Tricaprin can prevent the development of AAA by attenuating aortic degeneration.

Medical therapeutic options to prevent rupture of abdominal aortic aneurysm (AAA), a critical event, must be developed. Moreover, further understanding of the process of AAA development and rupture is crucial. Previous studies have revealed that aortic hypoperfusion can induce the development of AAA, and we successfully developed a hypoperfusion-induced AAA animal model. In this study, we examined the effects of medium-chain triglycerides (MCTs), tricaprylin (C8-TG) and tricaprin (C10-TG), on hypoperfusion-induced AAA rat model. We estimated the effects of MCTs on aortic pathologies, mechanical properties of the aorta, and development of AAA. C10-TG, but not C8-TG, significantly suppressed AAA development and completely prevented the rupture. We observed that C10-TG prevented the development and rupture of AAA, but not C8-TG. Additionally, regression of AAA diameter was observed in the C10-TG group. Pathological analysis revealed C10-TG improved the hypoperfusion-induced increase in hypoxia-inducible factor-1α levels, medial smooth muscle cells (SMCs) loss, degeneration of aortic elastin and collagen fibers, and loss of aortic wall elasticity. In addition, regression of the formed AAA was observed by administration of C10-TG after AAA formation. C10-TG administration after AAA formation improved degeneration of AAA wall including degradation of aortic elastin and collagen fibers, stenosis of vasa vasorum, and loss of medial SMCs. These data suggest C10-TG can prevent AAA by attenuating aortic hypoperfusion and degeneration. Considering the clinical safety of C10-TG, C10-TG can be a promising AAA drug candidate.

Survey of Food Intake in Patients with Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a vascular disease that involves asymptomatic progressive expansion of the abdominal aorta. Aneurysm rupture is associated with a high mortality rate. Dietary conditions may be associated with the development and rupture of AAA. However, the relationship between nutrition and AAA is not completely understood. In this study, a nutrition survey was conducted using a brief self-administered diet history questionnaire (BDHQ) to evaluate the relationship between AAA and dietary habits. One-hundred and twenty-six Japanese people participated in the nutrition survey. Food intake status was analyzed in four groups: the analyzed group-1 (all men), analyzed group-2 (men with smoking history), analyzed group-3 (all women) and analyzed group-4 (women without smoking history). In group-2 and group-3, the intake of citrus fruits was significantly lower in the AAA group than in the non-AAA group. In group-2, the intake of soybean and soybean products was significantly lower in the AAA group than in the non-AAA group. In analyzed group-3, the intake of other vegetables (vegetables except for green and yellow vegetables and soybeans) and seafood was significantly lower in the AAA group than in the non-AAA group. This study suggests that AAA onset may be associated with low intake of fruits, soybeans, vegetables, and seafood.

Visualization of Functional Food Factors by Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry.

Dietary habit is closely associated with healthspan. Functional food factors are key to maintaining a health metabolism in our bodies. Because functional food factors are main components to determine the quality of foods, many technologies have been established to analyze functional factors in foods. High-performance liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry is a solid approach to detect functional food factors with high sensitivity and specificity. Findings obtained from these mass spectrometric approaches play essential roles in estimating the quality of foods. However, these technologies are not available for the analysis of the spatial distribution of molecules of interest in foods. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is considered an ideal approach to visualize distribution of molecules in foods. MALDI-MSI is a two-dimensional MALDI-MS technology that can detect compounds in a tissue section without purification, separation, or labeling. MALDI-MSI can be used to visualize the spatial distribution of wide range of food components including protein, peptides, amino acids, lipids, carbohydrate, and vitamins. Although the methodology of MALDI-MSI in food science is not yet fully established, the versatility of MALDI-MSI is expected to open a new frontier in food science. In this mini review, we briefly summarized the applications of MALDI-MSI in the field of food science.

Eicosapentaenoic acid is associated with the attenuation of dysfunctions of mesenchymal stem cells in the abdominal aortic aneurysm wall.

