Serum neutrophil gelatinase-associated lipocalin concentration reflects severity of coronary artery disease in patients without heart failure and chronic kidney disease.

Serum neutrophil gelatinase-associated lipocalin (NGAL) is recognized as a useful biomarker for acute kidney injury. Recently, elevated NGAL levels were reported in patients with heart failure and cardiac events, but the association between serum NGAL and severity of coronary artery disease (CAD) has not been investigated adequately. This study aimed to evaluate the association between serum NGAL concentration and CAD severity in patients without heart failure and chronic kidney disease. Two-hundred thirteen patients [mean age: 66.2 ± 9.2 (SD)] without heart failure and chronic kidney disease (estimated glomerular filtration rate >60 mL/min/1.73 m(2)) who underwent coronary angiography were retrospectively analyzed using the SYNTAX score. The mean concentration of serum NGAL was 134.3 ± 111.3 ng/mL. A statistically significant correlation was observed between serum NGAL levels and the SYNTAX score (R = 0.18, P = 0.0091). Multivariable analysis also showed elevated serum NGAL as an independent risk factor for a high SYNTAX score (P < 0.01). Moreover, we evaluated the association of serum NGAL and brain natriuretic peptide (BNP) with the SYNTAX score. Patients with high levels of serum NGAL (>100 ng/mL) and high levels of BNP (>25 pg/mL) had a higher SYNTAX score (low-low vs. high-high: 13.8 ± 13.4 vs. 20.8 ± 18.9, P < 0.05). Serum NGAL levels were positively and significantly associated with CAD severity, and the evaluation of both serum NGAL and BNP was useful for predicting CAD in patients without renal dysfunction and heart failure. Serum NGAL might be a biomarker for CAD severity.

Periodontitis May Deteriorate Sinus of Valsalva Dilatation in Marfan Syndrome Patients.

Marfan syndrome (MFS) is a systemic connective tissue disorder that is caused by mutations of fibrillin-1. While MFS patients are at a high risk of periodontitis and aortic diseases, little causal information has been provided to date. To clarify the relationship, their oral condition and sinus of Valsalva (SoV) were evaluated.The subjects were patients with MFS (n = 33) who attended the University of Tokyo Hospital. We divided them into two groups; MFS patients with highly dilated (the diameters were equal to or more than 39 mm) SoV (high group, n = 18) and MFS patients with mildly dilated (less than 39 mm) SoV (mild group, n = 15). Blood examinations, echocardiograms, and full-mouth clinical measurements, including number of teeth, probing pocket depth (PPD), bleeding on probing (BOP), and community periodontal index (CPI) were performed.We found that the high group patients had greater rates of BOP compared to that of the mild group. Furthermore, the high group tended to have higher serum levels of C-reactive protein, matrix metalloproteinase-9, and transforming growth factor-ß compared to the mild group.Periodontitis may deteriorate SoV dilatation in MFS patients.

Diverse contribution of bone marrow-derived late-outgrowth endothelial progenitor cells to vascular repair under pulmonary arterial hypertension and arterial neointimal formation.

