Correction to: Randomized trial of an increased dose of calcium channel blocker or angiotensin II type 1 receptor blocker as an add-on intensive depressor therapy in type 2 diabetes mellitus patients with uncontrolled essential hypertension: the ACADEMIE Study.

In the Original publication of the article, the legend appearing inside the flow chart has been incorrectly published.

Influence of chronic kidney disease on coronary plaque components in coronary artery disease patients with both diabetes mellitus and hypertension.

Chronic kidney disease (CKD) is well known to be associated with an increased incidence of coronary artery disease (CAD). Diabetes mellitus (DM) and hypertension (HTN), both of which are traditional risk factors for CAD, are the two most common causes of CKD. However, the influence of CKD on coronary atherosclerosis in CAD patients who have both DM and HTN remains uncertain. In these patients, we examined the relationship between CKD and coronary plaque using integrated backscatter intravascular ultrasound (IB IVUS). Two hundred two CAD patients with both DM and HTN who underwent percutaneous coronary intervention using IB IVUS were included. The patients were divided into two groups: CKD group (n = 106) and non-CKD group (n = 96). Gray-scale and IB IVUS examinations were conducted for the non-culprit segment of a coronary artery. As a result, although there was no significant difference in the percentage of plaque volume, the percentage of lipid volume was significantly higher in the CKD group than in the non-CKD group [median (IQR): 56.7% (45.4-67.0%) vs. 52.0% (38.3-60.2%), p = 0.03]. In all of the patients, estimated glomerular filtration rate levels were negatively correlated with the percentage of lipid volume (r = - 0.15, p = 0.03) and positively correlated with the percentage of fibrosis volume (r = 0.15, p = 0.04). A multivariate regression analysis showed that CKD was an independent predictor associated with the increased lipid volume (ß = 0.15, p = 0.047) and decreased fibrosis volume (ß = - 0.16, p = 0.03) in coronary plaques. In conclusion, among CAD patients who had both DM and HTN, CKD was associated with lipid-rich coronary plaques. CKD may contribute to the vulnerability of coronary plaque in these very high-risk patients.

Correction to: Association between discordance of LDL-C and non-HDL-C and clinical outcomes in patients with stent implantation: from the FU-Registry.

Unfortunately, the Fig. 1 was published incorrectly in the original publication of the article. The correct figure is as below.

Randomized trial of an increased dose of calcium channel blocker or angiotensin II type 1 receptor blocker as an add-on intensive depressor therapy in type 2 diabetes mellitus patients with uncontrolled essential hypertension: the ACADEMIE Study.

There is a lack of data on how to treat hypertensive patients with diabetes when treatment with medium doses of calcium channel blocker and angiotensin II type 1 receptor blocker (ARB) is insufficient to achieve the target blood pressure (BP). A total of 121 participants with type 2 diabetes and uncontrolled essential hypertension, who were receiving medium doses of amlodipine (5 mg/day) and ARB, were enrolled. Participants were randomized to receive either a high dose of amlodipine (10 mg/day) plus a medium dose of ARB (high-AML) or a medium dose of amlodipine (5 mg/day) plus a high dose of ARB (high-ARB). The depressor effects of these two regimens were monitored using a telemonitoring home BP-measuring system. Fifty-four patients were excluded after an observation period, and the remaining 67 eligible participants were randomized into the two groups; 42 which had a record of their home BP for analysis. The change in morning home systolic and diastolic BP was greater in the high-AML than in the high-ARB (systolic BP; - 7.9 mmHg vs. + 2.7 mmHg; p = 0.0002, diastolic BP; - 3.9 mmHg vs. + 0.6 mmHg; p = 0.0007). In addition, the home systolic and diastolic BP before going to bed and office systolic BP were significantly reduced from week 0 only in the high-AML. An increased dose of amlodipine, but not ARB, reduced home morning BP in hypertensive patients with type 2 diabetes who were already receiving combination therapy with medium doses of amlodipine and ARB.

Impact of the triglyceride level on coronary plaque components in female patients with coronary artery disease treated with statins.

