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We tested the hypothesis that CYP1B1 (cytochrome P450 1B1)-17β-estradiol metabolite 2-methoxyestradiol protects against Ang II (angiotensin II)–induced hypertension by inhibiting group IV cPLA 2 α (cytosolic phospholipase A 2 α) activity and production of prohypertensive eicosanoids in female mice. Ang II (700 ng/kg per minute, SC) increased mean arterial blood pressure (BP), systolic and diastolic BP measured by radiotelemetry, renal fibrosis, and reactive oxygen species production in wild-type mice ( cPLA 2 α +/+ /Cyp1b1 +/+ ) that were enhanced by ovariectomy and abolished in intact and ovariectomized -cPLA 2 α −/− /Cyp1b1 +/+ mice. Ang II–induced increase in SBP measured by tail-cuff, renal fibrosis, reactive oxygen species production, and cPLA 2 α activity measured by its phosphorylation in the kidney, and urinary excretion of prostaglandin E 2 and thromboxane A 2 metabolites were enhanced in ovariectomized- cPLA 2 α +/+ /Cyp1b1 +/+ and intact cPLA 2 α +/+ /Cyp1b1 −/− mice. 2-Methoxyestradiol and arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid attenuated the Ang II–induced increase in SBP, renal fibrosis, reactive oxygen species production, and urinary excretion of prostaglandin E 2 , and thromboxane A 2 metabolites in ovariectomized- cPLA 2 α +/+ /Cyp1b1 +/+ and intact cPLA 2 α +/+ /Cyp1b1 −/− mice. Antagonists of prostaglandin E 2 and thromboxane A 2 receptors EP1 and EP3 and TP, respectively, inhibited Ang II–induced increases in SBP and reactive oxygen species production and renal fibrosis in ovariectomized- cPLA 2 α +/+ /Cyp1b1 +/+ and intact cPLA 2 α +/+ /Cyp1b1 −/− mice. These data suggest that CYP1B1-generated metabolite 2-methoxyestradiol mitigates Ang II–induced hypertension and renal fibrosis by inhibiting cPLA 2 α activity, reducing prostaglandin E 2 , and thromboxane A 2 production and stimulating EP1 and EP3 and TP receptors, respectively. Thus, 2-methoxyestradiol and the drugs that selectively block EP1 and EP3 and TP receptors could be useful in treating hypertension and its pathogenesis in females.

This study was conducted to test the hypothesis that the CYP1B1 (cytochrome P450 1B1)-testosterone metabolite 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension by promoting activation of group IV cPLA 2 α (cytosolic phospholipase A 2 α) and generation of prohypertensive eicosanoids in male mice. Eight-week-old male intact or orchidectomized cPLA 2 α +/+ / Cyp1b1 +/+ and cPLA 2 α –/– / Cyp1b1 +/+ and intact cPLA 2 α +/+ / Cyp1b1 –/– mice were infused with angiotensin II (700 ng/kg/min, subcutaneous) for 2 weeks and injected with 6β-hydroxytestosterone (15 μg/g/every third day, intraperitoneal). Systolic blood pressure was measured by tail-cuff and confirmed by radiotelemetry. Angiotensin II-induced increase in systolic blood pressure, cardiac and renal collagen deposition, and reactive oxygen species production were reduced by disruption of the cPLA 2 α or Cyp1b1 genes or by administration of the arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid to cPLA 2 α +/+ / Cyp1b1 +/+ mice. 6β-hydroxytestosterone treatment restored these effects of angiotensin II in cPLA 2 α +/+ / Cyp1b1 –/– mice but not in orchidectomized cPLA 2 α –/– / Cyp1b1 +/+ mice, which were lowered by 5,8,11,14-eicosatetraynoic acid in cPLA 2 α +/+ / Cyp1b1 –/– mice. Antagonists of prostaglandin E 2 -EP1/EP3 receptors and thromboxane A 2 -TP receptors decreased the effect of 6β-hydroxytestosterone in restoring the angiotensin II-induced increase in systolic blood pressure, cardiac and renal collagen deposition, and reactive oxygen species production in cPLA 2 α +/+ / Cyp1b1 –/– mice. These data suggest that 6β-hydroxytestosterone promotes angiotensin II-induced increase in systolic blood pressure and associated pathogenesis via cPLA 2 α activation and generation of eicosanoids, most likely prostaglandin E 2 and thromboxane A 2 that exerts prohypertensive effects by stimulating EP1/EP3 and TP receptors, respectively. Therefore, agents that selectively block these receptors could be useful in treating testosterone exacerbated angiotensin II-induced hypertension and its pathogenesis.

Recently, we showed that 17β-estradiol (E2)-cytochrome P450 (CYP) 1B1-generated metabolite 2-methoxyestradiol (2-ME) in the paraventricular nucleus (PVN) protects from angiotensin (Ang) II-induced hypertension. Moreover, we showed that 2-ME produces this action by inhibiting the cytosolic phospholipase (cPLA) 2 α/arachidonic acid (AA)-cyclooxygenase (COX)-generated metabolites prostaglandin (PG)E 2 and thromboxane (TX)A 2 exerting prohypertensive effects via prostanoid receptors EP1, EP3, and TP, respectively, in female mice. 12/15 lipoxygenase (ALOX15), which also metabolizes AA, is present in the brain in neural tissue, endothelial cells, microglia, and astrocytes. This study was conducted to determine the contribution of central 12/15 lipoxygenase (ALOX15) and its relationship to CYP1B1 in Ang II-induced hypertension in the female mice. ALOX15 knockdown in the PVN by transduction with adenovirus (Ad)-ALOX15-short hairpin (sh)RNA (200 nL, bilaterally 7.04х10 11 pfu/mL) but not its control Ad-scrambled (Scr)-shRNA (6.4х10 11 pfu/mL) produced a greater reduction in systolic blood pressure (SBP, mmHg) measured by tail-cuff in response to Ang II (700 ng/kg/min, subcutaneous, osmotic pump, two weeks) in intact Cyp1b1 knockout (KO, E2 present but lacking 2-ME) than wild-type (WT, endogenous E2 and 2-ME present) female mice (Day 12: 177±4 vs 143±1 and 133±3 vs 124±1, respectively, PAlox15 KO female mice (Day 0 vs Day 12: 103±4 vs 167±2 and 103±2 vs 128±1, respectively, P

Supplemental Digital Content is available in the text., Previously, we showed that peripheral administration of 6β-hydroxytestosterone, a CYP1B1 (cytochrome P450 1B1)-generated metabolite of testosterone, promotes angiotensin II-induced hypertension in male mice. However, the site of action and the underlying mechanism by which 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension is not known. Angiotensin II increases blood pressure by its central action, and CYP1B1 is expressed in the brain. This study was conducted to determine whether testosterone-CYP1B1 generated metabolite 6β-hydroxytestosterone locally in the brain promotes the effect of systemic angiotensin II to produce hypertension in male mice. Central CYP1B1 knockdown in wild-type (Cyp1b1+/+) mice by intracerebroventricular-adenovirus-GFP (green fluorescence protein)-CYP1B1-short hairpin (sh)RNA attenuated, whereas reconstitution of CYP1B1 by adenovirus-GFP-CYP1B1-DNA in the paraventricular nucleus but not in subfornical organ in Cyp1b1−/− mice restored angiotensin II-induced increase in systolic blood pressure measured by tail-cuff. Intracerebroventricular-testosterone in orchidectomized (Orchi)-Cyp1b1+/+ but not in Orchi-Cyp1b1−/−, and intracerebroventricular-6β-hydroxytestosterone in the Orchi-Cyp1b1−/− mice restored the angiotensin II-induced: (1) increase in mean arterial pressure measured by radiotelemetry, and autonomic imbalance; (2) reactive oxygen species production in the subfornical organ and paraventricular nucleus; (3) activation of microglia and astrocyte, and neuroinflammation in the paraventricular nucleus. The effect of intracerebroventricular-6β-hydroxytestosterone to restore the angiotensin II-induced increase in mean arterial pressure and autonomic imbalance in Orchi-Cyp1b1−/− mice was inhibited by intracerebroventricular-small interfering (si)RNA-androgen receptor (AR) and GPRC6A (G protein-coupled receptor C6A). These data suggest that testosterone-CYP1B1-generated metabolite 6β-hydroxytestosterone, most likely in the paraventricular nucleus via AR and GPRC6A, contributes to angiotensin II-induced hypertension and neuroinflammation in male mice.

