Glutaredoxin-1 levels in plasma can predict future events in patients with cardiovascular diseases.

Reactive oxygen species that increase during cardiovascular disease (CVD) react with protein cysteine residues to form a glutathione adduct by S-glutathionylation, which is selectively removed by glutaredoxin-1 (Glrx). We previously showed that S-glutathionylation and Glrx play important roles in mouse models of CVD, such as heart failure and peripheral artery disease models. However, there are few clinical studies on Glrx in CVD. Although Glrx is a cytosolic protein expressed in various organs, it is detectable in human plasma. Studies have reported that Glrx in plasma is a potential disease maker, such as CVD and chronic kidney disease and diabetes, however, it remains unclear whether Glrx is related to the prognosis of patients with CVD. The purpose of this study was to elucidate whether Glrx levels in plasma are associated with future events in patients with CVD. Plasma levels of Glrx were measured in 555 patients with CVD who underwent cardiac catheterization using enzyme-linked immunosorbent assay. All patients were followed prospectively for ≤36 months or until occurrence of adverse events, including all-cause death, non-fatal myocardial infarction, and worsening heart failure. During a mean follow-up period of 33 months, 54 adverse events occurred. Kaplan-Meier analysis showed that higher levels of Glrx (>0.622 ng/mL, determined by receiver-operating characteristic curve) resulted in a higher probability for adverse events compared with lower levels of Glrx (≤0.622 ng/mL) (P < 0.01, log-rank test). Multivariate Cox proportional hazards analysis showed that Glrx was a significant predictor of adverse events after adjustment for known risk factors. In conclusion, levels of plasma Glrx >0.662 ng/mL can predict future events in patients with CVD.

Contrast-enhanced ultrasound imaging of carotid plaque neovascularization is useful for identifying high-risk patients with coronary artery disease.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) in the carotid artery has potential as a technique for imaging plaque neovascularization. This study examined whether CEUS could provide information on the severity and instability of coronary artery disease (CAD). METHODS AND RESULTS: A total of 304 patients with CAD and carotid plaque underwent CEUS examination of the carotid artery. Intraplaque neovascularization was identified on the basis of microbubbles within the plaque and graded as: G0, not visible; G1, moderate; or G2, extensive microbubbles. The complexity and extent of the coronary lesions were assessed angiographically. A higher grade of CEUS-assessed plaque neovascularization of the carotid artery was associated significantly with greater complexity (ρ=0.48 by Spearman's rank correlation test) and extent (ρ=0.51) of coronary lesions. G2 plaque neovascularization was a risk for acute coronary syndrome, independent of traditional risk factors (odds ratio 1.91, 95% confidence interval 1.04-3.53, P<0.01). Subgroup analysis showed that carotid CEUS-assessed neovascularization regressed in 12 (46%) of 26 plaques in patients during 6 months of statin treatment, whereas regression occurred in 2 (14%) of 14 plaques in patients not taking a statin (P=0.04, Chi-square test). CONCLUSIONS: CEUS examination of the carotid artery may provide valuable information on the severity and instability of CAD and also the efficacy of antiatherosclerotic treatment.

Endoscopic submucosal dissection of multiple flat adenomas in the radiated rectum.

We report a case of multiple flat adenomas and cancer of the rectum that occurred 15 years after pelvic irradiation following surgery for uterine cancer. Adenoma borders were diagnosed accurately by magnifying chromoendoscopy, leading to their adequate excision using endoscopic submucosal dissection. This enabled minimal dissection of the irradiated pelvis that would have otherwise been difficult. Furthermore, our approach probably helped minimize loss of bowel function, thereby preserving the patient's quality of life as much as possible. Pathology of the resected specimens revealed thickened walls of the submucosal layer vessels, indicating chronic radiation proctitis. Pelvic irradiation of the bowel carries a high risk of causing flat adenomas and cancer. Close and long-term surveillance may be useful in such cases, using not only conventional colonoscopy but also chromoendoscopy with indigo carmine dye spray and magnifying endoscopy.

Chronic depletion of glutathione exacerbates ventricular remodelling and dysfunction in the pressure-overloaded heart.