Several studies have reported that elevated triglyceride (TG) levels may be more strongly associated with an increased risk of coronary artery disease (CAD) in females than in males. We examined gender differences in the relationship between TG levels and coronary atherosclerosis using integrated backscatter intravascular ultrasound (IB IVUS) in CAD patients treated with statins. Three hundred seventy-eight CAD patients (105 females and 273 males) who underwent percutaneous coronary intervention using IB IVUS, and who were already receiving statin treatment, were included. Gray-scale and IB IVUS examinations were performed for the non-culprit segment of a coronary artery and fasting serum TG concentrations were measured. We found that TG levels were significantly correlated with increased lipid (r = 0.40, p < 0.001) and decreased fibrous (r = - 0.37, p < 0.001) plaque components in females, but not in males. Low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were not related to either the gray-scale or IB IVUS parameters in both genders. After adjustment for conventional coronary risk factors by a multivariate stepwise regression analysis, higher TG levels in females were independently associated with increased lipid (ß = 0.31, p< 0.001) contents in coronary plaques. In conclusion, among CAD patients treated with statins, TG levels were associated with lipid-rich coronary plaques in females, but not in males. TG levels may be more important indicators of residual risk after statin treatment in females than in males.

Association between discordance of LDL-C and non-HDL-C and clinical outcomes in patients with stent implantation: from the FU-Registry.

It is not yet clear whether the discordance of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) predicts the follow-up clinical outcome (major adverse cardiovascular events: MACEs) in patients with coronary stent implantation. Among 2015 patients with coronary stent implantation (Fukuoka University [FU]-Registry), excluding those with acute coronary syndrome or hemodialysis, we selected 801 patients who had undergone successful stent implantation with a follow-up until 18 months, and classified them into 3 groups according to baseline LDL-C and non-HDL-C levels [percentile(P)non-HDL-C more than (P)LDL-C, (P)non-HDL-C equal to (P)LDL-C, and (P)non-HDL-C less than (P) LDL-C]. We found that the discordance of (P)LDL-C and (P)non-HDL-C was not a significant predictor of MACEs. Higher LDL-C level was consistently and independently associated with higher incidences of MACEs after controlling for conventional risk factors and the type of stent used by multivariate Cox regression analyses. In conclusion, LDL-C levels are more important than non-HDL-C levels and the discordance of LDL-C and non-HDL-C levels as predictors of MACEs in patients with stable angina after stent implantation.

Evaluation of the antithrombotic abilities of non-vitamin K antagonist oral anticoagulants using the Total Thrombus-formation Analysis System®.

The Total Thrombus-formation Analysis System (T-TAS®) is a novel automated microchip flow-chamber system for the quantitative evaluation of thrombus formation under blood flow conditions. T-TAS® uses two types of microchip to evaluate thrombus formation: the AR-chip quantifies white thrombus formation and the PL-chip quantifies platelet thrombus formation. We assessed the antithrombotic abilities of various non-vitamin K antagonist oral anticoagulants (NOACs) using T-TAS®. One hundred and three consecutive patients who were hospitalized with cardiovascular diseases were enrolled. We divided the patients into 2 groups; a control group that did not receive an anticoagulant (non-AC group) and an anticoagulant group (AC group). The AC group was further divided into warfarin, dabigatran, rivaroxaban and apixaban groups. We performed common coagulation tests and evaluated the area under the flow pressure curve (AR-AUC and PL-AUC) to quantify antithrombotic ability using T-TAS® at the trough. There were no significant differences in patient characteristics between the non-AC and AC groups. Only 55.1 % of patients in the AC group achieved the target blood pressure (BP) of less than 130/80 mmHg. Compared with the non-AC group, AR-AUC was significantly decreased in the AC, warfarin, dabigatran and apixaban groups. Only the rivaroxaban group did not show a significant decrease in AR-AUC. NOACs showed a significant decrease in PL-AUC compared with the non-AC group. In conclusion, T-TAS® was a useful tool for evaluating anticoagulation activity. NOACs was significantly effective as an antiplatelet agent. BP control should be a higher priority than the selection of an anticoagulant drug, especially NOACs.

Significance of the percentage of cholesterol efflux capacity and total cholesterol efflux capacity in patients with or without coronary artery disease.