AIMS: It is still controversial whether bone marrow (BM)-derived endothelial progenitor cells (EPCs) can contribute to vascular repair and prevent the progression of vascular diseases. We aimed to characterize BM-derived EPC subpopulations and to evaluate their therapeutic efficacies to repair injured vascular endothelium of systemic and pulmonary arteries. METHODS AND RESULTS: BM mononuclear cells of Fisher-344 rats were cultured under endothelial cell-conditions. Early EPCs appeared on days 3-6. Late-outgrowth and very late-outgrowth EPCs (LOCs and VLOCs) were defined as cells forming cobblestone colonies on days 9-14 and 17-21, respectively. Among EPC subpopulations, LOCs showed the highest angiogenic capability with enhanced proliferation potential and secretion of proangiogenic proteins. To investigate the therapeutic effects of these EPCs, Fisher-344 rats underwent wire-mediated endovascular injury in femoral artery (FA) and were concurrently injected intraperitoneally with 60mg/kg monocrotaline (MCT). Injured rats were then treated with six injections of one of three EPCs (1×10(6) per time). After 4weeks, transplanted LOCs, but not early EPCs or VLOCs, significantly attenuated neointimal lesion formation in injured FAs. Some of CD31(+) LOCs directly replaced the injured FA endothelium (replacement ratio: 11.7±7.0%). In contrast, any EPC treatment could neither replace MCT-injured endothelium of pulmonary arterioles nor prevent the progression of pulmonary arterial hypertension (PAH). LOCs modified protectively the expression profile of angiogenic and inflammatory genes in injured FAs, but not in MCT-injured lungs. CONCLUSION: BM-derived LOCs can contribute to vascular repair of injured systemic artery; however, even they cannot rescue injured pulmonary vasculature under MCT-induced PAH.

Involvement of P2Y12 receptor in vascular smooth muscle inflammatory changes via MCP-1 upregulation and monocyte adhesion.

Antiplatelet drugs, frequently used for cardiovascular events with thrombotic involvement, are also regarded as possible promising agents for cardiovascular primary prevention. The roles of P2Y12, an ADP receptor and the target of thienopyridine antiplatelet drugs, are not satisfactorily known in the vascular wall. We investigated the hypothesis that vascular smooth muscle cell (VSMC) P2Y12 is involved in vascular wall inflammatory changes by upregulating monocyte chemoattractant protein-1 (MCP-1) and promoting monocyte adhesion. ADP at 10(-5) M induced a 3.6 ± 0.3-fold upregulation of MCP-1 mRNA in cultured rat VSMCs, which was significantly inhibited by R-138727, the active metabolite of P2Y12 inhibitor prasugrel and siRNAs against P2Y12. ADP also induced MCP-1 protein upregulation, which was diminished by R-138727 and P2Y12 siRNAs. JNK (c-Jun NH2-terminal kinase) inhibition attenuated ADP-induced MCP-1 mRNA and protein upregulation. R-138727 and P2Y12 siRNAs inhibited ADP-induced JNK activation. The reactive oxygen species (ROS) inhibitors N-acetylcysteine (NAC), diphenyleneiodonium (DPI), and Tempol also diminished MCP-1 upregulation and JNK activation induced by ADP. ADP induced MCP-1 promoter activation, which was inhibited by R-138727 and P2Y12 siRNAs. Nuclear factor-κB (NF-κB) consensus sites in the MCP-1 promoter region were involved in this activation. ADP-induced NF-κB pathway activation, examined by a plasmid containing multiple NF-κB sites, was diminished by P2Y12 inhibition. For cellular function analysis, stimulation of VSMC with ADP increased subsequent THP-1 monocyte adhesion. P2Y12 siRNAs and CCR2 antagonism diminished this ADP-induced monocyte adhesion. These data suggested that ADP, via the VSMC P2Y12 receptor, induces vascular inflammatory changes by upregulating MCP-1 and promoting monocyte adhesion.

Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: Case report and review of literature.

Congenital contractural arachnodactyly (CCA) is a connective tissue disease caused by mutations of the FBN2, which encodes fibrillin-2. CCA patients have a marfanoid habitus; however, aortic dilatation and/or dissection as observed in Marfan syndrome have been rarely documented. Here, we report on a Japanese familial case of CCA resulting from a FBN2 splicing mutation (IVS32+5g→a), which leads to exon 32 being skipped, and the patients developed aortic dilatation and type A dissection. Although CCA patients have been believed to have favorable prognoses, repetitive aortic imaging studies must be performed in some patients to detect possible aortic disease early, and genetic testing of FBN2 might be useful to identify such high-risk patients.

Effect of purified eicosapentaenoic acid on red cell distribution width in patients with ischemic heart disease.