Supplemental Digital Content is available in the text., Previously, we showed that peripheral administration of 2-ME (2-methoxyestradiol), a CYP1B1 (cytochrome P450 1B1)-catechol-O-methyltransferase (COMT) generated metabolite of E2 (17β-Estradiol), protects against angiotensin II-induced hypertension in female mice. The demonstration that central E2 inhibits angiotensin II-induced hypertension, together with the expression of CYP1B1 in the brain, led us to hypothesize that E2-CYP1B1 generated metabolite 2-ME in the brain mediates its protective action against angiotensin II-induced hypertension in female mice. To test this hypothesis, we examined the effect of intracerebroventricularly (ICV) administered E2 in ovariectomized (OVX)-wild-type (Cyp1b1+/+) and OVX-Cyp1b1−/− mice on the action of systemic angiotensin II. ICV-E2 attenuated the angiotensin II-induced increase in mean arterial blood pressure, impairment of baroreflex sensitivity, and sympathetic activity in OVX-Cyp1b1+/+ but not in ICV-injected short interfering (si)RNA-COMT or OVX-Cyp1b1−/− mice. ICV-2-ME attenuated the angiotensin II-induced increase in blood pressure in OVX-Cyp1b1−/− mice; this effect was inhibited by ICV-siRNA estrogen receptor-α (ERα) and G protein-coupled estrogen receptor 1 (GPER1). ICV-E2 in OVX-Cyp1b1+/+ but not in OVX-Cyp1b1−/− mice and 2-ME in the OVX-Cyp1b1−/− inhibited angiotensin II-induced increase in reactive oxygen species production in the subfornical organ and paraventricular nucleus, activation of microglia and astrocyte, and neuroinflammation in paraventricular nucleus. Furthermore, central CYP1B1 gene disruption in Cyp1b1+/+ mice by ICV-adenovirus-GFP (green fluorescence protein)-CYP1B1-short hairpin (sh)RNA elevated, while reconstitution by adenovirus-GFP-CYP1B1-DNA in the paraventricular nucleus but not in subfornical organ in Cyp1b1−/− mice attenuated the angiotensin II-induced increase in systolic blood pressure. These data suggest that E2-CYP1B1-COMT generated metabolite 2-ME, most likely in the paraventricular nucleus via estrogen receptor-α and GPER1, protects against angiotensin II-induced hypertension and neuroinflammation in female mice.

Supplemental Digital Content is available in the text., We tested the hypothesis that CYP1B1 (cytochrome P450 1B1)-17β-estradiol metabolite 2-methoxyestradiol protects against Ang II (angiotensin II)–induced hypertension by inhibiting group IV cPLA2α (cytosolic phospholipase A2α) activity and production of prohypertensive eicosanoids in female mice. Ang II (700 ng/kg per minute, SC) increased mean arterial blood pressure (BP), systolic and diastolic BP measured by radiotelemetry, renal fibrosis, and reactive oxygen species production in wild-type mice (cPLA2α+/+/Cyp1b1+/+) that were enhanced by ovariectomy and abolished in intact and ovariectomized-cPLA2α−/−/Cyp1b1+/+ mice. Ang II–induced increase in SBP measured by tail-cuff, renal fibrosis, reactive oxygen species production, and cPLA2α activity measured by its phosphorylation in the kidney, and urinary excretion of prostaglandin E2 and thromboxane A2 metabolites were enhanced in ovariectomized-cPLA2α+/+/Cyp1b1+/+ and intact cPLA2α+/+/Cyp1b1−/− mice. 2-Methoxyestradiol and arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid attenuated the Ang II–induced increase in SBP, renal fibrosis, reactive oxygen species production, and urinary excretion of prostaglandin E2, and thromboxane A2 metabolites in ovariectomized-cPLA2α+/+/Cyp1b1+/+ and intact cPLA2α+/+/Cyp1b1−/− mice. Antagonists of prostaglandin E2 and thromboxane A2 receptors EP1 and EP3 and TP, respectively, inhibited Ang II–induced increases in SBP and reactive oxygen species production and renal fibrosis in ovariectomized-cPLA2α+/+/Cyp1b1+/+ and intact cPLA2α+/+/Cyp1b1−/− mice. These data suggest that CYP1B1-generated metabolite 2-methoxyestradiol mitigates Ang II–induced hypertension and renal fibrosis by inhibiting cPLA2α activity, reducing prostaglandin E2, and thromboxane A2 production and stimulating EP1 and EP3 and TP receptors, respectively. Thus, 2-methoxyestradiol and the drugs that selectively block EP1 and EP3 and TP receptors could be useful in treating hypertension and its pathogenesis in females.

Recently we showed that 2-methoxyestradiol (2-ME), an estrogen (E2) metabolite generated by CYP1B1 (cytochrome P450 1B1) in the paraventricular nucleus (PVN), protects female mice from Ang (angiotensin) II-induced hypertension and increased renal sympathetic activity. We also demonstrated that group IV cPLA 2 α (cytosolic phospholipase A 2 α) in the brain contributes to Ang II-induced hypertension in male mice. This study was conducted to determine the contribution of central cPLA 2 α and its relationship to CYP1B1 in Ang II-induced hypertension in female mice. cPLA 2 α knockdown in the PVN by transduction with adenovirus (Ad)-cPLA 2 α-short hairpin (sh)RNA (200 nL, bilaterally, 1.0х10 12 pfu/mL) but not its control Ad-scrambled (Scr)-shRNA (2.5х10 11 pfu/mL) in ovariectomized (OVX) wild-type ( cPLA 2 α +/+ / Cyp1b1 +/+ , n=8/group) and intact cPLA 2 α +/+ / Cyp1b1 -/- (n=12/group) female mice attenuated the effect of Ang II (700 ng/kg/min, subcutaneous, osmotic pump, 2 weeks) to increase the systolic blood pressure (SBP, mmHg) as measured by tail-cuff (Day 12: 129±3 vs 168±7 and 119±3 vs 172±5, respectively, P2 α in the PVN by transduction with Ad-cPLA 2 α-DNA (1.1х10 12 pfu/mL) but not its control Ad-GFP-DNA (1.0х10 11 pfu/mL) in OVX- cPLA 2 α -/- / Cyp1b1 +/+ mice (n=4/group) restored the effect of Ang II to increase SBP (Day 12: 163±7 vs 124±4, P2 α-shRNA but not Ad-Scr-shRNA transduction in the PVN in OVX- cPLA 2 α +/+ / Cyp1b1 +/+ and intact cPLA 2 α +/+ / Cyp1b1 -/- mice reduced and Ad-cPLA 2 α-DNA but not Ad-GFP-DNA transduction in the PVN in OVX- cPLA 2 α -/- / Cyp1b1 +/+ mice restored the effect of Ang II to increase the renal sympathetic activity as indicated by urinary norepinephrine level (ng/mL, 324±36 vs 707±94, 359±49 vs 979±70, 690±44 vs 421±43, respectively, n=4/group, P2 α activity in the PVN. Thus, 2-ME and/or agents inhibiting cPLA 2 α activity could be useful for treating hypertension and its pathogenesis in females.