AIMS: Chronic depletion of myocardial glutathione (GSH) may play a role in cardiac remodelling and dysfunction. This study examined the relationship between chronic GSH depletion and cardiac failure induced by pressure overload in mice lacking the modifier subunit (GCLM) of glutamate-cysteine ligase, the rate-limiting enzyme for GSH synthesis. In addition, we examined the association between idiopathic dilated cardiomyopathy (DCM) in humans and -588C/T polymorphism of the GCLM gene, which reduces plasma levels of GSH. METHODS AND RESULTS: Pressure overload in mice was created by transverse aortic constriction (TAC). Myocardial GSH levels after TAC in GCLM(-/-) mice were 31% of those in GCLM(+/+) mice. TAC resulted in greater heart and lung-weight-to-body-weight ratios, greater dilation and dysfunction of left ventricle, more extensive myocardial fibrosis, and worse survival in GCLM(-/-) than GCLM(+/+) mice. Supplementation of GSH diethyl ester reversed the left-ventricular dilation and contractile dysfunction and the increased myocardial fibrosis after TAC in GCLM(-/-) mice. The prevalence of -588T polymorphism of the GCLM gene was significantly higher in DCM patients (n = 205) than in age- and sex-matched control subjects (n = 253) (36 vs. 19%, respectively, P < 0.001). The -588T polymorphism increased the risk of DCM that was independent of age, diabetes, and systolic blood pressure (OR 3.13, 95% CI: 2.28-4.44; P < 0.0001). CONCLUSION: Chronic depletion of GSH exacerbates remodelling and dysfunction in the pressure-overloaded heart. The clinical relevance of this mouse model is supported by a significant association between -588T polymorphism of the GCLM gene and patients with DCM.

Colonic epithelial cells express specific ligands for mucosal macrophage immunosuppressive receptors siglec-7 and -9.

Immune cells are known to express specific recognition molecules for cell surface glycans. However, mechanisms involved in glycan-mediated cell-cell interactions in mucosal immunity have largely been left unaccounted for. We found that several glycans preferentially expressed in nonmalignant colonic epithelial cells serve as ligands for sialic acid-binding Ig-like lectins (siglecs), the immunosuppressive carbohydrate-recognition receptors carried by immune cells. The siglec ligand glycans in normal colonic epithelial cells included disialyl Lewis(a), which was found to have binding activity to both siglec-7 and -9, and sialyl 6-sulfo Lewis(x), which exhibited significant binding to siglec-7. Expression of these siglec-7/-9 ligands was impaired upon carcinogenesis, and they were replaced by cancer-associated glycans sialyl Lewis(a) and sialyl Lewis(x), which have no siglec ligand activity. When we characterized immune cells expressing siglecs in colonic lamina propriae by flow cytometry and confocal microscopy, the majority of colonic stromal immune cells expressing siglec-7/-9 turned out to be resident macrophages characterized by low expression of CD14/CD89 and high expression of CD68/CD163. A minor subpopulation of CD8(+) T lymphocytes also expressed siglec-7/-9. Siglec-7/-9 ligation suppressed LPS-induced cyclooxygenase-2 expression and PGE(2) production by macrophages. These results suggest that normal glycans of epithelial cells exert a suppressive effect on cyclooxygenase-2 expression by resident macrophages, thus maintaining immunological homeostasis in colonic mucosal membranes. Our results also imply that loss of immunosuppressive glycans by impaired glycosylation during colonic carcinogenesis enhances inflammatory mediator production.

Disruption of group IVA cytosolic phospholipase A(2) attenuates myocardial ischemia-reperfusion injury partly through inhibition of TNF-α-mediated pathway.