A recent study showed eicosapentaenoic acid (EPA) is a promising treatment for prevention of coronary events in hypercholesterolemic patients. Meanwhile, a high red blood cell distribution width (RDW) is a known risk factor for cardiovascular events. However, few studies have addressed the association between EPA levels and RDW. We examined whether EPA administration reduced the levels of RDW in patients with ischemic heart disease (IHD). We retrospectively analyzed the data of 66 EPA-treated IHD patients, and these EPA-treated patients were compared with control IHD patients. The median follow-up period was 189 days in EPA-treated patients. All patients were not associated with anemia. In the follow-up period, the ratio of EPA levels to arachidonic acid levels (EPA/AA) was significantly increased. A significant decrease was observed in RDW at follow-up [ΔRDW (%); EPA vs. control = -0.34 ± 0.84 (SD) vs. 0.08 ± 0.86, P < 0.01]. These RDW changes were more marked in diabetic patients with high serum levels of high-sensitive C-reactive protein (hs-CRP) [ΔRDW (%); EPA vs. control = -0.53 ± 0.69 vs. 0.56 ± 0.85, P < 0.01]. There was no correlation between the amount of change in EPA/AA and RDW (R = 0.037, P = 0.32), but a significant negative correlation was observed in diabetic patients with high hs-CRP levels (N = 14, R = -0.506, P = 0.046). In conclusion, EPA has the potential to reduce RDW in IHD patients. This effect was intensified especially among diabetic patients with high hs-CRP levels. IHD patients with high RDW levels may be suitable for treatment with purified EPA.

Response of urinary liver-type fatty acid-binding protein to contrast media administration has a potential to predict one-year renal outcome in patients with ischemic heart disease.

Urinary liver-type fatty acid-binding proteins (uL-FABP) have recently been recognized as a useful biomarker for predicting contrast-induced nephropathy. Although accumulating studies have evaluated short-term outcomes, its prognostic value for long-term renal prognosis in patients undergoing coronary angiography (CAG) has not been fully examined. This study aimed to evaluate the predictive value of uL-FABP for long-term renal outcome in patients with ischemic heart disease (IHD). Consecutive 24 patients with impaired renal function (serum creatinine >1.2 mg/dL) who underwent CAG were enrolled. uL-FABP was measured before CAG, 24 and 48 h after CAG. The changes in estimated glomerular filtration rate (eGFR) throughout CAG and at 1 year later were compared with the uL-FABP levels. The patients with a greater decrease in eGFR 1 year later had higher uL-FABP levels at all points, but only the value at 48 h after CAG reached statistical significance (lower vs. higher decreased eGFR group, 4.61 ± 3.87 vs. 17.71 ± 12.96; P < 0.01). Measurement of uL-FABP at 48 h after CAG (48h-uL-FABP) showed better correlation with the change in eGFR (pre-CAG uL-FABP vs. 48h-uL-FABP: R = 0.27, P = 0.20 vs. R = 0.65, P < 0.01). Moreover, the high-pre and high-48h-uL-FABP group showed a significantly larger decrease in eGFR compared with the high-pre and low-48h-uL-FABP group (change in eGFR; 8.12 ± 4.06 vs. 1.25 ± 2.23 mL/min/1.73 m2, P < 0.01), although the baseline eGFR levels were similar between these two groups. In this pilot study, measurement of uL-FABP levels at 48 h after CAG may be useful in detecting renal damage, and in predicting 1-year renal outcome in IHD patients undergoing CAG.

High incidence and severity of periodontitis in patients with Marfan syndrome in Japan.

Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the extracellular matrix protein fibrillin-1. While it is known that patients with MFS are at high risk of dental disorders and cardiovascular diseases, little information has been provided to date. To clarify the prevalence of periodontitis in patients with MFS, their oral condition and cardiovascular complications were evaluated. The subjects were patients with MFS (n = 40) who attended the University of Tokyo hospital; age- and gender-matched healthy individuals (n = 14) constituted a control group. Cardiovascular complications and full-mouth clinical measurements, including number of teeth, probing of pocket depth (PD), bleeding on probing (BOP), and community periodontal index (CPI) were recorded. MFS patients had more frequent cardiovascular complications (95 %) compared with the controls (0 %). MFS patients had periodontitis (CPI 3 and 4) more frequently (87.5 %) than the age- and gender-matched control subjects (35.7 %). Furthermore, MFS patients had significantly more severe periodontitis (CPI 2.90 ± 0.12 vs 1.64 ± 0.32) and fewer remaining teeth (26.7 ± 0.4 vs 28.4 ± 0.4) compared with the controls. However, PD and BOP were comparable between MFS patients and the control group. A high incidence of periodontitis and cardiovascular complications was observed in Japanese MFS patients.

Incidence of periodontitis in Japanese patients with cardiovascular diseases: a comparison between abdominal aortic aneurysm and arrhythmia.

Although there is a link between periodontitis and cardiovascular disease (CVD), the influence of periodontitis on CVD is unclear. The aim of this study was to assess the relationship between periodontal bacterial burden and CVD. We studied 142 patients with tachyarrhythmia (TA) and 25 patients with abdominal aortic aneurysm (AAA). We examined periodontitis and the presence of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans and Prevotella intermedia in the patients' saliva and subgingival plaque using PCR. We also measured serum antibody titers against the pathogens using ELISA. We found that the patients with AAA had fewer remaining teeth (14.6 ± 2.0 vs. 20.9 ± 0.7, P < 0.05) and deeper pocket depth (3.01 ± 0.26 vs. 2.52 ± 0.05 mm, P < 0.05) compared to the TA patients. The existence of each periodontal bacterium in their saliva or subgingival plaque and serum antibody titers was comparable between the two groups. Periodontitis may have a larger affect on aneurysm progression compared to arrhythmia.

Effect of periodontitis on cardiovascular manifestations in Marfan syndrome. Critical common role of TGF-ß.

Marfan syndrome (MFS) is a systemic connective tissue disorder that is caused by mutations in the extracellular matrix protein fibrillin-1. While MFS patients are considered to be at high risk of dental disorders and cardiovascular complications, little causal relationship has been provided to date. It is well known that an elevated level of active TGF-ß in the plasma is a major manifestation of MFS. TGF-ß is known to play a critical role in the development of cardiovascular diseases and its levels were also elevated in the serum and saliva of periodontitis patients. These findings may suggest an association between periodontitis and the cardiovascular complications of MFS. In this article, we review the influence of periodontitis in MFS patients with cardiovascular complications in order to identify critical therapeutic targets of TGF-ß.

A design strategy for small molecule-based targeted MRI contrast agents: their application for detection of atherosclerotic plaques.

Gadolinium(III) ion (Gd(3+)) complexes are widely used as contrast agents in magnetic resonance imaging (MRI), and many attempts have been made to couple them to sensor moieties in order to visualize biological phenomena of interest inside the body. However, the low sensitivity of MRI has made it difficult to develop practical MRI contrast agents for in vivo imaging. We hypothesized that practical MRI contrast agents could be designed by targeting a specific biological environment, rather than a specific protein such as a receptor. To test this idea, we designed and synthesized a Gd(3+)-based MRI contrast agent, 2BDP3Gd, for visualizing atherosclerotic plaques by linking the Gd(3+)-complex to the lipophilic fluorophore BODIPY to stain lipid-rich environments. We found that 2BDP3Gd was selectively accumulated into lipid droplets of adipocytes at the cellular level. Atherosclerotic plaques in the aorta of Watanabe heritable hyperlipidemic (WHHL) rabbits were clearly visualized in T1-weighted MR images after intravenous injection of 2BDP3Gd in vivo.