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by progressive dilation of the aorta which is reportedly associated with inflammation. Previous studies suggested that eicosapentaenoic acid (EPA) has suppressive effects on AAA development via anti-inflammatory activities. However, relationships between the anti-inflammatory effects and the cells in the AAA wall are poorly understood. In this study, we visualized the distribution of EPA-containing phosphatidylcholine (EPA-PC) in the AAA wall. EPA-PC was not ubiquitously distributed in both animal (hypoperfusion-induced AAA model) and human AAA walls, suggesting the preferential incorporation of EPA into certain cells. In the EPA-PC-high region of both animal and human AAAs, mesenchymal stem cell (MSC) marker positive areas were significantly higher than those in the EPA-PC-low region. Matrix metalloproteinase-positive MSCs were significantly lower in the AAA wall of the animal model which was administered EPA-rich fish oil. These data suggest that EPA is associated with the attenuation of MSC dysfunctions, which result in the suppression of AAA development.

Administration of Isoflavone Attenuates Ovariectomy-induced Degeneration of Aortic Wall.

Women are more resistant to vascular diseases; however, the resistance is reduced after menopause. It has been reported that the risk of vascular diseases such as atherosclerosis and abdominal aortic aneurysm is increased in postmenopausal women. Currently, methods to prevent vascular disease in postmenopausal women have not been established. Isoflavones are promising functional food factors that have a chemical structure similar to estrogen. In this study, we investigated the effects of isoflavones on ovariectomized (OVX)-induced degeneration of the aortic wall in mice. Increased destruction of elastic fibers in the thoracic and abdominal aorta was observed in the OVX group, and isoflavones attenuated the destruction of elastic fibers. The positive areas of matrix metalloproteinase (MMP)-2 and MMP-9 in the OVX group were higher than those in the control group. Isoflavones decreased the positive areas of MMP-2 and MMP-9 compared to those in the OVX group. These data suggest that isoflavones have a suppressive effect on OVX-induced degeneration of the aortic wall by inhibiting the increase in MMP-2 and MMP-9.

Ovariectomy Causes Degeneration of Perivascular Adipose Tissue.

Women are more resistant than men to the development of vascular diseases. However, menopause is a factor leading to deterioration of female vascular integrity, and it is reported that the risk of vascular diseases such as atherosclerosis and abdominal aortic aneurysm is increased in postmenopausal women. Although it is suggested that perivascular adipose tissue (PVAT) is deeply involved in the increased risk of vascular disease development, the effect of menopause on PVAT integrity is unknown. In this study, we aimed to elucidate the effect of menopause on PVAT in ovariectomized (OVX) rats. PVAT was divided into 4 regions based on characteristics. Hypertrophy and increased inflammation of adipocytes in the PVAT were observed in the OVX group, but the effects of OVX were different for each region. OVX induced matrix metalloproteinase (MMP) -9 which degrade extracellular matrix such as elastin and collagen fibers in PVAT. Degeneration of the arterial fibers of the thoracic and abdominal aorta were observed in the OVX group. These results indicate that OVX can cause dysfunction of PVAT which can cause degradation of arterial fibers. Appropriate management of PVAT may play an important role in the prevention and treatment of diseases originating from ovarian hypofunction.

Different effects of high-fat and high-sucrose diets on the physiology of perivascular adipose tissues of the thoracic and abdominal aorta.