Supplemental Digital Content is available in the text., This study was conducted to test the hypothesis that the CYP1B1 (cytochrome P450 1B1)-testosterone metabolite 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension by promoting activation of group IV cPLA2α (cytosolic phospholipase A2α) and generation of prohypertensive eicosanoids in male mice. Eight-week-old male intact or orchidectomized cPLA2α+/+/Cyp1b1+/+ and cPLA2α–/–/Cyp1b1+/+ and intact cPLA2α+/+/Cyp1b1–/– mice were infused with angiotensin II (700 ng/kg/min, subcutaneous) for 2 weeks and injected with 6β-hydroxytestosterone (15 μg/g/every third day, intraperitoneal). Systolic blood pressure was measured by tail-cuff and confirmed by radiotelemetry. Angiotensin II-induced increase in systolic blood pressure, cardiac and renal collagen deposition, and reactive oxygen species production were reduced by disruption of the cPLA2α or Cyp1b1 genes or by administration of the arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid to cPLA2α+/+/Cyp1b1+/+ mice. 6β-hydroxytestosterone treatment restored these effects of angiotensin II in cPLA2α+/+/Cyp1b1–/– mice but not in orchidectomized cPLA2α–/–/Cyp1b1+/+ mice, which were lowered by 5,8,11,14-eicosatetraynoic acid in cPLA2α+/+/Cyp1b1–/– mice. Antagonists of prostaglandin E2-EP1/EP3 receptors and thromboxane A2-TP receptors decreased the effect of 6β-hydroxytestosterone in restoring the angiotensin II-induced increase in systolic blood pressure, cardiac and renal collagen deposition, and reactive oxygen species production in cPLA2α+/+/Cyp1b1–/– mice. These data suggest that 6β-hydroxytestosterone promotes angiotensin II-induced increase in systolic blood pressure and associated pathogenesis via cPLA2α activation and generation of eicosanoids, most likely prostaglandin E2 and thromboxane A2 that exerts prohypertensive effects by stimulating EP1/EP3 and TP receptors, respectively. Therefore, agents that selectively block these receptors could be useful in treating testosterone exacerbated angiotensin II-induced hypertension and its pathogenesis.

BACKGROUND Recently, we reported that angiotensin II (Ang II)-induced hypertension is mediated by group IV cytosolic phospholipase A2α (cPLA2α) via production of prohypertensive eicosanoids. Since Ang II increases blood pressure (BP) via its action in the subfornical organ (SFO), it led us to investigate the expression and possible contribution of cPLA2α to oxidative stress and development of hypertension in this brain area. METHODS Adenovirus (Ad)-green fluorescence protein (GFP) cPLA2α short hairpin (sh) RNA (Ad-cPLA2α shRNA) and its control Ad-scrambled shRNA (Ad-Scr shRNA) or Ad-enhanced cyan fluorescence protein cPLA2α DNA (Ad-cPLA2α DNA) and its control Ad-GFP DNA were transduced into SFO of cPLA2α+/+ and cPLA2α−/− male mice, respectively. Ang II (700 ng/kg/min) was infused for 14 days in these mice, and BP was measured by tail-cuff and radio telemetry. cPLA2 activity, reactive oxygen species production, and endoplasmic reticulum stress were measured in the SFO. RESULTS Transduction of SFO with Ad-cPLA2α shRNA, but not Ad-Scr shRNA in cPLA2α+/+ mice, minimized expression of cPLA2α, Ang II-induced cPLA2α activity and oxidative stress in the SFO, BP, and cardiac and renal fibrosis. In contrast, Ad-cPLA2α DNA, but not its control Ad-GFP DNA in cPLA2α−/− mice, restored the expression of cPLA2α, and Ang II-induced increase in cPLA2 activity and oxidative stress in the SFO, BP, cardiac, and renal fibrosis. CONCLUSIONS These data suggest that cPLA2α in the SFO is crucial in mediating Ang II-induced hypertension and associated pathogenesis. Therefore, development of selective cPLA2α inhibitors could be useful in treating hypertension and its pathogenesis.

Previously we reported that angiotensin (Ang) II-induced hypertension is mediated by group IV cytosolic phospholipase A 2 α (cPLA 2 α) activation resulting in arachidonic acid (AA) release, and generation predominantly of eicosanoids with prohypertensive effects. Androgen dihydrotestosterone increases the expression of AA metabolizing enzyme cytochrome P450 (CYP) 4A1 and production of 20-HETE in the male rats and mice and an increase in blood pressure (BP). However, female mice that are resistant to Ang II-induced hypertension produce lower renal levels of 20-HETE, compared with males. Cyp4a12a, which has been identified as the predominant 20-HETE producing synthase in the mouse kidney, is expressed in very low levels in the female compared to male mice. Previously, we showed that the protection against Ang II-induced hypertension and associated pathogenesis in the female mice are mediated by CYP1B1-estradiol (E2) generated metabolite 2-methoxyestradiol (2-ME). These observations raised the possibility that CYP1B1-E2 metabolite 2-ME might protect against Ang II-induced hypertension by inhibiting expression of CYP4A1 and 20-HETE production. To test this hypothesis, we examined the effect of 20-HETE receptor antagonist 20-SOLA on Ang II (700 ng/kg/min, s.c. for two weeks)-induced hypertension in 8 weeks old wild type intact, ovariectomized (OVX), and intact Cyp1b1 -/- female mice. The systolic blood pressure (SBP, mmHg) was measured by tail-cuff. At the end of 2 weeks, Ang II caused greater increase in SBP in OVX- Cyp1b1 +/+ (161±6) and Cyp1b1 -/- intact female mice (165±2) compared to the intact Cyp1b1 +/+ mice (128±7) (p Cyp1b1 +/+ (116±4, Δ45) and Cyp1b1 -/- female mice (135±9, Δ30) (PCyp1b1 +/+ and intact Cyp1b1 -/- compared to intact Cyp1b1 +/+ mice, which was inhibited by E2 in the former but not the later mice; however, 2-ME inhibited CYP4A1 expression in the intact Cyp1b1 -/- mice. These data suggest that CYP1B1-E generated metabolite 2-ME protects against Ang II-induced hypertension by inhibiting the expression of CYP4A1 and production of 20-HETE.

This paper empirically explores the determinants of stop episodes driven by bond flows using quarterly data from 38 economies over the period 1995&ndash, 2011. Drastic bond-led stop episodes may greatly destabilize domestic financial markets and lead to financial crisis, threatening the sustainability of the financial system. Using the complementary log&ndash, log regression method, we found that bond-led stop episodes were associated with contagion and domestic factors rather than global factors. The results of our estimation showed that the probability of bond-led stop episodes was higher in countries with larger financial markets or with more overvalued real exchange rates. The main policy implications of our results, particularly for emerging economies, are that bond-led stop episodes were less likely to occur in countries with higher levels of institutional quality, lower capital account restrictions, or more flexible exchange-rate regimes. Finally, we found that capital control played a relatively greater role in predicting bond-led stops in emerging economies than did exchange-rate regimes.

Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) II–induced abdominal aortic aneurysm (AAA). Male Apoe −/− / Cyp1b1 +/+ and Apoe −/− / Cyp1b1 −/− mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe −/− / Cyp1b1 +/+ mice was coadministered the CYP1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound and ex vivo by Vernier calipers, mice were euthanized, and tissues were harvested. Ang II produced AAAs in Apoe −/− / Cyp1b1 +/+ mice; mice treated with TMS or Apoe −/− / Cyp1b1 −/− mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased platelet-derived growth factor D, Pdgfrb , Itga2 , and matrix metalloproteinases 2 and 9 expression in aortic lesions; these changes were inhibited in mice treated with TMS and in Apoe −/− / Cyp1b1 −/− mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized in Apoe −/− / Cyp1b1 +/+ mice treated with TMS and in Apoe −/− / Cyp1b1 −/− mice and by concurrent treatment with the superoxide scavenger 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl. CYP1B1 contributed to the development of Ang II–induced AAA and associated pathogenic events in mice, likely by enhancing oxidative stress and associated signaling events. Thus, CYP1B1 may serve as a target for therapeutic agents for AAA in males.