Group IVA cytosolic phospholipase A(2) (cPLA(2)α), which preferentially cleaves arachidonic acid from phospholipids, plays a role in apoptosis and tissue injury. Downstream signals in response to tumor necrosis factor (TNF)-α, a mediator of myocardial ischemia-reperfusion (I/R) injury, involve cPLA(2)α activation. This study examined the potential role of cPLA(2)α and its mechanistic link with TNF-α in myocardial I/R injury using cPLA(2)α knockout (cPLA(2)α(-/-)) mice. Myocardial I/R was created with 10-wk-old male mice by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. As a result, compared with wild-type (cPLA(2)α(+/+)) mice, cPLA(2)α(-/-) mice had a 47% decrease in myocardial infarct size, preservation of echocardiographic left ventricle (LV) function (%fractional shortening: 14 vs. 21%, respectively), and lower content of leukotriene B(4) and thromboxane B(2) (62 and 50% lower, respectively) in the ischemic myocardium after I/R. Treatment with the TNF-α inhibitor (soluble TNF receptor II/IgG1 Fc fusion protein, sTNFR:Fc) decreased myocardial I/R injury and LV dysfunction in cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) mice. sTNFR:Fc also suppressed cPLA(2)α phosphorylation in the ischemic myocardium after I/R of cPLA(2)α(+/+) mice. Similarly, sTNFR:Fc exerted protective effects against hypoxia-reoxygenation (H/R)-induced injury in the cultured cardiomyocytes from cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) cardiomyocytes. H/R and TNF-α induced cPLA(2)α phosphorylation in cPLA(2)α(+/+) cardiomyocytes, which was reversible by sTNFR:Fc. In cPLA(2)α(-/-) cardiomyocytes, TNF-α induced apoptosis and release of arachidonic acid to a lesser extent than in cPLA(2)α(+/+) cardiomyocytes. In conclusion, disruption of cPLA(2)α attenuates myocardial I/R injury partly through inhibition of TNF-α-mediated pathways.

Group X secretory PLA2 in neutrophils plays a pathogenic role in abdominal aortic aneurysms in mice.

Group X secretory PLA(2) (sPLA(2)-X) is expressed in neutrophils and plays a role in the pathogenesis of neutrophil-mediated tissue inflammation and injury. This study tested the hypothesis that sPLA(2)-X in neutrophils may contribute to the pathogenesis of abdominal aortic aneurysms (AAA) using sPLA(2)-X(-/-) mice. AAA was created by application of CaCl(2) to external surface of aorta. As a result, the aortas of sPLA(2)-X(-/-) mice had smaller diameters (percent increase from baseline; 24.8 ± 3.5% vs. 49.9 ± 9.1%, respectively; P < 0.01), a reduced grade of elastin degradation, and lower activities of elastase and gelatinase (26% and 19% lower, respectively) after CaCl(2) treatment compared with sPLA(2)-X(+/+) mice. In sPLA(2)-X(+/+) mice, immunofluorescence microscopic images showed that the immunoreactivity of sPLA(2)-X was detected only in neutrophils within aortic walls 3 days, 1, 2, and 6 wk after CaCl(2) treatment, whereas the immunoreactivity was not detected in macrophages or mast cells in aortic walls. sPLA(2)-X immunoreactivity also was colocalized in cells expressing matrix metalloproteinase (MMP)-9. Neutrophils isolated from sPLA(2)-X(-/-) mice had lower activities of elastase, gelatinase, and MMP-9 in response to stimuli compared with sPLA(2)-X(+/+) mice. The attenuated release of elastase and gelatinase from sPLA(2)-X(-/-) neutrophils was reversed by exogenous addition of mouse sPLA(2)-X protein. The adoptive transfer of sPLA(2)-X(+/+) neutrophils days 0 and 3 after CaCl(2) treatment reversed aortic diameters and elastin degradation grades in the lethally irradiated sPLA(2)-X(+/+) mice reconstituted with sPLA(2)-X(-/-) bone marrow to an extent similar to that seen in sPLA(2)-X(+/+) mice. In conclusion, sPLA(2)-X in neutrophils plays a pathogenic role in AAA in a mice model.

[Recommendation for revision of the General Principles of Suicide Prevention Policy].

Since the promulgation of the Basic Act for Suicide Prevention, suicide prevention in Japan has developed rapidly. In order to further reinforce such activities, it is necessary to balance universal, selective, and indicated prevention. For the revision of the General Principles of Suicide Prevention Policy, the Center for Suicide Prevention announced this recommendation with 29 societies. We hope that it will promote suicide prevention in Japan and lead to expansion of the suicide prevention network by academic organizations, NGOs, as well as local and central government.

Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis.

BACKGROUND & AIMS: TWEAK, a member of the tumor necrosis factor (TNF) superfamily, promotes intestinal epithelial cell injury and signals through the receptor Fn14 following irradiation-induced tissue damage and during development of colitis in mice. Interleukin (IL)-13, an effector of tissue damage in similar models, has been associated with the pathogenesis of ulcerative colitis (UC). We investigated interactions between TWEAK and IL-13 following mucosal damage in mice. METHODS: We compared patterns of gene expression in intestinal tissues from wild-type and TWEAK knockout mice following γ-irradiation. Intestinal explants from these mice were used to detect cell damage induced by IL-13 and TNF-α. Levels of messenger RNA for IL-13, TWEAK, and Fn14 were measured in mucosal samples from patients with UC. RESULTS: Based on gene expression analysis, TWEAK mediates γ-irradiation-induced epithelial cell cycle arrest and apoptosis. However, TWEAK alone did not induce damage or apoptosis of primary intestinal epithelial cells. On the other hand, exogenous IL-13 activated caspase-3 in naïve intestinal explants; this process required TWEAK, Fn14, and secretion of endogenous TNF-α which was mediated by ADAM17. Conversely, activation of caspase by exogenous TNF-α required IL-13, TWEAK, and Fn14. In mucosa from patients with UC, messenger RNA levels of IL-13, TWEAK, and Fn14 increased with level of disease severity. CONCLUSIONS: IL-13-induced damage of intestinal epithelial cells requires TWEAK, its receptor (Fn14), and TNF-α. IL-13, TNF-α, TWEAK, and Fn14 could perpetuate and aggravate intestinal inflammation in patients with UC.

Lymph node ratio is a powerful prognostic index in patients with stage III distal rectal cancer: a Japanese multicenter study.

PURPOSE: The present study aims to define the prognostic impact of the lymph node ratio (LNR) in patients with stage III distal rectal cancer. METHODS: We analyzed data from 501 patients who underwent curative resection (total mesorectal excision, TME) for stage III distal rectal cancer at 12 institutions between 1991 and 1998. Patients were divided into four groups according to quartiles based on LNR. RESULTS: Among the 501 patients, 381 underwent TME with pelvic sidewall dissection (PSD). The median numbers of lymph nodes retrieved with and without PSD were 45 and 17, respectively (P < 0.0001). Forty-nine patients with lymph node retrieved less than 12 were excluded from further analyses. Among various clinicopathological parameters, univariate analysis identified age (P = 0.0059), histological grade (P < 0.0001), depth of tumor invasion (P = 0.0003), and number of positive nodes (P < 0.0001) and LNR (P < 0.0001) as prognostic factors. The Cox proportional hazards model revealed that age (P = 0.014), histological grade (P < 0.0001), depth of tumor invasion (P = 0.0002), and LNR (group 3, P = 0.0012; group 4, P < 0.0001) were independent prognostic factors. When the American Joint Committee on Cancer (AJCC) seventh staging system was added as a covariate, both AJCC stage (P < 0.0001) and LNR (P < 0.0001) were independent prognostic factors. CONCLUSIONS: Adding the LNR concept to the AJCC cancer staging system will improve accuracy in evaluating the nodal status of distal rectal cancer.

High-risk stage II colon cancer after curative resection.