We hypothesized that cholesterol efflux capacity is more useful than the lipid profile as a marker of the presence and the severity of coronary artery disease (CAD). Therefore, we investigated the associations between the presence and the severity of CAD and both the percentage of cholesterol efflux capacity and total cholesterol efflux capacity and the lipid profile including the high-density lipoprotein cholesterol (HDL-C) level in patients who underwent coronary computed tomography angiography (CTA). The subjects consisted of 204 patients who were clinically suspected to have CAD and underwent CTA. We isolated HDL from plasma by ultracentrifugation and measured the percentage of cholesterol efflux capacity using 3H-cholesterol-labeled J774 macrophage cells and calculated total cholesterol efflux capacity as follows: the percentage of cholesterol efflux capacity/100× HDL-C levels. While the percentage of cholesterol efflux capacity was not associated with the presence or the severity of CAD, total cholesterol efflux capacity and HDL-C in patients with CAD were significantly lower than those in patients without CAD. In addition, total cholesterol efflux capacity and HDL-C, but not the percentage of cholesterol efflux capacity, significantly decreased as the number of coronary arteries with significant stenosis increased. Total cholesterol efflux capacity was positively correlated with HDL-C, whereas the percentage of cholesterol efflux capacity showed only weak association. In a logistic regression analysis, the presence of CAD was independently associated with total cholesterol efflux capacity, in addition to age and gender. Finally, a receiver-operating characteristic curve analysis indicated that the areas under the curves for total cholesterol efflux capacity and HDL-C were similar. In conclusion, the percentage of cholesterol efflux capacity using the fixed amount of isolated HDL was not associated with CAD. On the other hand, the calculated total cholesterol efflux capacity that was dependent of HDL-C levels had a significant correlation with the presence of CAD.

Improved 68 Ga-labeling method using ethanol addition: Application to the α-helical peptide DOTA-FAMP.

We examined the 68 Ga labeling of the α-helical peptide, DOTA-FAMP, and evaluated conformational changes during radiolabeling. 68 Ga-DOTA-FAMP is a positron emission tomography probe candidate for atherosclerotic plaques. The labeling yield achieved by Zhernosekov's method (using acetone for 68 Ga purification) was compared with that achieved by the original and 2 modified Mueller's methods (using NaCl solution). Modified method I involves desalting the 68 Ga prior to labeling, and modified method II involves the inclusion of ethanol in the labeling solution. The labeling yield using Zhernosekov's method was 62% ± 5.4%. In comparison, Mueller's original method gave 8.9% ± 1.7%. Modified method I gave a slight improvement of 32% ± 2.1%. Modified method II further increased the yield to 66% ± 3.4%. Conformational changes were determined by circular dichroism spectroscopy, revealing that these differences could be attributed to conformational changes. Heat treatment affects peptide conformation, which leads to aggregation and decreases the labeling yield. Mueller's method is simpler, but harsh conditions preclude its application to biomolecules. To suppress aggregation, we included a desalting process and added ethanol in the labeling solution. These changes significantly improved the labeling yield. Before use for imaging, conformational changes of biomolecules during radiolabeling should be evaluated by circular dichroism spectroscopy to ensure the homogeneity of the labeled product.

Association between cholesterol efflux capacity and coronary restenosis after successful stent implantation.

The measurement of high-density lipoprotein (HDL) functionality could be useful for identifying patients who have an increased risk of coronary restenosis after stent implantation. In the present study, we elucidates whether HDL functionality can predict restenosis. The participants included 48 consecutive patients who had stable angina and were successfully implanted with a drug-eluting stent (DES) or bare-metal stent. Follow-up coronary angiography was performed after 6-8 months of stenting. Cholesterol efflux and the anti-inflammatory capacity of HDL were measured before stenting (at baseline) and at follow-up. The mean age was 64 ± 11 years and the body mass index was 24 ± 3 kg/m(2). While HDL cholesterol (HDL-C) significantly increased from baseline to follow-up, there was no significant association between HDL-C level at baseline and in-stent late loss. Cholesterol efflux capacity was significantly increased from baseline to follow-up. The efflux capacity at baseline was negatively correlated with in-stent late loss, whereas the anti-oxidative activity of HDL at baseline was not associated with in-stent late loss. We analyzed the predictors of in-stent late loss using independent variables (efflux capacity and anti-oxidative capacity at baseline in addition to age, gender, HDL-C and low-density lipoprotein cholesterol at baseline, hypertension, diabetes mellitus, smoking, lesion length and DES implantation, history of myocardial infarction and prior percutaneous coronary intervention) by a multiple regression analysis. The efflux capacity at baseline was only independently associated with in-stent late loss. In conclusion, cholesterol efflux capacity at baseline could predict coronary restenosis in patients with successful stent implantation.

Addition of a Nitric Oxide Donor to an Angiotensin II Type 1 Receptor Blocker May Cancel Its Blood Pressure-Lowering Effects.

While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.

Impact of cigarette smoking cessation on high-density lipoprotein functionality.