Vascular diseases such as atherosclerosis and aneurysms are associated with diet. Perivascular adipose tissue (PVAT) was reportedly involved in the regulation of vascular functions. It is suggested that imbalanced diets can cause PVAT inflammation and dysfunction as well as impaired vascular function. However, the association between diets and PVAT are not clearly understood. Here, we showed that a high-fat and a high-sucrose diet affected PVAT at different sites. A high-fat diet induced increased number of large-sized lipid droplets and increased CD (Cluster of differentiation) 68+ macrophage- and monocyte chemotactic protein (MCP)-1-positive areas in the abdominal aortic PVAT (aPVAT). In addition, a high-fat diet caused decreased collagen fibre-positive area and increased CD68+ macrophage- and MCP-1-positive areas in the abdominal aorta. In contrast, a high-sucrose diet induced increased number of large-sized lipid droplets, increased CD68+ macrophage- and MCP-1-positive areas, and decreased UCP-1 positive area in the thoracic aortic PVAT (tPVAT). A high-sucrose diet caused decreased collagen fibre-positive area and increased CD68+ macrophage- and MCP-1-positive areas in the thoracic aorta. These results could be attributed to the different adipocyte populations in the tPVAT and aPVAT. Our results provide pathological evidence to improve our understanding of the relationship between diet and vascular diseases.

Low glucose and serum levels cause an increased inflammatory factor in 3T3-L1 cell through Akt, MAPKs and NF-кB activation.

Abdominal aortic aneurysm (AAA) involves the degradation of vascular fibres, and dilation and rupture of the abdominal aorta. Hypoperfusion in the vascular walls due to stenosis of the vasa vasorum is reportedly a cause of AAA onset and involves the induction of adventitial ectopic adipocytes. Recent studies have reported that ectopic adipocytes are associated with AAA rupture in both human and hypoperfusion-induced animal models, highlighting the pathological importance of hypoperfusion and adipocytes in AAA. However, the relationship between hypoperfusion and AAA remains unknown. In this study, we investigated the changes in inflammation-related factors in adipocytes at low glucose and serum levels. Low glucose and serum levels enhanced the production of AAA-related factors in 3T3-L1 cells. Low glucose and serum levels increased the activation of protein kinase B (also known as Akt), extracellular signal-regulated protein kinase 1/2, p38, c-Jun N-terminal kinase, and nuclear factor (NF) кB at the protein level. The inflammatory factors and related signalling pathways were markedly decreased following the return of the cells to normal culture conditions. These data suggest that low glucose and serum levels increase the levels of inflammatory factors through the activation of Akt, mitogen activated protein kinase, and NF-κB signalling pathways.

Similar distribution of orally administered eicosapentaenoic acid and M2 macrophage marker in the hypoperfusion-induced abdominal aortic aneurysm wall.

Abdominal aortic aneurysm (AAA) is an aortic disease in which the aortic diameter is ≥3.0 cm; if left untreated, the aortic wall continues to weaken, resulting in progressive dilatation. Effective therapeutic drugs for AAA patients have not been discovered. Eicosapentaenoic acid (EPA) reportedly attenuates the development of AAA in experimental AAA animal models. However, the underlying mechanism of action is still not totally clear. To understand the mechanism, we visualized the distribution of EPA-containing phosphatidylcholine (PC) in the AAA wall by matrix-assisted laser desorption ionization-mass spectrometry imaging. EPA-containing PC was characteristically distributed in the AAA wall, and the positive area for the M2 macrophage marker was significantly higher in the region where EPA-containing PC was highly detected (region 2) than in the region where EPA-containing PC was poorly detected (region 1). The M1 macrophage marker levels were not different between regions 1 and 2. A comparative observation showed a similar distribution of the M2 macrophage marker and EPA-containing PC. These data suggest the preferential incorporation of EPA into M2 macrophages. Positive areas for matrix metalloproteinase 2 and malondialdehyde in region 2 were significantly lower than those in region 1. The reported suppressive effect of EPA on the development of AAA may be partly attributed to the increased anti-inflammatory property of M2 macrophages.

Time-Dependent Pathological Changes in Hypoperfusion-Induced Abdominal Aortic Aneurysm.