OBJECTIVES: This study was designed to clarify which attributes of stage II colon cancer are associated with tumor recurrence and survival after curative resection, and the effects of adjuvant chemotherapy (ACT). METHODS: We retrospectively reviewed outcomes and clinicopathological characteristics of 1476 patients with stage II colon cancer who underwent curative resection. RESULTS: Of 1476 patients, 204 (13.8%) developed recurrence. Macroscopic type, serum CA19-9 levels, venous invasion, emergency operation, and postoperative ileus were independently associated with overall recurrence. Carbohydrate antigen (CA)19-9 levels, the number of dissected lymph nodes (LN), sex, age, ACT, emergency operation, venous invasion, and macroscopic type were independently associated with poor prognosis. Prognosis was significantly better in patients who received ACT than in those who did not. Among patients with extensive venous invasion, those with fewer than 13 dissected LNs, male patients, and patients >50 years old, the prognosis was significantly better in patients who received ACT than in those who did not. CONCLUSIONS: ACT for stage II colon cancer is recommended to improve the prognosis of patients with extensive venous invasion, patients with fewer than 13 dissected LNs, patients >50 years old, and male patients, particularly patients with more than two of these risk factors.

Characteristics of recurrence after curative resection for T1 colorectal cancer: Japanese multicenter study.

BACKGROUND: Because the rate of recurrence after curative resection for T1 colorectal cancer is low, the characteristics of recurrence remain obscure. This multicenter study attempted to clarify the characteristics of recurrence after curative resection for T1 colorectal cancer. METHODS: We analyzed the associations between recurrence and various clinicopathological features in 798 patients who had undergone curative resection alone for T1 colorectal cancer at 14 hospitals between 1991 and 1996. RESULTS: The rate of lymph node metastasis (LNM) in patients with T1 colorectal cancer was 10.5% (84/798), and 18 (2.3%) of the 798 patients developed recurrence during the median follow-up of 7.8 years. The recurrence rates in patients with colon cancer with and without LNM were 3.6 and 1.3%, respectively (p = 0.19). These rates in patients with cancer of the rectum were 25.0 and 1.1% (p < 0.0001). Among various parameters, histological grade (p < 0.0001), location (p = 0.025), LNM (p < 0.0001), and venous invasion (p = 0.0013) were risk factors for recurrence. Among them, LNM (p = 0.0008) and histological grade (p = 0.041) were independent risk factors for recurrence after curative resection for T1 colorectal cancer. Time to recurrence was more likely to be shorter for patients with, than without nodal involvement. In patients with an unfavorable histological grade, all recurrences developed within 1 year. CONCLUSIONS: The recurrence rate after curative resection for node-negative T1 colorectal cancer was very low. The effectiveness of surveillance to detect recurrence after curative resection for T1 colorectal cancer should be validated in further studies.

Is total mesorectal excision always necessary for T1-T2 lower rectal cancer?

BACKGROUND: The goal of this multicenter study was to clarify the determinants of local excision for patients with T1-T2 lower rectal cancer. METHODS: Data from 567 consecutive patients who underwent radical resection for T1-T2 lower rectal cancer at 12 institutions between 1991 and 1998 were reviewed. Rates of lymph node metastasis were investigated using a tree analysis, which was hierarchized using independent risk factors for nodal involvement. RESULTS: The independent risk factors for lymph node metastasis were female gender, depth of tumor invasion, histology other than well-differentiated adenocarcinoma, and lymphatic invasion. According to the first three parameters that can be obtained preoperatively, only 0.99% of the patients without risk factors had lymph node metastasis. On the other hand, even if the lower rectal cancer was at stage T1, women with histological types other than well-differentiated adenocarcinoma had an approximately 30% probability of having lymph node metastasis. Lymphatic invasion was most useful to predict nodal involvement among patients with T2 lower rectal cancer. The rates of lymph node metastasis in T2 patients with and without lymphatic invasion were 32.9% and 9.1%, respectively. CONCLUSIONS: Gender is one of the most important predictors for lymph node metastasis in patients with early distal rectal cancer. Three parameters, including depth of tumor invasion, histology, and gender, are useful determinants for local excision. Additional studies are required to establish the minimum optimal treatment for T2 lower rectal cancer.

Mice lacking the glutamate-cysteine ligase modifier subunit are susceptible to myocardial ischaemia-reperfusion injury.