Background We have reported that cytochrome P450 1B1 ( CYP 1B1), expressed in cardiovascular tissues, contributes to angiotensin II –induced vascular smooth muscle cell ( VSMC ) migration and proliferation and development of hypertension in various experimental animal models via generation of reactive oxygen species. This study was conducted to determine the contribution of CYP 1B1 to platelet‐derived growth factor‐BB–induced VSMC migration and proliferation in vitro and to neointimal growth in vivo. Methods and Results VSMC s isolated from aortas of male Cyp1b1 +/+ and Cyp1b1 −/− mice were used for in vitro experiments. Moreover, carotid arteries of Cyp1b1 +/+ and Cyp1b1 −/− mice were injured with a metal wire to assess neointimal growth after 14 days. Platelet‐derived growth factor‐ BB –induced migration and proliferation and H 2 O 2 production were found to be attenuated in VSMC s from Cyp1b1 −/− mice and in VSMC s of Cyp1b1 +/+ mice treated with 4‐hydroxy‐2,2,6,6‐tetramethylpiperidin‐1‐oxyl, a superoxide dismutase and catalase mimetic. In addition, wire injury resulted in neointimal growth, as indicated by increased intimal area, intima/media ratio, and percentage area of restenosis, as well as elastin disorganization and adventitial collagen deposition in carotid arteries of Cyp1b1 +/+ mice, which were minimized in Cyp1b1 −/− mice. Wire injury also increased infiltration of inflammatory and immune cells, as indicated by expression of CD 68 + macrophages and CD 3 + T cells, respectively, in the injured arteries of Cyp1b1 +/+ mice, but not Cyp1b1 −/− mice. Administration of 4‐hydroxy‐2,2,6,6‐tetramethylpiperidin‐1‐oxyl attenuated neointimal growth in wire‐injured carotid arteries of Cyp1b1 +/+ mice. Conclusions These data suggest that CYP 1B1‐dependent oxidative stress contributes to the neointimal growth caused by wire injury of carotid arteries of male mice.

Cytochrome P450 1B1 (CYP1B1)-generated testosterone (T) metabolite 6β-hydroxytestosterone (6β-OHT) contributes to angiotensin (Ang) II-induced hypertension in the male mice. However, the site of action of CYP1B1-testosterone metabolite 6β-OHT in Ang II-induced hypertension is unknown. The demonstration that Ang II increases blood pressure by its action in the subfornical organ and the presence of CYP1B1 in the brain led us to hypothesize that T contributes to Ang II-induced hypertension via its metabolism to 6β-OHT in the brain. To test this hypothesis, we examined the effect of intracerebroventricularly (ICV) administered T in castrated (Cas) wild-type ( Cyp1b1 +/+ ) and Cas Cyp1b1 -/- mice on the action of systemic Ang II (700 ng/kg/min) for 14 days. T (3 μg/2μL/injection/every 2nd day) or its vehicle (2-Hydroxypropyl-β-cyclodextrin dissolved in artificial CSF) was injected via a cannula implanted in the brain. Mean arterial blood pressure (MAP, mmHg) was measured by radiotelemetry (n=4-5). Ang II increased MAP in T but not its vehicle-injected Cas Cyp1b1 +/+ mice on Day 12 (159±2 vs. 98±2, PCyp1b1 -/- mice Ang II increased MAP in ICV injected 6β-OHT (1.5 μg/2μL/injection every 2nd day) but not T (151±3 vs. 123±5, PCyp1b1 +/+ but not Cas Cyp1b1 -/- mice (3.8±0.0.4 vs. 1.9±0.0); whereas ICV 6β-OHT in the later mice increased this ratio (4.7±0.6). Ganglionic blocker hexamethonium (30 mg/Kg, ip) on day 14 of Ang II infusion resulted in greater reduction in MAP (PCyp1b1 -/- , and T-injected Cas Cyp1b1 +/+ (Δ81±11 and Δ87±10) than in T injected Cas Cyp1b1 -/- mice (Δ50±8). Furthermore, in intact Cyp1b1 -/- , but not Cas Cyp1b1 -/- mice transduction with adenovirus (Ad) of CYP1B1-DNA (ICV 2μL of 1.0 X 10 12 particles/mL) increased Ang II-induced systolic blood pressure (P

Previously we showed that the protection against angiotensin (Ang) II-induced hypertension and associated pathophysiological changes in female mice are mediated by cytochrome P450 (CYP) 1B1-estradiol (E2) generated metabolite 2-methoxyestradiol (2-ME). Also, we demonstrated that Ang II-induced hypertension is mediated by group IV cytosolic phospholipase A 2 α (cPLA 2 α) activation resulting in arachidonic acid (AA) release, and generation predominantly of eicosanoids with pro-hypertensive effects in male mice. This study was conducted to determine the contribution of cPLA 2 α/AA system, and its relationship to CYP1B1 in Ang II-induced hypertension in the female mice. Ang II infusion (700 ng/kg/min, s.c. micro-osmotic pump) for 14 days increased the systolic blood pressure (SBP), measured by tail-cuff in wild-type mice (cPLA 2 α +/+ ) but not in cPLA 2 α gene-disrupted mice (cPLA 2 α -/- ) (151±8 vs. 126±9 mmHg, P 2 α +/+ mice but not in OVX cPLA 2 α -/- mice (175±3 vs. 121±2 mmHg, P rd day) attenuated ( P 2 α +/+ mice (124±5 mmHg, n=4). E2 attenuated Ang II-induced increase in SBP in OVX Cyp1b1 +/+ mice, but not in OVX Cyp1b1 -/- mice (125±5 vs. 158±4 mmHg, P Cyp1b1 -/- mice (129±7 vs. 185±7 mmHg, P 2 α +/+ activity examined in the kidneys was inhibited in Cyp1b1 -/- mice treated with 2-ME. Antagonists of prostaglandin (PG) E2 receptors EP1 (SC19220) and EP3 (L-798106) (28 μg/g, s.c. every 2 nd day) minimized Ang II-induced increase in SBP in OVX cPLA 2 α +/+ mice (126±2 and 127±5 vs. 175±3 mmHg, respectively, n=5). These data suggest that CYP1B1-E2 generated metabolite 2-ME protects against Ang II-induced hypertension by inhibiting cPLA 2 α activity and production of AA-derived PGE2 that exerts pro-hypertensive effects by stimulating EP1 and EP3 receptors. Thus, 2-ME and the drugs that selectively block EP1 and EP3 receptors could be useful for the treatment of hypertension and its pathogenesis in females.

This paper examines the determinants of surge and stop episodes in foreign loans using quarterly data from 55 countries covering 1990Q1 to 2011Q4. The estimation results show that, first, global, contagion and domestic factors are all significantly associated with both loan-led surge and stop episodes. Second, domestic factors are more relevant to stops than to surges and are associated more strongly with episodes in emerging countries than with those in advanced countries. Third, global risk and domestic growth shock are most consistent and important in predicting both types of episodes. Fourth, financial linkage is the most important contagion channel in the occurrence of loan-led episodes. Fifth, capital control is not a useful tool for avoiding either type of episode and may actually increase their likelihood. Finally, stops in emerging countries are strongly related to macroeconomic fundamentals such as inflation, current account balance, net foreign assets, real exchange rate, and previous occurrence of surge episodes. Our results strongly suggest that emerging countries with lower institutional quality levels are more likely to experience both surges and stops.

Angiotensin II activates cytosolic phospholipase A 2 α (cPLA 2 α) and releases arachidonic acid from tissue phospholipids, which mediate or modulate ≥1 cardiovascular effects of angiotensin II and has been implicated in hypertension. Because arachidonic acid release is the rate limiting step in eicosanoid production, cPLA 2 α might play a central role in the development of angiotensin II–induced hypertension. To test this hypothesis, we investigated the effect of angiotensin II infusion for 13 days by micro-osmotic pumps on systolic blood pressure and associated pathogenesis in wild type (cPLA 2 α +/+ ) and cPLA 2 α −/− mice. Angiotensin II–induced increase in systolic blood pressure in cPLA 2 α +/+ mice was abolished in cPLA 2 α −/− mice; increased systolic blood pressure was also abolished by the arachidonic acid metabolism inhibitor, 5,8,11,14-eicosatetraynoic acid in cPLA 2 α +/+ mice. Angiotensin II in cPLA 2 α +/+ mice increased cardiac cPLA 2 activity and urinary eicosanoid excretion, decreased cardiac output, caused cardiovascular remodeling with endothelial dysfunction, and increased vascular reactivity in cPLA 2 α +/+ mice; these changes were diminished in cPLA 2 α −/− mice. Angiotensin II also increased cardiac infiltration of F4/80 + macrophages and CD3 + T lymphocytes, cardiovascular oxidative stress, expression of endoplasmic reticulum stress markers p58 IPK , and CHOP in cPLA 2 α +/+ but not cPLA 2 α −/− mice. Angiotensin II increased cardiac activity of ERK1/2 and cSrc in cPLA 2 α +/+ but not cPLA 2 α −/− mice. These data suggest that angiotensin II–induced hypertension and associated cardiovascular pathophysiological changes are mediated by cPLA 2 α activation, most likely through the release of arachidonic acid and generation of eicosanoids with predominant prohypertensive effects and activation of ≥1 signaling molecules, including ERK1/2 and cSrc.