Hypoperfusion due to vasa vasorum stenosis can cause wall hypoxia and abdominal aortic aneurysm (AAA) development. Even though hypoperfusion is an important contributor toward pathological changes in AAA, the correlation between hypoperfusion and AAA is not fully understood. In this study, a time-dependent semi-quantitative pathological analysis of hypoperfusion-induced aortic wall changes was performed to understand the mechanisms underlying the gradual degradation of the aortic wall leading to AAA formation. AAA-related factors evaluated in this study were grouped according to the timing of dynamic change, and five groups were formed as follows: first group: angiotensin II type 1 receptor, endothelin-1 (ET-1), and malondialdehyde (MDA); second group: matrix metalloproteinase (MMP)-2, -9, -12, M1 macrophages (Mac387+ cells), and monocyte chemotactic protein-1; third group: synthetic smooth muscle cells (SMCs); fourth group: neutrophil elastase, contractile SMCs, and angiotensinogen; and the fifth group: M2 macrophages (CD163+ cells). Hypoxia-inducible factor-1α, ET-1, MDA, and MMP-9 were colocalized with alpha-smooth muscle actin cells in 3 h, suggesting that hypoperfusion-induced hypoxia directly affects the activities of contractile SMCs in the initial stage of AAA. Time-dependent pathological analysis clarified the cascade of AAA-related factors. These findings provide clues for understanding complicated multistage pathologies in AAA.

The Seed Coat Extract of Black Soybean Decreases Nicotine-Induced Vascular Fiber Degradation by Suppressing Matrix Metalloproteinase 2 Expression.

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by weakening of vascular walls and progressive dilation of the abdominal aorta. Nicotine, the main component of tobacco, is reportedly associated with the development and rupture of AAA. It is desirable to attenuate the destructive effect of nicotine on vascular walls, using dietary food components. However, effective methods for preventing AAA progression using dietary food components remain unestablished. This study focuses on proanthocyanidins, well known for their potent antioxidant activity. We speculated that proanthocyanidins can suppress nicotine-induced weakening of vascular walls. To estimate the effect of black soybean seed coat extract (BSSCE), rich in proanthocyanidins, on nicotine-induced weakening of the aortic wall, mice were divided into four groups: the control diet and distilled water group (named C), BSSCE solution diet and distilled water group (named B), control diet and 0.5 mg/mL nicotine solution group (named CN), and BSSCE solution diet and 0.5 mg/mL nicotine solution group (named BN). Nicotine-induced degradation of elastin and collagen fibers were significantly suppressed in BN group. The positive areas for matrix metalloproteinase (MMP)-2 and oxidative stress in BN group were significantly decreased compared to those in CN group. These results suggest that proanthocyanidins-rich BSSCE can prevent the weakening of the aortic wall via inhibiting MMP-2 upregulation.

The Role of Animal Models in Elucidating the Etiology and Pathology of Abdominal Aortic Aneurysms: Development of a Novel Rupture Mechanism Model.

Existing animal models do not replicate all aspects of abdominal aortic aneurysms (AAAs), including the rupture mechanisms. From histopathological analyses conducted in humans, it has been found that the vasa vasorum of the AAA wall is the starting point of circulatory failure and that bulging and dilatation of the abdominal aorta occurs through inflammation and tissue degeneration. We created a new animal model (the hypoperfusion-induced model) of AAAs. In this study, we describe the current animal models of AAAs and present the utility of our new model of AAAs.

Ovariectomy increases the incidence and diameter of abdominal aortic aneurysm in a hypoperfusion-induced abdominal aortic aneurysm animal model.

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by weakening of the vascular walls. Male sex is a risk factor for AAA, and peak AAA incidence occurs in men 10 years earlier than in women. However, the growth rate of AAA is faster in women, and women have a higher mortality due to AAA rupture. The mechanisms underlying sex-related differences in AAA remain unknown. Herein, we evaluated the effects of ovariectomy (OVX) on AAA in rats. Upon evaluation of the effects of OVX and AAA induction, AAA incidence rate and the aneurysm diameter increased in the OVX group. However, the histopathology in the developed AAA wall was not different between groups. When the effects of OVX on the vascular wall without AAA induction were evaluated, elastin and collagen levels were significantly decreased. Furthermore, the level of matrix metalloproteinase-9 significantly increased in the OVX group. According to our results, it is speculated that decreased levels of collagen and elastin fibers induced by OVX might be involved in increased incidence rate and diameter of AAA. Weakening of the vascular wall before the onset of AAA might be one reason for the faster rate of AAA growth in women.