BACKGROUND: Smoking cessation reduces the risk of cardiovascular disease (CVD) and improves clinical outcomes in public health. We studied the effect of smoking cessation on high-density lipoprotein (HDL) functionality. METHODS AND RESULTS: We randomly treated 32 smokers with varenicline or a transdermal nicotine patch as part of a 12-week smoking cessation program (The VN-SEESAW Study). The plasma lipid profiles, plasma and HDL malondialdehyde (MDA) levels, HDL subfractions as analyzed by capillary isotachophoresis, cholesterol efflux capacity, and antiinflammatory activity of HDL were measured before and after the anti-smoking intervention. After smoking cessation, HDL-C, apoA-I levels and HDL subfractions were not significantly different from the respective baseline values. However, cholesterol efflux capacity and the HDL inflammatory index (HII) were significantly improved after smoking cessation. The changes in both parameters (%∆ cholesterol efflux capacity and ∆HII) were also significantly improved in the successful smoking cessation group compared with the unsuccessful group. The changes in cholesterol efflux capacity and HII also correlated with those in end-expiratory CO concentration and MDA in HDL, respectively. CONCLUSIONS: Our findings indicate that smoking cessation leads to improved HDL functionality, increased cholesterol efflux capacity and decreased HII, without changing HDL-C or apoA-I levels or HDL subfractions. This may be one of the mechanisms by which smoking cessation improves the risk of CVD.

Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer.

We examined whether reduced levels of Apolipoprotein A-I (apoA-I) in ovarian cancer patients are causal in ovarian cancer in a mouse model. Mice expressing a human apoA-I transgene had (i) increased survival (P < 0.0001) and (ii) decreased tumor development (P < 0.01), when compared with littermates, following injection of mouse ovarian epithelial papillary serous adenocarcinoma cells (ID-8 cells). ApoA-I mimetic peptides reduced viability and proliferation of ID8 cells and cis-platinum-resistant human ovarian cancer cells, and decreased ID-8 cell-mediated tumor burden in C57BL/6J mice when administered subcutaneously or orally. Serum levels of lysophosphatidic acid, a well-characterized modulator of tumor cell proliferation, were significantly reduced (>50% compared with control mice, P < 0.05) in mice that received apoA-I mimetic peptides (administered either subcutaneously or orally), suggesting that binding and removal of lysophosphatidic acid is a potential mechanism for the inhibition of tumor development by apoA-I mimetic peptides, which may serve as a previously unexplored class of anticancer agents.

Associations of High-Density Lipoprotein Functionality with Coronary Plaque Characteristics in Diabetic Patients with Coronary Artery Disease: Integrated Backscatter Intravascular Ultrasound Analysis.

High-density lipoprotein (HDL) functionality has been reported to be associated with coronary artery disease (CAD). However, little is known about the impact of HDL functionality on coronary atherosclerosis. Thirty-eight type 2 diabetic patients with CAD who underwent percutaneous coronary intervention were examined. Coronary atheroma burden and plaque composition of the culprit lesions were assessed using conventional gray-scale and integrated backscatter intravascular ultrasound. HDL-mediated cholesterol efflux capacity (HDL-CEC) and HDL antioxidant capacity, estimated as HDL inflammatory index (HII), were examined. The associations between HDL functionality and coronary plaques were analyzed using multivariate data analysis, including principal components analysis and orthogonal partial least squares (OPLS) models. Percent atheroma volume was correlated with HDL-CEC (r = 0.34, p = 0.04) but not with HII (p = 0.65). The OPLS model demonstrated that the percentage lipid volume was significantly associated with HDL functionality [coefficient (95% confidence interval); HDL-CEC: -0.26 (-0.49, -0.04); HII: 0.34 (0.08, 2.60), respectively]. HII exhibited the highest variable importance in projection score, indicating the greatest contribution. HDL functionality was associated with coronary plaque composition, a key component of plaque vulnerability. Our findings highlight the potential importance of HDL functionality for coronary plaque stabilization.

Macrophage paraoxonase 2 regulates calcium homeostasis and cell survival under endoplasmic reticulum stress conditions and is sufficient to prevent the development of aggravated atherosclerosis in paraoxonase 2 deficiency/apoE-/- mice on a Western diet.