AIMS: Glutamate-cysteine ligase (GCL), a rate-limiting enzyme for glutathione (GSH) synthesis, is composed of catalytic and modifier subunits. This study examined the pathogenic role of GCL modifier subunits (GCLM) in myocardial ischaemia-reperfusion (I/R) injury using mice lacking the GCLM (GCLM(-/-)). METHODS AND RESULTS: The GCLM(-/-)mice had an increase in myocardial I/R injury and apoptosis in ischaemic myocardium compared with GCLM(+/+) mice. There was a decrease in mitochondrial glutathione (GSH) levels in ischaemic myocardium that was more pronounced in GCLM(-/-) mice than in GCLM(+/+) mice (12 vs. 55% of baseline GCLM(+/+), respectively). The ESR signal intensity of the dimethyl-1-pyrroline-N-oxide-hydroxyl radical adducts in ischaemic myocardium was higher in GCLM(-/-) mice than in GCLM(+/+) mice. Hypoxia-reoxygenation induced greater mitochondrial damage in cultured cardiomyocytes from GCLM(-/-) mice than from GCLM(+/+) mice, as evidenced by a reduced membrane potential and increased protein carbonyl content in isolated mitochondria, together with enhanced cytochrome c translocation into the cytosol. Administration of GSH ethyl-ester attenuated myocardial I/R injury and reversed the mitochondrial damage in parallel with the mitochondrial GSH restoration in the myocardium or the cardiomyocytes of GCLM(-/-) mice. CONCLUSION: GCLM(-/-) mice were susceptible to myocardial I/R injury partly through an increased vulnerability of mitochondria to oxidative damage owing to mitochondrial GSH reduction.

Timing of relapse and outcome after curative resection for colorectal cancer: a Japanese multicenter study.

BACKGROUND: The aim of this multicenter study was to clarify the influence of timing of relapse after curative resection for colorectal cancer on prognosis. METHODS: We enrolled 5,230 consecutive patients who underwent curative resection for colorectal cancer at 14 hospitals from 1991 to 1996. All patients were intensively followed up. Time to relapse (TR) was classified into three groups as follows: group A, TR < or =1 year; group B, TR >1 year and < or =3 years, and group C, TR >3 years. The prognoses after relapse were compared among the three groups. RESULTS: Of the 5,230 patients, 906 experienced relapse (17.3%). The curative resection rates for recurrent tumors were 35.2% in group A, 46.6% in group B, and 45.1% in group C (p = 0.0045). There were significant differences in the prognoses after relapse among the three TR groups in patients with relapse to the liver (p = 0.0175) and in those with local relapses (p = 0.0021), but not in those with pulmonary or anastomotic recurrence. There were no differences in prognoses after relapse in any recurrence site among the three groups in patients who underwent curative resection for relapse. CONCLUSION: If patients can undergo curative resection for relapse, they receive a survival benefit regardless of the timing of relapse.

[Two cases of cancer in the reconstructed gastric tube after resection of esophageal cancer -An analysis of 7 cases in our hospital-].

We review 7 cases of cancer in the reconstructed gastric tube after resection for esophageal cancer in our hospital. From this experience, we report 2 cases which were resected curatively by endoscopic or open surgery. Case 1, a 61-year-old man received a subtotal esophagectomy reconstructed by a gastric tube, retromediastinally. 85 months after operation, cancer in the gastric tube was detected endoscopically, and partial resection was performed. Case 2, a 75-year-old man received subtotal esophagectomy reconstructed by a gastric tube via a retro-mediastinal route. After 104 months, early cancer in the gastric tube was diagnosed and we performed endoscopic mucosal dissection (ESD). Long-term follow-up by regular endoscopy is necessary in patients after esophageal surgery to screen for cancer in the reconstructed gastric tube.

Rapid stabilization of vulnerable carotid plaque within 1 month of pitavastatin treatment in patients with acute coronary syndrome.