Impairment of flow-mediated dilation correlates with aortic dilation in patients with Marfan syndrome.

Marfan syndrome is an inherited disorder characterized by genetic abnormality of microfibrillar connective tissue proteins. Endothelial dysfunction is thought to cause aortic dilation in subjects with a bicuspid aortic valve; however, the role of endothelial dysfunction and endothelial damaging factors has not been elucidated in Marfan syndrome. Flow-mediated dilation, a noninvasive measurement of endothelial function, was evaluated in 39 patients with Marfan syndrome. Aortic diameter was measured at the aortic annulus, aortic root at the sinus of Valsalva, sinotubular junction and ascending aorta by echocardiography, and adjusted for body surface area (BSA). The mean value of flow-mediated dilation was 6.5 ± 2.4 %. Flow-mediated dilation had a negative correlation with the diameter of the ascending thoracic aorta (AscAd)/BSA (R = -0.39, p = 0.020) and multivariate analysis revealed that flow-mediated dilation was an independent factor predicting AscAd/BSA, whereas other segments of the aorta had no association. Furthermore, Brinkman index had a somewhat greater influence on flow-mediated dilation (R = -0.42, p = 0.008). Although subjects who smoked tended to have a larger AscAd compared with non-smokers (AscA/BSA: 17.3 ± 1.8 versus 15.2 ± 3.0 mm/m(2), p = 0.013), there was no significant change in flow-mediated dilation, suggesting that smoking might affect aortic dilation via an independent pathway. Common atherogenic risks, such as impairment of flow-mediated dilation and smoking status, affected aortic dilation in subjects with Marfan syndrome.

Pathophysiology and Japanese clinical characteristics in Marfan syndrome.

Marfan syndrome is an autosomal dominant heritable disorder of the connective tissue, caused by mutations of the gene FBN1, which encodes fibrillin-1, a major component of the microfibrils of the extracellular matrix. Fibrillin-1 interacts with transforming growth factor-ß (TGF-ß), and dysregulated TGF-ß signaling plays a major role in the development of connective tissue disease and familial aortic aneurysm and dissection, including Marfan syndrome. Losartan, an angiotensin II blocker, has the potential to reduce TGF-ß signaling and is expected to be an additional therapeutic option. Clinical diagnosis is made using the Ghent nosology, which requires comprehensive patient assessment and has been proven to work well, but evaluation of some of the diagnostic criteria by a single physician is difficult and time-consuming. A Marfan clinic was established at the University of Tokyo Hospital in 2005, together with cardiologists, cardiac surgeons, pediatricians, orthopedists, and ophthalmologists in one place, for the purpose of speedy and accurate evaluation and diagnosis of Marfan syndrome. In this review, we discuss the recent progress in diagnosis and treatment of Marfan syndrome, and the characteristics of Japanese patients with Marfan syndrome.

High incidence of periodontitis in Japanese patients with abdominal aortic aneurysm.

Periodontitis is known to be a risk factor for abdominal aortic aneurysm (AAA). However, the influence of periodontitis on AAA in Japanese patients has not yet been elucidated. The aim of this clinical investigation was to assess the relationship between periodontal bacterial burden in AAA patients.We studied 12 AAA patients and 24 age- and sex-matched non-AAA cardiovascular patients. We examined periodontitis and the presence of the periodontal pathogens Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia in oral samples using polymerase chain reaction assays.We found that the AAA patients had deeper pocket depth compared to the non-AAA patients (3.53 ± 0.38 mm versus 2.67 ± 0.17 mm, P < 0.05). However, the populations of periodontal bacteria were comparable between the two groups. Periodontitis may have a greater effect on aneurysm progression compared to other cardiovascular diseases.

Clinical correlation of brachial artery flow-mediated dilation in patients with systemic sclerosis.