Paraoxonase 2 deficiency (PON2-def) alters mitochondrial function and exacerbates the development of atherosclerosis in mice. PON2 overexpression protects against ER stress in cell culture. In this paper, we examined the role of PON2 in the unexplored link between ER stress and mitochondrial dysfunction and tested whether restoration of PON2 in macrophages is sufficient to reduce aggravated atherosclerosis in PON2-def/apoE(-/-) mice on a Western diet. ER stress response genes, intracellular calcium levels, and apoptotic nuclei were significantly elevated in PON2-def/apoE(-/-) macrophages compared to apoE(-/-) macrophages in response to ER stressors, but not at the basal level. In contrast, PON2-def/apoE(-/-) macrophages exhibited greater mitochondrial stress at the basal level, which was further worsened in response to ER stressors. There was no difference in ER stress response genes and apoptotic nuclei between apoE(-/-) and PON2-def/apoE(-/-) macrophages when pretreated with xestospongin (which blocks the release of calcium from ER) suggesting that PON2 modulates cell survival and ER stress by maintaining calcium homeostasis. Treatment with a mitochondrial calcium uptake inhibitor, RU360, attenuated ER stressor mediated mitochondrial dysfunction in PON2-def/apoE(-/-) macrophages. CHOP expression (ER stress marker) and apoptotic nuclei were significantly higher in aortic lesions of PON2-def/apoE(-/-) mice compared to apoE(-/-) mice fed a Western diet. Restoration of PON2 in macrophages reduced ER stress, mitochondrial dysfunction and apoptosis in response to ER stressors. Furthermore, restoration of PON2 in macrophages reduced lesional apoptosis and atherosclerosis in PON2-def/apoE(-/-) mice on a Western diet. Our data suggest that macrophage PON2 modulates mechanisms that link ER stress, mitochondrial dysfunction and the development of atherosclerosis.

Reactivity of direct assays for low-density lipoprotein (LDL) cholesterol toward charge-modified LDL in hypercholesterolemia.

BACKGROUND: The aim of the present study was to compare 2 direct measurements for low-density lipoprotein cholesterol (LDL-C) with the Friedewald calculation (LDL-C [F]) in serum and their relationship with size-and charge-based LDL subfractions in serum ultracentrifugation fractions in patients with hypercholesterolemia (HC). METHODS AND RESULTS: Serum samples from 283 HC patients who participated in a statin trial (the PATROL trial) were analyzed. Homogeneous assays for LDL-C were performed using reagents from Sekisui Medical (LDL-C [Se]) and Kyowa Medex (LDL-C [Ky]). Charge-based LDL subfractions were analyzed by capillary isotachophoresis (cITP). In whole serum in HC patients at baseline, LDL-C (Se) and LDL-C (Ky) negatively and positively deviated, respectively, from LDL-C (F). The negative deviation of LDL-C (Se) from LDL-C (F) increased with increasing LDL-C, while the positive deviation of LDL-C (Ky) from LDL-C (F) was positively correlated with charge-modified LDL (cmLDL) as analyzed by cITP. In serum d>1.006 g/ml and >1.040 g/ml fractions (LDL and small, dense LDL fractions, respectively), the deviation of LDL-C (Ky) from LDL-C (Se) was positively correlated with LDL-apoB (the number of LDL particles) and cmLDL. CONCLUSIONS: The 2 homogenous assays for LDL-C differed with regard to reactivity toward LDL particles and cmLDL in patients with HC. Direct measurement of LDL-C that reflects modified LDL, could be a better marker for the risk of coronary heart disease.

Pressure-Induced Superconductivity in Iron-Based Spin-Ladder Compound BaFe2+δ(S1-xSex)3.

The iron-based superconductors had a significant impact on condensed matter physics. They have a common structural motif of a two-dimensional square iron lattice and exhibit fruitful physical properties as a strongly correlated electron system. During the extensive investigations, quasi-one-dimensional iron-based spin-ladder compounds attracted much attention as a platform for studying the interplay between magnetic and orbital ordering. In these compounds, BaFe2S3 and BaFe2Se3 were found to exhibit superconductivity under high pressure, having a different crystal and magnetic structure at low temperature. We report a brief review of the iron-based spin-ladder compound and recent studies for BaFe2+δ(S1-xSex)3. BaFe2(S0.75 Se0.25)3 is in the vicinity of the boundary of two different magnetic phases and it is intriguing to perform high pressure experiments for studying superconductivity, since effects of large magnetic fluctuations on superconductivity are expected. The effect of iron stoichiometry on the interplay between magnetism and superconductivity is also studied by changing the iron concentration in BaFe2+δSe3.

Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally.