We empirically examine the determinants of the short-term cross-country impacts of Lehman Brothers’ bankruptcy on the volatility of stock prices. According to the results of this study, countries with lower financial openness and greater stock market depth experienced a smaller increase in stock price volatility. This suggests that capital control and greater stock market development were relatively more useful in maintaining the stability of stock markets at the time of Lehman’s failure. On the other hand, we find little evidence for the role of international imbalances, trade openness, economic sizes and income levels, and macroeconomic fundamentals.

(ProQuest: ... denotes formulae omitted.)I. IntroductionThe purpose of this paper is to show that country fundamentals matter for the cross-section of currency excess returns. We include the variables reflecting macroeconomic fundamentals, such as interest rate, default risk, and foreign exchange rate regime. We also include the variables reflecting the degree of capital control and the size of capital market. We speculate that variations of country fundamentals may significantly affect the currency returns through increasing or decreasing the currency risks. For example, the adoption of more flexible exchange rate regime may increase the currency risks substantially. Our analysis shows that these variables do have explanatory power for the cross-section of currency excess returns.Some previous works also considered the country fundamentals as important determinants of currency returns. For example, Jorda and Taylor (2012) and Coudert and Mignon (2013) emphasize the relation of the real exchange rate and default risk with the currency returns, respectively. However, we consider a more extensive set of country fundamentals in this paper and adopt an empirical method basically different from the previous studies.This paper's empirical methodology is partly motivated both by Lustig et al. (2011), and Lustig and Verdelhan (2007). They explain the cross-section of currency returns with a single factor-the global carry profits in case of Lustig et al. (2011) and the global consumption growth in case of Lustig and Verdelhan (2007).We adopt the factor model framework of these authors, but we include new factors that are based on country fundamentals.1In a series of their highly original papers, Pojarliev and Levich (2008, 2010, 2011) build a multi-factor currency returns model from the popular currency strategies such as carry, value, trend following, and volatility. Pojarliev and Levich used the factor model to explain the performance of currency fund managers. We modify the work of Pojarliev and Levich in two directions. First, we construct factors from country fundamentals rather than from investment-style returns. Second, we use the factor model to explain the performance of currencies, rather than currency fund managers.Our main empirical results are based on monthly currency excess returns of 19 major currencies for the 10-year period between January 2001 and December 2010. The 19 currencies have been selected after dropping those currencies with inadequate fundamental data. Our main findings can be summarized as follows:First, when the currencies are sorted on the basis of forward premium, exchange rate regime, the degree of capital control, and the size of capital markets, there are persistent return differences between high-ranked and low-ranked currencies. When the currencies are sorted by default risk, the return differences between high-ranked and low-ranked currencies are not persistent. As far as forward premium is concerned, the pattern has been discussed extensively in the previous literature. The results regarding the other fundamental variables are original in this paper.Second, a parsimonious model with three factors-forward premium, default risk, and foreign exchange rate regime-explains a large part of the cross-section of currency excess returns.Also the zero-intercept restriction of the factor model is not rejected for 13 out of 19 currencies. In comparison, a factor model with three investment-style factors is rejected for 14 out of 19 currencies.In recent years, the persistent profits of so-called carry trades have drawn many authors' attention.2 Carry traders buy a high-yield currency and sell a low-yield currency, or, equivalently, take a long forward position in a high-yield currency against a low-yield currency. Such trades exploit the failure of the uncovered interest parity (UIP). If the UIP holds, the excess returns cannot be predicted by interest rate or forward premium. …

Currency carry trades–buying high-deposit-rate currencies and selling low-deposit-rate currencies–earn positive excess returns over time. The literature has heretofore explained this phenomenon based on currency differences. We examine the possibility that the bank default risk of destination countries contributes to positive carry trade profit. We measure the bank default risk of a country by averaging the distance to default–an option-pricing-based measure of default risk–of individual banks in that country. The average distance to default is strongly correlated both with deposit rate and with currency excess return. Also, “distance-to-default premium” explains a significant part of the time variation in carry trade profit.

In this research, we will present Al doped ZnO thin films for transparent conducting oxide applications. Aluminum doped zinc oxide (AZO) thin films have been deposited on the glass substrates by sol-gel spin-coating method using zinc acetate dehydrate (Zn(CH3COO)2 2H2O) and aluminum chloride hexahydrate (AlCl3 x 6H2O) as cation sources. In this study, we investigated the effects of near infrared ray (NIR) annealing on the structural, optical and electrical characteristics of the AZO thin films. The experimental results showed that AZO thin films have a hexagonal wurtzite crystal structure and had a good transmittance higher than 85% within the visible wavelength region. It was also found that the additional energy of NIR helps to improve the electrical properties of Al doped ZnO transparent conducting oxides.

We investigated the contribution of cytochrome P-450 1B1 (CYP1B1) to renal dysfunction and organ damage associated with ANG II-induced hypertension in rats. ANG II (300 ng·kg−1·min−1) or vehicle were infused for 2 wk, with daily injections of a selective CYP1B1 inhibitor, 2,4,3′,5′-tetramethoxystilbene (TMS; 300 μg/kg ip), or its vehicle. ANG II increased blood pressure and renal CYP1B1 activity that were prevented by TMS. ANG II also increased water intake and urine output, decreased glomerular filtration rate, increased urinary Na+ and K+ excretion, and caused proteinuria, all of which were prevented by TMS. ANG II infusion caused hypertrophy, endothelial dysfunction, and increased reactivity of renal and interlobar arteries to vasoconstrictor agents and renal vascular resistance and interstitial fibrosis as indicated by accumulation of α-smooth muscle actin, fibronectin, and collagen, and inflammation as indicated by increased infiltration of CD-3+ cells; these effects were inhibited by TMS. ANG II infusion also increased production of reactive oxygen species (ROS) and activities of NADPH oxidase, ERK1/2, p38 MAPK, and c-Src that were prevented by TMS. TMS alone had no effect on any of the above parameters. These data suggest that CYP1B1 contributes to the renal pathophysiological changes associated with ANG II-induced hypertension, most likely via increased ROS production and activation of ERK1/2, p38 MAPK, and c-Src and that CYP1B1 could serve as a novel target for treating renal disease associated with hypertension.

This paper argues that renminbi (RMB) internationalization and China's strategic interests in ASEAN will combine to deepen economic integration and pave the way for creating a de facto RMB bloc consisting of the 10 ASEAN countries, China, Hong Kong, and Taiwan—a grouping we call ASEAN+New3. Such a currency bloc is likely to weaken the initiatives of the existing ASEAN+3 (China, Japan, and Korea) for regional monetary-financial cooperation because neither Japan nor can Korea join the new currency bloc for economic and political reasons. This paper also argues that RMB internationalization would delay the resolution of the trade imbalance between East Asia and the United States because China would be pressured by the other members of ASEAN+New3 to maintain stability of the RMB vis-à-vis the U.S. dollar.