We determined time course of stabilization of echolucent carotid plaques by statin therapy in patients with acute coronary syndrome (ACS). Treatment with 4 mg/d pitavastatin (n = 33) or placebo (n = 32) was initiated within 3 days after onset of ACS in 65 patients with echolucent carotid plaque. Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) analysis before and 1 month after treatment in all patients. The calibrated IBS value (intima-media IBS value minus adventia IBS) of vulnerable carotid plaques favorably changed at 1 month after treatment in both groups, but the echolucency at 1 month improved more in the pitavastatin than in the placebo group (pitavastatin group: -18.7 +/- 3.3 dB at pretreatment versus -12.7 +/- 2.3 dB at 1 month *P < 0.001; placebo: -19.0 +/- 3.5 dB versus -16.9 +/- 3.2 dB, P < 0.05, *P < 0.01 versus the value at 1 month in placebo group). Levels of CRP, VEGF, and TNFalpha at 1 month were significantly lower in pitavastatin than placebo group. In conclusion, pitavastatin improved carotid plaque echolucency within 1 month of therapy in patients with ACS, in association with decrease in the inflammatory biomarkers related to vulnerable plaques.

Statin reverses reduction of adiponectin receptor expression in infarcted heart and in TNF-alpha-treated cardiomyocytes in association with improved glucose uptake.

Statin treatment improves insulin resistance in skeletal muscle. Thus this study assessed whether statin may affect the myocardial expression levels of AdipoR1 and AdipoR2, receptors of adiponectin that enhance insulin sensitivity, and whether statin may improve insulin resistance in cardiomyocytes. Myocardial infarction (MI) was created by the ligation of the left coronary artery in male mice. Expression levels of mRNA and protein levels of AdipoR1 but not of AdipoR2 were significantly decreased in the remote area as well as in the healed infarcted area in the left ventricles 4 wk after MI. Oral administration of pravastatin (50 mg.kg(-1).day(-1) for 4 wk after MI) reversed the decrease in myocardial expression levels of AdipoR1 independently of changes in serum lipid profiles and insulin levels. With the use of cultured cardiomyocytes, incubation with tumor necrosis factor (TNF)-alpha, a mediator of postinfarction myocardial dysfunction, inhibited AdipoR1 mRNA and protein expression levels. Coincubation of the cells with pravastatin reversed the inhibitory effects of TNF-alpha on AdipoR1 expression. In parallel, pravastatin reversed the TNF-alpha-induced decrease in globular adiponectin-induced 2-deoxy-d-[(3)H]glucose uptake in insulin-treated cultured cells. Moreover, this effect of pravastatin was inhibited by the suppression of AdipoR1 expression by small-interfering RNA specific for AdipoR1. Incubation with H(2)O(2) reduced AdipoR1 expression in cultured cardiomyocytes that were attenuated by N-acetyl-l-cysteine or pravastatin. Pravastatin suppressed TNF-alpha-induced intracellular oxidants in cultured cardiomyocytes. In conclusion, pravastatin reversed the reduction of AdipoR1 expression in postinfarction mouse myocardium and in TNF-alpha-treated cardiomyocytes partly through an antioxidative mechanism in association with improved glucose uptake.

Relation between transcardiac gradient of VEGF and coronary flow response in humans.

BACKGROUND: Angiogenic growth factors, produced in the myocardium and coronary vascular bed, increase myocardial blood flow. This study examined whether plasma levels of vascular endothelial growth factor (VEGF) in coronary circulation may be related to coronary blood flow responses. METHODS: Blood flow responses in the left anterior descending coronary artery to an intracoronary infusion of acetylcholine (ACh) were measured by an intracoronary flow wire technique in 46 consecutive control subjects with normal coronary angiograms and left ventriculograms. Circulating VEGF levels were measured by ELISA in plasma obtained from the aortic root (AO) and anterior interventricular vein (AIV). RESULTS: The transcardiac gradient of VEGF, calculated by the difference in VEGF concentrations between the AIV and AO, showed a positive correlation with the coronary blood flow increase in response to ACh independently of traditional coronary risk factors. In patients with cardiac syndrome X (n=17), defined as a positive exercise stress test with a normal coronary angiograms and left ventriculogram, the transcardiac VEGF gradient was significantly lower than in the risk factors-matched control subjects (n=21). CONCLUSIONS: The transcardiac gradient of plasma VEGF was independently and positively correlated with the coronary blood flow increase in response to ACh. A reduced transcardiac VEGF gradient was present in cardiac syndrome X, a condition with a blunted coronary blood flow response.