Isoflavone Ameliorated Oxidative Stress and Vascular Damages in Nicotine-Administrated Mice.

Nicotine has been linked to the development of abdominal aortic aneurysms. Isoflavones, a group of polyphenolic compounds, reportedly exhibit antioxidant and anti-inflammatory properties and facilitate cardiovascular protection. However, the effects of isoflavone on nicotine-induced abdominal aortic aneurysms have not yet been elucidated. The objective of the current study was to evaluate the inhibitory effect of isoflavone on nicotine-induced weakening of the aortic wall in mouse models. Nicotine reportedly increases the occurrence of abdominal aortic aneurysms by activating endothelin-1 (ET-1), angiotensinogen and the angiotensin II type 1 (AT1) receptor, leading to an increase in neutrophil elastase, oxidative stress, and matrix metalloproteinase (MMP)-2 expression, which causes vascular wall weakness and damage. Immunohistological analyses have indicated that isoflavone significantly inhibits the activation of ET-1, angiotensinogen and the AT1 receptor in nicotine-administered mice. Additionally, isoflavone suppressed elastic fiber destruction and decreased areas positive for MMP-2, neutrophil elastase, and malondialdehyde in the vascular wall of nicotine-administered mice. Considered together, these findings suggest that isoflavone shows potential for preventing vascular wall injury induced by nicotine administration, and that food containing isoflavone may protect against abdominal aortic aneurysms.

The role of perivascular adipose tissue in the appearance of ectopic adipocytes in the abdominal aortic aneurysmal wall.

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by the dilation of the abdominal aorta, resulting in a high mortality rate caused by vascular rupture. Previous studies have suggested that the abnormal appearance of adipocytes in the vascular wall is associated with the development of AAA. However, the mechanisms underlying the appearance of the ectopic adipocytes remain unknown. In this study, we showed that CD44+CD90+ MSCs express adipogenic transcription factors in the AAA wall of a hypoperfusion-induced AAA model. The number of CD44+CD90+ cells and adipocytes in the AAA wall significantly decreased in the perivascular adipose tissue (PVAT)-removed vascular wall. The AAA diameter significantly decreased in the PVAT-removed vascular wall compared with that in the vascular wall with PVAT. These data suggested that PVAT plays important roles in the differentiation of MSCs into adipocytes in response to vascular hypoperfusion. The decreased number of adipocytes in the PVAT-removed vascular wall might be associated with the decreased AAA diameter.

Sesame Extract Attenuates the Degradation of Collagen and Elastin Fibers in the Vascular Walls of Nicotine-administered Mice.

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by the weakening of the vascular walls and the progressive dilation of the abdominal aorta. Nicotine, a primary component of cigarette smoke, is associated with AAA development and rupture. Nicotine induces AAA development by weakening vascular walls. However, little is known about preventive methods using functional food factors for nicotine-induced vascular destruction. Sesamin and sesamolin are functional food factors that are fat-soluble lignans found in Sesamum indicum seeds. Previous reports indicated that sesamin and sesamolin have anti-oxidative and anti-inflammatory effects. In this study, we evaluated the effects of sesamin and sesamolin-rich sesame extract on the weakening of vascular walls in nicotine-administered mice. Sesame extract attenuated the degradation of collagen and elastin fibers caused by nicotine. In addition, sesame extract decreased the area positive for matrix metalloproteinase 12 (MMP-12) and oxidative stress in the vascular walls. These results suggest that sesame extract may decrease the weakening of vascular walls by suppressing the nicotine-induced degradation of collagen and elastin fibers. Sesame extract may be effective in preventing AAA development by decreasing both, MMP-12 expression and oxidative stress in vascular walls.

