish oil supplementation (1 g/kg/day body weight) on glucose and lipid metabolism in rats treated with dexamethasone for 15 days. [32] Another study demonstrated a reduction of inflammation due to O3FA intake (30 mg/kg/day for 10 days) through the expression and location of occludin in the aorta of adult Wistar rats after exposure to bacterial lipopolysaccharide. [33] With regards to atherosclerosis, the vast majority of the studies using O3FA have focused on cardiovascular disease. In contrast, very few O3FA studies and its effects on ICAS have been carried out. [28],[34],[35]
Given the gap of knowledge and the significant relationship between ICAS and stroke, it is crucial to understand whether O3FA intake might have similar antiatherogenic effects in intracranial vessels as those previously studied in cardiovascular disease. [36] This is particularly important from a public health perspective to develop an optimal preventative strategy for ICAS. A recent study carried out in our laboratory was designed to study O3FA intake in the context of cerebral atherosclerosis. [37] We examined the antiatherogenic mechanisms behind O3FA with regards to intracranial vessels, specifically, O3FA's efficacy on underlying anti-inflammatory and metabolic mechanisms for the prevention of ICAS.
O3FAs have been shown to prevent pro-inflammatory cytokines including monocyte chemotactic protein (MCP-1) and interferon-γ (IFN-γ) expression, both of which have been shown to be proatherogenic by attracting monocytes and macrophages to lesion sites. [35] Similarly, O3FA has been shown to decrease inducible NOS (iNOS), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), all of which are pro-inflammatory agents [38] involved in atherosclerosis. [39] In detail, iNOS has been shown to be a marker for M1 macrophages, which play a key role in atherosclerotic disease, while TNF-α and IL-6 are markers expressed by macrophages. [40] Of note, IL-6 is known to be involved in many inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis. [41] Shen et al. determined that O3FA consumption can prevent these harmful molecular cascades through multiple mechanisms at a concentration of 5 mg/kg/day by gavage. [37]
Endothelial activation, macrophage infiltration, and foam cell formation are early steps in atherogenesis. As such, atherosclerosis is primarily triggered in response to activation of the arterial endothelium which stimulates the release of monocytes and T-lymphocytes through the release of chemokines, such as MCP-1 and IFN-γ, which are expressed highly in atherosclerotic regions. [42] Although there are various factors known to induce the chemotactic migration of monocytes, the MCP-1 is the most potent and powerful inductor of their migration into atherosclerotic lesions. [43] In addition, there is an upregulation of adhesion molecules involved in the interaction of blood cells with the endothelium, such as vascular cell adhesion molecule-1 (VCAM-1). [44],[45],[46] Possessing immunoglobulin-like characteristics, VCAM-1 is expressed by endothelial cells in atherosclerotic lesions. It is thought to participate in neointima formation because it facilitates monocyte infiltration into injured arteries and also might directly enhance smooth muscle cell proliferation. [42],[44] VCAM-1 has been also been shown to increase the CHO efflux from macrophages through upregulation of the ATP-binding cassette transporter A1 (ABCA1) transporter in animal models. This is thought to be caused through the activation of silent information regulator 1 (SIRT1), an NAD + dependent deacetylase in endothelial cells that has been shown to be involved in protection against atherosclerosis. [47] The action of ABCA1 is important in reducing the CHO embedded in vascular plaques by transferring CHO from macrophages into circulating HDL particles. [47] The cytokine IFN-γ, a key regulator of immune function, is highly expressed in atherosclerotic lesions and has emerged as a significant factor in atherogenesis. [48] It has been shown that IFN-γ reduces the expression of ABCA1 at the protein and mRNA level. [49] O3FA intake promotes CHO efflux by indirectly upregulating ABCA1, which is important in reducing vascular plaques. Our results show that O3FA intake increases ABCA1 through SIRT1 activation, which is in concordance with previous studies. [50] In addition, O3FA intake reduces the level of IFN-γ, thereby sparing ABCA1 activity and preventing the buildup of CHO in the vessel walls.
O3FA administration can dramatically blunt the development of intracranial atherogenesis induced by a high-CHO diet. Our morphometric data show that O3FA treatment not only increased the MCA lumen diameter but also decreased both its media thickness and media-lumen ratio altered by a high-CHO diet. The anti-inflammatory effects of O3FA may contribute to its protective actions towards atherosclerosis formation and plaque rupture. [51] It was reported that O3FA reduces IFN-γ, iNOS, TNF-α, IL-6, VCAM-1, and MCP-1 protein expressions, thereby inhibiting the proatherogenic signaling cascade. These markers reflect changes in monocyte activity and serve as a better gauge for pro-inflammatory changes causing atherosclerosis. O3FA also critically inhibits the expression of these molecules in endothelial cells which are activated by various proinflammatory and proatherogenic stimuli. [52] DHA and EPA were shown to inhibit most of the critical events connected with endothelial activation, including the expression of VCAM-1. [28]
While LDL, CHO, and TG levels were significantly elevated and HDL levels were decreased by a high-CHO diet, they were reversed by O3FA treatment. These results are in agreement with other studies where O3FA supplementation led to the resolution of dyslipidemia and increased circulating HDL levels. [50],[53] In addition, O3FA has been found to favorably alter monocyte subsets independently from effects on plasma CHO. [28]
ICAS has been found to be especially prevalent in Black, Asian, Hispanic, Indian, and several Arabian populations, which suggests a substantial increase in strokes as aged populations in these regions continue to grow. [54] It is, therefore, pertinent and timely to explore novel therapeutic and preventative strategies to decrease the prevalence of this disease in high-risk populations. While O3FA intake has shown beneficial properties in numerous studies mostly centering around its primary prevention of cardiovascular atherosclerotic disease, [2],[28],[55],[56] few studies on O3FA's effects on the cerebral vasculature have been carried out to date. The improvement in ICAS modeling will hopefully facilitate new research in this area. Since ICAS is a major risk factor for ischemic stroke and cerebral aneurysms, further studies of atherosclerosis in the cerebral vasculature are warranted. [27],[46],[52] Despite the limitations of animal studies in relation to human physiology, there is sufficient evidence to continue investigations of O3FA intake for preventing ICAS.
Financial support and sponsorship
This work was partially supported by American Heart Association Grant-in-Aid (14GRNT20460246), Merit Review Award (I01RX-001964-01) from the US Department of Veterans Affairs Rehabilitation R and D Service, National Natural Science Foundation of China (81501141), Science and Technology Plan of Beijing Tongzhou District (KJ2016CX035) and Beijing New-star Plan of Science and Technology (xx2016061).
Conflicts of interest
There are no conflicts of interest.
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