OBJECTIVE: To investigate the clinical significance of flow-mediated dilation (FMD) in systemic sclerosis (SSc). METHODS: Thirty-three SSc patients and 12 healthy controls were studied. Ultrasound assessment of the brachial artery FMD was performed on all subjects. The results were expressed as the percentage of increase in brachial artery diameter following hyperemia. RESULTS: Limited cutaneous SSc (lcSSc) patients had significantly lower FMD values than healthy controls (5.3 ± 2.7 versus 7.7 ± 2.0 %, p < 0.05), while the values in diffuse cutaneous SSc (dcSSc) patients (6.7 ± 4.0 %) were comparable to those in lcSSc patients and healthy controls. Although FMD values did not correlate with any clinical features in dcSSc patients, there was an inverse correlation between FMD values and disease duration in lcSSc patients (r = -0.64, p < 0.05). Furthermore, lcSSc patients with decreased FMD values showed significantly higher prevalence of digital ulcers and elevated right ventricular systolic pressure than those with normal values (for each; 75 versus 10 %, p < 0.05). CONCLUSION: The FMD values represent the severity of vascular damages, which progress along with disease duration and lead to digital ulcers and pulmonary arterial hypertension, in lcSSc patients.

[Current status and future perspectives in the research of Marfan syndrome].

Marfan syndrome is an autosomal dominant disorder, characterized by tall stature, long arms and legs, ectopia lentis, and aortic aneurysms and dissections. Recent research has revealed that these phenotypes are caused by mutations in fibrillin-1, the major structural component of elastic microfibrils, and the continuing dysregulation of transforming growth factor beta (TGFbeta) signaling is principally considered to be contributing to the pathophysiological background of the disease. Blockade of TGFbeta signaling by angiotensin II receptor antagonism is a novel promising therapeutic option, and thus such large clinical randomized controlled trials are underway. Here, we review the past development, current status and future perspectives in the research field for Marfan syndrome.

Inhibition of NF-κB activation by a novel IKK inhibitor reduces the severity of experimental autoimmune myocarditis via suppression of T-cell activation.

NF-κB, which is activated by the inhibitor of NF-κB kinase (IKK), is involved in the progression of inflammatory disease. However, the effect of IKK inhibition on the progression of myocarditis is unknown. We examined the effect of IKK inhibition on the progression of myocarditis. Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354; 15 mg·kg(-1)·day(-1)) or vehicle to EAM rats daily. Hearts were harvested 21 days after immunization. Although the untreated EAM group showed increased heart weight-to-body weight ratio, and severe myocardial damage, these changes were attenuated in the IKK inhibitor-treated group. Moreover, IKK inhibitor administration significantly reduced NF-κB activation and mRNA expression of IFN-γ, IL-2, and monocyte chemoattractant protein-1 in myocardium compared with vehicle administration. In vitro study showed that the IKK inhibitor treatment inhibited T-cell proliferation and Th1 cytokines production induced by myosin stimulation. The IKK inhibitor ameliorated EAM by suppressing inflammatory reactions via suppression of T-cell activation.

Periodontal bacteria aggravate experimental autoimmune myocarditis in mice.

Periodontitis is one of the most common infections in humans. Recently, published reports assert that periodontitis is associated with cardiovascular disease. Although it is said that viral, bacterial infections and autoimmune diseases may be the cause of myocarditis, the pathogenesis of it remains unclear. The aim of this study was to investigate the influence of a periodontal pathogen on experimental autoimmune myocarditis (EAM). Porphyromonas gingivalis (P.g.), PBS as a control, were injected into the mice. Histopathological and immunohistochemical analyses were performed. We examined heart mRNA levels using quantitative RT-PCR. The anti-P.g. IgG antibody level in plasma samples of the P.g.-injected group significantly increased compared with the PBS-injected group. Histopathological analysis detected that the myocarditis-affected areas and the fibrotic area in the P.g.-injected EAM group significantly increased compared with the PBS-injected EAM group (P < 0.05). Immunohistochemical analysis detected that more CD11b-positive cells were shown in the heart of the P.g.-injected EAM group compared with the PBS EAM-injected group (P < 0.05). Hearts from the P.g.-injected EAM group showed significantly increased expression of monocyte chemoattractant protein-1, IFN-γ, and matrix metalloproteinase-9 (MMP-9) mRNA compared with the hearts from the PBS-injected EAM group (P < 0.05). On day 7, serum levels of IL-6 were significantly enhanced in the P.g.-injected EAM group compared with the PBS-injected EAM group (P < 0.05). These results showed that P.g. injection could deteriorate EAM in mice through CD11b-positive cells, cytokines, and MMP-9 expression.