To determine if the dose of peptide administered or the plasma level was more important, doses of 0.15, 0.45, 4.5, or 45 mg/kg/day of the peptide D-4F were administered orally or subcutaneously (SQ) to apoliptotein (apo)E null mice. Plasma levels of peptide were ∼1,000-fold higher when administered SQ compared with orally. Regardless of the route of administration, doses of 4.5 and 45 mg/kg significantly reduced plasma serum amyloid A (SAA) levels and the HDL inflammatory index (P < 0.0001); doses of 0.15 or 0.45 mg/kg did not. A dose of 45 mg/kg/day administered to apoE null mice on a Western diet reduced aortic atherosclerosis by ∼50% (P < 0.0009) whether administered orally or SQ and also significantly reduced plasma levels of SAA (P < 0.002) and lysophosphatidic acid (P < 0.0009). Remarkably, for each dose administered, the concentration and amount of peptide in the feces was similar regardless of whether the peptide was administered orally or SQ. We conclude: i) the dose of 4F administered and not the plasma level achieved determines efficacy; ii) the intestine may be a major site of action for the peptide regardless of the route of administration.

Enhancement by LDL of transfer of L-4F and oxidized lipids to HDL in C57BL/6J mice and human plasma.

The apoA-I mimetic peptide L-4F [(Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2) synthesized from all L-amino acids] has shown potential for the treatment of a variety of diseases. Here, we demonstrate that LDL promotes association between L-4F and HDL. A 2- to 3-fold greater association of L-4F with human HDL was observed in the presence of human LDL as compared with HDL by itself. This association further increased when LDL was supplemented with the oxidized lipid 15S-hydroxy-5Z, 8Z, 11Z, 13E-eicosatetraenoic acid (15HETE). Additionally, L-4F significantly (P = 0.02) promoted the transfer of 15HETE from LDL to HDL. The transfer of L-4F from LDL to HDL was demonstrated both in vitro and in C57BL/6J mice. L-4F, injected into C57BL/6J mice, associated rapidly with HDL and was then cleared quickly from the circulation. Similarly, L-4F loaded onto human HDL and injected into C57BL/6J mice was cleared quickly with T(1/2) = 23.6 min. This was accompanied by a decline in human apoA-I with little or no effect on the mouse apoA-I. Based on these results, we propose that i) LDL promotes the association of L-4F with HDL and ii) in the presence of L-4F, oxidized lipids in LDL are rapidly transferred to HDL allowing these oxidized lipids to be acted upon by HDL-associated enzymes and/or cleared from the circulation.

Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids.

CYP2S1 is a recently described dioxin-inducible cytochrome P450. We previously demonstrated that human CYP2S1 oxidizes a number of carcinogens but only via the peroxide shunt. In this article, we investigated whether human CYP2S1 can metabolize cyclooxygenase- and lipoxygenase-derived lipid peroxides in a NADPH-independent fashion. Human CYP2S1 metabolizes prostaglandin G(2) (PGG(2)) (K(m) = 0.267 ± 0.072 µM) into several products including 12S-hydroxy-5Z,8E,10E-heptadecatrienoic acid (12-HHT). It also metabolizes prostaglandin H(2) (PGH(2)) (K(m) = 11.7 ± 2.8 µM) into malondialdehyde, 12-HHT, and thromboxane A(2) (TXA(2)). The turnover to 12-HHT by human CYP2S1 (1.59 ± 0.04 min(-1)) is 40-fold higher than that of TXA(2) (0.04 min(-1)). In addition to PGG(2) and PGH(2) metabolism, human CYP2S1 efficiently metabolizes the hydroperoxyeicosatetraenoic acids (5S-, 12S-, and 15S-) and 13S-hydroperoxyoctadecadienoic acid into 5-oxo-eicosatetraenoic acid (turnover = 16.7 ± 0.3 min(-1)), 12-oxo-eicosatetraenoic acid 1 (11.5 ± 0.9 min(-1)), 15-oxo-eicosatetraenoic acid (16.9 ± 0.8 min(-1)), and 13-octadecadienoic acid (20.2 ± 0.9 min(-1)), respectively. Other cytochromes P450 such as CYP1A1, 1A2, 1B1, and 3A4 underwent similar conversions but at slower rates. The fatty acid hydroperoxides were also converted by human CYP2S1 to several epoxyalcohols. Our data indicate that fatty acid endoperoxides and hydroperoxides represent endogenous substrates of CYP2S1 and suggest that the enzyme CYP2S1 may play an important role in the inflammatory process because some of the products that CYP2S1 produces play important roles in inflammation.