Sahan-Firat S, Jennings BL, Yaghini FA, Song CY, Estes AM, Fang XR, Farjana N, Khan AI, Malik KU. 2,3',4,5'-Tetramethoxystilbene prevents deoxycorticosterone-salt-induced hypertension: contribution of cytochrome P-450 1B1. Am J Physiol Heart Circ Physiol 299: H1891-H1901, 2010. First published September 17, 2010; doi:10.1152/ajpheart.00655.2010.-Reactive oxygen species (ROS) contribute to various models of hypertension, including deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Recently, we have shown that ROS, generated by cytochrome P-450 1B1 (CYP1B1) from arachidonic acid, mediate vascular smooth muscle cell growth caused by angiotensin II. This study was conducted to determine the contribution of CYP1B1 to hypertension and associated pathophysiological changes produced by DOCA (30 mg/kg) given subcutaneously per week with 1% NaCl + 0.1% KCl in drinking water to uninephrectomized rats for 6 wk. DOCA-salt treatment increased systolic blood pressure (SBP). Injections of the selective inhibitor of CYP1B1, 2,3',4,5'-tetramethoxystilbene (TMS; 300 mu g/kg ip every 3rd day) initiated at the 4th week of DOCA-salt treatment normalized SBP and decreased CYP1B1 activity but not its expression in the aorta, heart, and kidney. TMS also inhibited cardiovascular and kidney hypertrophy, prevented the increase in vascular reactivity and endothelial dysfunction, and minimized the increase in urinary protein and K+ output and the decrease in urine osmolality, Na+ output, and creatinine clearance associated with DOCA-salt treatment. These pathophysiological changes caused by DOCA-salt treatment and associated increase in vascular superoxide production, NADPH oxidase activity, and expression of NOX-1, and ERK1/2 and p38 MAPK activities in the aorta, heart, and kidney were inhibited by TMS. These data suggest that CYP1B1 contributes to DOCA-salt-induced hypertension and associated pathophysiological changes, most likely as a result of increased ROS production and ERK1/2 and p38 MAPK activity, and could serve as a novel target for the development of agents like TMS to treat hypertension.

Injured podocytes proliferate in cellular focal segmental glomerulosclerosis (FSGS), collapsing FSGS and crescentic glomerulonephritis, where TGF-β1 is overexpressed in hyperplastic podocytes. Yet effects of podocyte TGF-β on podocyte growth and development of glomerulosclerosis have not been clearly defined. TGF-β activates Smads, Ras/extracellular signal-regulated kinase (ERK) and phosphatidyl inositol-3-kinase (PI3K) pathways in podocytes, of which the major TGF-β/Smad signaling pathway appears to override the minor TGF-β-induced Ras/ERK/PI3K pathways. We provide evidence that increasedTGF-β/Smad signaling activity by hyperplastic podocytes may lead to mesangial cell matrix overproduction and eventually to podocyte apoptosis and/or detachment, culminating in the development of glomerulosclerosis. In this regard, TGF-β, which is overexpressed by hyperplastic podocytes, may play an important role for the cellular and collapsing variants of FSGS to evolve into the classic FSGS pattern. In contrast, podocyte proliferation that is induced by Ras/ERK signaling activity in proliferative podocyte diseases seems to be mostly independent of TGF-β1 activity. Collectively, these data bring new insights into our understanding of the overexpression of TGF-β in hyperplastic podocytes in progressive glomerular diseases.

This paper examined the patterns of Japanese vocal intervention and its influence on the yen/dollar exchange rate using the daily data between January 2000 and August 2003. The major findings of this paper are as follows. First, vocal intervention that is leaning against the wind was found to be successful as opposed to lean-with-the-wind intervention which had mixed results in its effectiveness. Second, vocal intervention turned out to be more effective when it was intended for yen depreciation than for yen appreciation. Third, in the cases of leaning against the wind and yen depreciation intended interventions, the Japanese authorities normally relied on vocal intervention and engaged in actual intervention only when repeated vocal intervention proved ineffective.

Oxidized low-density lipoprotein (Ox-LDL) activates transforming growth factor-beta (TGF-beta)/Smad signaling to stimulate plasminogen activator inhibitor-1 (PAI-1) expression in mesangial cells. Smad-binding sequences, termed CAGA boxes, are present in the promoter of human PAI-1 gene, and they mediate TGF-beta transcriptional induction. However, the functional role of each CAGA box in the Ox-LDL-induced PAI-1 promoter activation is unknown. In this study, mutation of 1 of the 3 CAGA boxes located at -730, -580, and -280 of the PAI-1 promoter decreased the Ox-LDL-induced luciferase activity by 40 to 58%, whereas mutations in 2 sites reduced it over 75% or completely abolished it. Overexpression of Smad3 in N-terminal tagged Smad3-transfected cells increased the Ox-LDL-induced transcriptional activation of the PAI-1 promoter, whereas mutation of Smad3 abolished it. Electrophoretic mobility shift assay showed that the labeled -280, -580, and -730 CAGA box probes detected DNA/protein complexes induced by Ox-LDL, whereas mutant probes did not. When nuclear extracts were preincubated with a 100-fold of an unlabeled -280, -580, and -730 CAGA oligonucleotide, the formation of complexes was prevented but not with mutant CAGA box competitors. The addition of anti-Smad3 to the reaction with the labeled -280 or -580 CAGA box probe resulted in a supershift, but not with the -730 CAGA box probe. These results suggest that the 3 CAGA elements in the PAI-1 promoter mediate the Ox-LDL-induced PAI-1 transcription to a different degree, of which the -280 and -580 CAGA regions directly bind to Smad3.

The role of transforming growth factor-beta (TGF-beta) receptor complex in the pathogenesis of crescentic glomerulonephritis (GN) is not clear. To test the hypothesis that TGF-beta signaling plays a crucial role in the development and progression of crescentic GN by inducing the activation of extracellular signal-regulated kinase (ERK) and expression of its target genes, anti-glomerular basement membrane (GBM) GN was induced in TGF-beta type II receptor (TGF-betaIIR) gene heterozygous (TGF-betaIIR(+/-)) C57BL/6J mice and wild-type animals. GN was initiated in preimmunized mice by administration of rabbit anti-mouse GBM serum. TGF-betaIIR deficiency was significantly associated with decreased renal damage at days 14, 21, and 28 after induction of GN: renal function impairment, proteinuria, proportion of crescents, glomerular accumulation of periodic acid-Schiff-positive material, relative cortical interstitial volume, as well as renal cortical phosphorylation of ERK and plasminogen activator inhibitor type I (PAI-1) and alpha2(I) collagen mRNA levels were significantly decreased in TGF-betaIIR(+/-) mice compared with wild-type animals. These results provide the first direct evidence that TGF-betaIIR deficiency protects against renal injury in crescentic GN, possibly by inhibiting the sustained activation of ERK and PAI-1 and alpha2(I) collagen gene expression. Thus, TGF-beta signaling appears to play an important role in the development and progression of crescentic GN by inducing the ERK activity, and PAI-1 and alpha2(I) mRNA expression.

Supplemental Digital Content is available in the text., Cytochrome P450 (CYP) 1B1 contributes to vascular smooth muscle cell growth and hypertension in male mice. This study was conducted to determine the contribution of CYP1B1 to the development of atherosclerosis and hypertension and associated pathogenesis in 8-week-old male apolipoprotein E–deficient (ApoE−/−/Cyp1b1+/+), and ApoE- and CYP1B1-deficient (ApoE−/−/Cyp1b1−/−) mice fed a normal or atherogenic diet for 12 weeks. A separate group of ApoE−/−/Cyp1b1+/+ mice on an atherogenic diet was injected every third day with the CYP1B1 inhibitor, 2,3′,4,5′-tetramethoxystilbene (300 μg/kg), or its vehicle, dimethyl sulfoxide (30 μL, IP); systolic blood pressure was measured by the tail cuff method. After 12 weeks, mice were euthanized, blood collected for lipid analysis, and aortas harvested for measuring lesions and remodeling, and for infiltration of inflammatory cells by histological and immunohistochemical analysis, respectively, and for reactive oxygen species production. Blood pressure, areas of lipids and collagen deposition, elastin breaks, infiltration of macrophages and T lymphocytes, reactive oxygen species generation in the aorta, and plasma lipid levels were increased in ApoE−/−/Cyp1b1+/+ mice on an atherogenic diet; these changes were minimized in mice given 2,3′,4,5′-tetramethoxystilbene, and in ApoE−/−/Cyp1b1−/− mice on an atherogenic diet; absorption/production of lipids remained unaltered in these mice. These data suggest that aortic lesions, hypertension, and associated pathogenesis in ApoE−/−/Cyp1b1+/+ mice on an atherogenic diet are most likely dependent on CYP1B1-generated oxidative stress and increased plasma lipid levels independent of blood pressure and absorption of lipids. CYP1B1 could serve as a novel target for developing drugs to treat atherosclerosis and hypertension caused by hypercholesterolemia.