Appearance of Adipocytes in Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) is a lethal vascular disease that involves localized dilation of the thoracic aorta. The detailed mechanisms of TAA development and rupture are not fully understood. Recent reports have shown that the abnormal appearance of adipocytes in the vascular wall is associated with abdominal aortic aneurysm (AAA) progression or rupture. However, the presence of adipocytes in the TAA wall remains unknown. In this study, we observed the pathology of thoracic aortae to investigate whether adipocytes abnormally appear in the TAA wall. Abnormal appearance of adipocytes was mainly observed in the adventitia in the TAA vascular walls. The adipocyte area in the vascular wall was significantly increased in the TAA wall compared to the control wall. Destruction of collagen fibers, and increase in areas positive for matrix metalloproteinase (MMP) -2, MMP-9, and Mac387+ macrophages were observed in the area around adipocytes in the vascular wall. This study demonstrated the appearance of adipocytes in the TAA wall. The accumulation of adipocytes in AAA wall reportedly facilitates the destruction of fibers surrounding adipocytes, and thereby, leads to vascular wall weakness. Therefore, adipocytes in the TAA wall can be associated with the weakening of the vascular wall as well as the AAA wall. The appropriate control of adipocytes in the vascular wall may prevent weakening of the vascular wall in TAA.

Dietary DNA Attenuates the Degradation of Elastin Fibers in the Aortic Wall in Nicotine-Administrated Mice.

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by chronic inflammation in the infrarenal aorta. Epidemiologic data have clearly linked tobacco smoking to aneurysm formation and a faster rate of expansion. It suggested that nicotine, one of the main ingredients of tobacco, has been suggested to be associated with AAA development and rupture. In the condition where no established drugs are available; therefore, an effective approach to prevent the vascular damage from nicotine consumption may be the use of dietary functional food factors. However, little is known about the relationship between dietary components and AAA. In this study, we estimated the effect of dietary deoxyribonucleic acid (DNA) on the vascular wall. After habituation for 5 d, the mice were divided into four groups: control diet and distilled water group (C), DNA-Na diet and distilled water group (DNA), control diet and 0.5 mg/mL nicotine solution group (C-Nic), DNA-Na diet, and 0.5 mg/mL nicotine solution group (DNA-Nic). The dietary DNA attenuated the degradation of elastin fibers induced by nicotine administration. The areas stained positive for MMP-2 in the DNA-Nic group were significantly suppressed compared to C-Nic mice. These data suggest that the dietary DNA may prevent the weakening of the aortic wall via inhibition of the MMP-2-dependent pathway. In conclusion, we have revealed the protective effect of dietary DNA on the vascular pathology of nicotine-administrated mice. A nucleic acid-rich diet might be useful for people who consume nicotine via smoking, chewing tobacco, or nicotine patches.

Pathological Implication of Adipocytes in AAA Development and the Rupture.

Abdominal aortic aneurysm (AAA) is a vascular disease that involves the gradual dilation of the abdominal aorta followed by its rupture. AAA is closely associated with weakening of the vascular wall due to oxidative stress, chronic inflammation, and degradation of the extracellular matrix. No effective drug therapy is currently available for preventing aneurysm progression or rupture. Adipocytes in the vascular wall are reportedly closely associated with AAA development and rupture. Fiber degradation in the aneurysm wall is enhanced by increased numbers of adipocytes, and rupture risk may increase as well. Recent studies suggested that appropriate control of adipocytes in the vascular wall may be an important strategy to prevent AAA rupture, and further studies may aid in the establishment of a method for preventing AAA rupture by therapeutic drugs or functional foods. In this review, we summarize adipocyte function and the correlation between AAA and adipocytes.