The ATP-binding cassette transporter ABCG2 protects against pressure overload-induced cardiac hypertrophy and heart failure by promoting angiogenesis and antioxidant response.

OBJECTIVE: ATP-binding cassette transporter subfamily G member 2 (ABCG2), expressed in microvascular endothelial cells in the heart, has been suggested to regulate several tissue defense mechanisms. This study was performed to elucidate its role in pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Pressure overload was induced in 8- to 12-week-old wild-type and Abcg2-/- mice by transverse aortic constriction (TAC). Abcg2-/- mice showed exaggerated cardiac hypertrophy and ventricular remodeling after TAC compared with wild-type mice. In the early phase after TAC, functional impairment in angiogenesis and antioxidant response in myocardium was found in Abcg2-/- mice. In vitro experiments demonstrated that ABCG2 regulates transport of glutathione, an important endogenous antioxidant, from microvascular endothelial cells. Besides, glutathione transported from microvascular endothelial cells in ABCG2-dependent manner ameliorated oxidative stress-induced cardiomyocyte hypertrophy. In vivo, glutathione levels in plasma and the heart were increased in wild-type mice but not in Abcg2-/- mice after TAC. Treatment with the superoxide dismutase mimetic ameliorated cardiac hypertrophy in Abcg2-/- mice after TAC to the same extent as that in wild-type mice, although cardiac dysfunction with impaired angiogenesis was observed in Abcg2-/- mice. CONCLUSION: ABCG2 protects against pressure overload-induced cardiac hypertrophy and heart failure by promoting angiogenesis and antioxidant response.

Angiopoietin-1 mediates adipose tissue-derived stem cell-induced inhibition of neointimal formation in rat femoral artery.

BACKGROUND: Adipose tissue-derived stem cells (ASC) produce a variety of cytokines that potentially mediate the proangiogenic and antiapoptotic effects of the ASC. We examined whether ASC produced angiopoietin-1 (Ang1) and whether Ang1 functionally mediated ASC-induced suppression of neointimal formation. METHODS AND RESULTS: Ang1 production was measured by enzyme-linked immunosorbent assay. Production of endogenous Ang1 by ASC was inhibited with small interfering RNA (siRNA) for Ang1. Overproduction of Ang1 was achieved with an adenovirus that expresses Ang1 (AdAng1). ASC expressing Ang1 siRNA, or AdAng1 were administered around the femoral artery after wire injury, and immunohistochemical analysis was performed to examine their effects on neointimal formation. ASC produced Ang1 in a time-dependent manner, especially when cultured in medium containing growth factors for vascular endothelial cells. When ASC were treated with Ang1 siRNA, the inhibitory effect of ASC on neointimal formation was significantly reduced. Knockdown of Ang1 significantly increased macrophage infiltration in the neointima, and significantly decreased endothelial regeneration. In contrast, forced expression of Ang1 using AdAng1 significantly suppressed neointimal formation and macrophage infiltration, and stimulated reendothelialization. CONCLUSIONS: Ang1 was implicated in ASC-induced suppression of neointimal formation. The results also suggested that Ang1 inhibited neointimal formation via stimulation of reendothelialization and suppression of macrophage infiltration in the neointima.