Background The kidney plays an important role in regulating blood pressure (BP). cPLA2α in the kidney is activated by various agents including angiotensin II (Ang II) and selectively releases arachidonic acid (AA) from tissue lipids, generating pro- and antihypertensive eicosanoids. Since activation of cPLA2α is the rate-limiting step in AA release, this study was conducted to determine its contribution to renal dysfunction and end-organ damage associated with Ang II-induced hypertension. Methods cPLA2α(+/+) and cPLA2α(-/-) mice were infused with Ang II (700 ng/ kg/min) or its vehicle for 13 days. Mice were placed in metabolic cages to monitor their food and water intake, and urine was collected and its volume was measured. Doppler imaging was performed to assess renal hemodynamics. On the 13th day of Ang II infusion, mice were sacrificed and their tissues and blood collected for further analysis. Results Ang II increased renal vascular resistance, water intake, and urine output and Na(+) excretion, decreased urine osmolality, and produced proteinuria in cPLA2α(+/+) mice. Ang II also caused accumulation of F4/80(+) macrophages and CD3(+) T cells and renal fibrosis, and increased oxidative stress in the kidneys of cPLA2α(+/+) mice. All these effects of Ang II were minimized in cPLA2α(-/-) mice. Conclusion cPLA2α contributes to renal dysfunction, inflammation, and end-organ damage, most likely via the action of pro-hypertensive eicosanoids and increased oxidative stress associated with Ang II-induced hypertension. Thus, cPLA2α could serve as a potential therapeutic target for treating renal dysfunction and end-organ damage in hypertension.

Korean Abstract: 본 연구에서는 신호접근법과 15개의 월별 지표를 이용하여 한국, 인도네시아, 말레이시아, 태국, 필리핀 등 1997년 극심한 외환위기를 경험한 동아시아 5개국을 대상으로 외환위기 예측모형을 구축하였다. 또한 예측모형의 성과를 평가하기 위하여 동아시아 이전과 동아시아 이후의 두 기간에서 표본외 예측을 따로 시행하였다. 기존의 연구와는 달리 본 연구에서는 표본외 예측시 표본내 기간을 고정하지 않았다. 동아시아 외환위기가 발생하기 이전 기간인 1995년 7월~1997년 6월에서의 표본외 예측결과에 따르면 실질환율과 수출변수를 중심으로 필리핀을 제외한 4개국에서 다수의 경보가 발생하였으며 위기발생 가능성의 확률도 크게 상승하였다. 이는 동아시아 5개국만을 대상으로 한 신호접근법이 동아시아 외환위기를 어느 정도 예측할 수 있었던 유효한 수단이었음을 시사한다. 그러나 본 연구에서 구축한 예측모형은 동아시아 외환위기 이후 이 지역에서 새로운 위기가 발생하지 않았음에도 불구하고 1999년 7월~2001년 6월의 표본외 기간에서 역시 다수의 경보를 발생하여 제2종 오류의 문제를 표출하였다. 한편 본 연구의 결과는 위기지표의 신호 발생 여부를 판단하기 위하여 사용하는 최적 임계치의 조정을 통해서 예측모형의 운영자의 선호도에 따라 제2종 오류의 문제를 어느 정도 완화할 수 있음을 보여주고 있다. English Abstract: In this paper, we have developed a forecasting system for currency crisis in East Asia based on a signaling approach. Our system uses 15 monthly indicators of five East Asian countries including Indonesia, Korea, Malaysia, the Philippines and Thailand that were severely hit by the currency crisis in 1997. We investigate the performance of the system through deploying out-of-sample forecasting for the periods both before and after the 1997 East Asian currency crisis. Unlike the existing research based on the signaling approach, our out-of-sample forecasting does not fix the in-sample period. The out-of-sample forecasting between July 1995 and June 1997 shows that prior to breakout of the crisis, several indicators including real exchange rates and exports sent frequent warnings to all crisis-hit East Asian countries except the Philippines. This may indicate that a signaling-based early warning system for currency crisis could have been an useful method of forecasting the East Asian crisis. On the other hand, we also find that our forecasting system often generates warning signals during the out-of-sample period between July 1999 and June 2001. Since we have not observed any currency crisis in this region after 1998, these are all false alarms, indicating that our system may be seriously exposed to the type II error. We can, however, mitigate this problem if we adjust the optimal critical values of indicators depending on the preferences of forecasting system manager.

This paper presents the development of an integrated micro high-temperature superconductor system for energy storage and attitude control of three-axis stabilized nano satellites. The micro HTS system consists of a flywheel/rotor, motor/generator, motor electronics, and a cooling system. The flywheel/rotor has been fabricated by using sintered NdFeB and the stator for motor/generator has been fabricated by micro fabrication technology. An alternative stator has been fabricated by cutting a 50 micron-thick copper film for comparison. A servo amplifier to drive the DC brushless motor of the integrated HTS system has been developed and successfully tested. A cooling system has been developed to test the system. It has been observed that the micro fabricated stator can make the flywheel rotate at a constant velocity of up to 12,000 rpm whereas the other stator generates a constant velocity of up to 2,500 rpm. Experiments show that the micro fabricated stator can significantly reduce the motor/generator losses.

Oxidized LDL activates PAI-1 transcription through autocrine activation of TGF-β signaling in mesangial cells. Background Lipid abnormalities and oxidative stress may be involved in the development of glomerulosclerosis. Plasminogen activator inhibitor-1 (PAI-1) is a component of extracellular matrix (ECM) and target gene of transforming growth factor-β (TGF-β). Smad proteins play a key role in TGF-β signaling, and Smad binding CAGA boxes are present in the PAI-1 promoter. This study examined whether oxidized low-density lipoprotein (Ox-LDL) activates PAI-1 transcription in human mesangial cells, mediated by increased Smad/DNA interactions. Methods Quiescent HMC were incubated with 50 μg/mL of Cu ++ -catalyzed Ox-LDL for 15 minutes to 4 hours, and the effects of Ox-LDL on TGF-β1 and PAI-1 mRNA expression, PAI-1 promoter activity, and DNA binding activity of Smad proteins were examined. Results Ox-LDL induced TGF-β1 and PAI-1 mRNA expression. Ox-LDL increased the transiently transfected PAI-1 promoter activity as compared with controls to 3.9-fold. Ox-LDL–treated cells increased Smad3 protein levels two times the control levels in the nuclei. Electrophoretic mobility shift assay (EMSA) performed using a CAGA sequence probe and nuclear extracts showed that Ox-LDL increased DNA/protein complexes. When nuclear extracts were preincubated with 100 molar excess of unlabeled CAGA oligonucleotide or SB-431542, an inhibitior of the TGF-β type I receptor, the formation of complex was prevented. The DNA binding protein was shown to be Smad3 by antibody supershift. Transfection of phosphorothioate CAGA oligonucleotides, which compete with the CAGA-containing PAI-1 promoter for Smad3 binding, inhibited the Ox-LDL–induced PAI-1 mRNA expression. Cotransfection of phosphorothioate CAGA oligonucleotides with PAI-1 reporter vector also blocked the Ox-LDL-induced PAI-1 promoter activity. Conclusion These results suggest that Ox-LDL activates TGF-β/Smad signaling to stimulate PAI-1 transcription in human mesangial cells. Thus, progression of glomerular disease may be promoted by PAI-1 up-regulation in human mesangial cells mediated by the Ox-LDL–induced TGF-β/Smad signaling pathways.

Heterozygous mice for TGF-bIIR gene are resistant to the pro- gression of streptozotocin-induced diabetic nephropathy. Background. Transforming growth factor-b (TGF-b) recep- tor complex and its downstream Smad signaling intermediates constitute an extracellular matrix (ECM) accumulation path- way. Methods. In the present study, we examined whether de- creased expression of the TGF-b type II receptor (TGF-bIIR) in TGF-bIIR gene heterozygous (TGF-bIIR +/− ) (HT) mice could inhibit the Smad signaling pathway and subsequent pro- gression of renal lesions when streptozotocin (STZ) diabetes is induced. Results. At the end of the 28-week experiment after STZ injections, wild-type diabetic mice showed severe glomerular hypertrophy and mesangial matrix accumulation occasionally featuring nodular glomerulosclerosis. In contrast, mean glomerular area and mesangial volume density were signifi- cantly decreased in the HT diabetic mice as compared with the wild-type diabetic mice. Immunostaining for phosphory- lated Smad2/Smad3 and TGF-bIIR in the glomerular cells was also significantly reduced in the HT diabetic mice. Southwest- ern histochemistry using digoxigenin-labeled CAGA sequence probes showed that localization of labeled probes to the nuclei of glomerular cells in the HT diabetic mice was significantly less frequent than that in the wild-type diabetic animals. Northern blot analysis showed that a1(IV) collagen mRNA levels were significantly reduced in the kidney tissue of HT diabetic mice as compared with the wild-type diabetic mice. Conclusion. These results suggest that decreased expression of TGF-bIIR in the HT diabetic mice can inhibit the progres- sion of diabetic renal injury by inhibiting the downstream Smad signaling pathway and subsequent ECM gene expression. Thus, TGF-bIIR appears to play an important role in the progres- sion of diabetic nephropathy by mediating intracellular Smad signaling.

Reactive oxygen species are involved in the pathogenesis of diabetic nephropathy. Amadori-modified glycated albumin modulates signaling pathways in mesangial cells that contribute to the development of diabetic nephropathy. However, the effects of glycated albumin on mesangial cell superoxide (O2-) production are unknown. Thus, we examined whether glycated albumin induces mesangial cell O2- generation and whether increased O2- production elicits cell growth.Quiescent human mesangial cells (HMC) were exposed to bovine serum albumin (BSA) or glycated BSA (Gly-BSA) with or without diphenylene iodonium (DPI) or apocynin, inhibitors of NAD(P)H oxidase, GF109203X (GFX), a protein kinase C (PKC) inhibitor.Gly-BSA increased PKC activity, particularly PKC-alpha and -alpha1, within 15 min of incubation with HMC, which decreased to the control value at 2 h. Gly-BSA incubated with HMC increased O2- production by 2 times vis-á-vis BSA-treated cells. The Gly-BSA-induced increased O2- generation was suppressed by DPI or GFX. Gly-BSA significantly increased mesangial [3H]-leucine incorporation, whereas these processes were abrogated by DPI, apocynin or GFX.Gly-BSA induces PKC/NAD(P)H oxidase-dependent O2- production in HMC, which in turn results in cell hypertrophy. Thus, O2- induced by glycated albumin might cause mesangial cell alterations in diabetes participating in the pathophysiology of diabetic nephropathy.

Lipid abnormalities and dysregulation of the plasminogen activator (PA)/plasmin system may be involved in the development of glomerulosclerosis. We investigated the effects of low-density lipoprotein (LDL) on PA inhibitor-1 (PAI-1), urokinase-type PA (uPA), and tissue-type PA (tPA) in relationship to protein kinase C (PKC) in cultured human mesangial cells (HMC). LDL (200 μg/ml) induced two peaks of PKC activation at hours 0.25 and 6, with translocation of PKC-α, -β1, and -δ from cytosol to the membrane. The second increase in PKC activity gradually decreased to the control value by hour 18. LDL downregulated 2.4-kb PAI-1, uPA, and tPA mRNA expression within 6 h of incubation with HMC. On the other hand, after 12–48 h, LDL-treated cells showed a significant increase in PAI-1, tPA, and uPA mRNA levels. LDL induced up to a twofold increase in PAI-1 antigen levels in the extracellular matrix of HMC after 24–48 h as well as increased PA inhibitory activity in the culture medium. Analysis of the adhesion plaques from cells incubated with LDL for 48 h by zymography showed increased intensity of lysis near molecular weights of ∼55,000 and 100,000. LDL slightly increased tPA release at hours 24 and 48 but did not increase PA activity in culture medium. The stimulatory effects of LDL on PAI-1, tPA, and uPA gene regulation in HMC were blocked by the inhibition of PKC using GF-109203X 12 h after treatment with LDL or downregulation of PKC using phorbol myristate acetate. In summary, LDL regulates PAI-1, uPA, and tPA in biphasic patterns in HMC, and the upregulation of PAI-1, uPA, and tPA after long-term LDL exposure seems to be mediated by a delayed PKC activation associated with an increased PA inhibitory activity. These results suggest that LDL, after prolonged incubations with HMC, causes a PA/inhibitor imbalance favoring accumulation of matrix.

mRNA expression of urokinase and plasminogen activator inhibitor-1 in human crescentic glomerulonephritis Aims: Weak staining for urokinase-plasminogen activator (uPA), tissue type plasminogen activator (tPA), or plasminogen activator inhibitor-1 (PAI-1) confined to crescents has been described in a few cases of severe crescentic glomerulonephritis. We evaluated the molecular mechanism by which these proteins are increased or induced within crescents. Methods and results: We examined uPA, tPA and PAI-1 mRNA expression in 12 renal biopsies with crescentic glomerulonephritis, and in six control renal biopsies with no detectable abnormalities by RNA in-situ hybridization. The expressions of uPA, tPA and PAI-1 proteins were also assessed by immunofluorescence. To better determine the cellular origin of uPA and PAI-1 transcripts, CD68 protein was studied by immunohistochemistry on the same sections on which in-situ hybridization had been performed. In controls, there were very low level signals of uPA and PAI-1 mRNAs in a few glomerular epithelial cells (GECs). Specific signals of uPA and PAI-1 mRNAs were detected in the cells forming crescents in all the cases with crescentic glomerulonephritis. However, weak expression of mRNA for tPA was detected in two cases only. Immunostaining for uPA and PAI-1 was positive in some but not all, cases of crescentic glomerulonephritis. A double-labelling study showed that the signal for PAI-1 and uPA mRNAs was mainly in CD68− cells. Conclusions: Local accumulation of uPA or PAI-1 in crescents is associated with enhanced mRNA expression of these proteins. The up-regulation of PAI-1 mRNA by GECs, in particular, could play a major role in the formation of persistent fibrin deposits and progression of the lesions in crescents. Whether up-regulation of uPA is an epiphenomenon or plays a pathogenic role in the formation of crescents remains to be clarified.

This paper empirically investigates the presence of contagion effects and their causes in the 1997 Southeast Asian crisis. Our empirical results indicate that the Thai crisis was transmitted to neighboring Southeast Asian countries through contagion. They also suggest that the international investors' institutional practice of securing sufficient liquidity and trade linkage were important in spreading the contagion, but the financial integration channel was not important. In addition, the similar macroeconomic conditions of the Southeast Asian countries, such as large capital inflows, large accumulation of current account deficit, and high level of external debt prior to the onset of the Thai crisis, were also responsible for the contagion. J. Japan. Int. Econ., June 2001, 15(2), pp. 199–224. Department of Ecnomics, Korea University, 5-1 Anam-dong, Songbuk-ku, Seoul 136-701, Republic of Korea; and School of Economics, Kookmin University, 861-1 Chongnung-dong, Songbuk-ku, Seoul 136-702, Republic of Korea. Copyright 2001 Academic Press. Journal of Economic Literature Classification Numbers: F30, F31.

One year after the crisis erupted in Thailand and spread to other countries in the region, East Asia is littered with idle plants, insolvent financial institutions, loan defaults, and bankrupt businesses, both large and small. All of the countries hit by the currency attack are now in deep recession. GDP growth in these countries will collapse in 1998 with no prospects for early recovery. The total volume of foreign capital inflows into these countries has dwindled to a trickle and will not likely exceed the level of 1997. Similarly the real exchange rates, which depreciated sharply in 1997, are not likely to change significantly for some time to come. The stock markets in the region remain depressed and show little sign of recovery.

This paper empirically and theoretically shows that thrift and the terms of trade in Japan, productivity of Japan and foreign countries, and the world long-term real interest rate are the economic fundamentals that determine the real exchange rate and the current account balance in Japan. This paper's empirical results imply that the large current account surplus in Japan can be explained by changes in those fundamentals to a great extent. They also provide an plausible explanation for how the simultaneous improvement of the current account balance and the appreciation of the real exchange rate in Japan could happen in the 1980s. J. Japan. Int. Econ. , June 1997, 11 (2), pp. 143–184. Korea Institute of Finance, 7th Floor, K.F.B. Building, 4-1 Myeong-Dong 1 Ga, Chung-Ku, Seoul 110-121, Korea.