economic growth. Whether these factors are sufficient to explain Europe’s deve-lopment or are more generally necessary to have growth elsewhere is difficultto determine. Recent Chinese economic developments suggest that once newtechnologies become available they can combine with local practices of longhistorical standing to create distinctive patterns of historical change. Empire in Chinese History
The durability of the Chinese empire can be explained, at least in part, by the
presence of practices that emerge later in European history and are often conside-red hallmarks of the modern age. The similarities and differences between certainlate imperial Chinese political practices and more familiar European ones suggestboth persistent differences between China and the West as well as enduringpriorities and problems in Chinese history. Taxing Transformations : Fiscal Features of Chinese States
Late imperial Chinese ideas about good governance included light taxation,
which the state could achieve through a combination of strategies. The govern-ment’s inabilities to sustain these strategies after the mid-nineteenth centuryhighlight major changes in the nature of the Chinese state, while post-1949 effortsat reasserting some features of earlier fiscal policies point out the challenges thecentral government has faced first in consolidating its power and authority andthen in managing the economic reforms of the past three decades. Interesting Associations : The Chinese State in Theory and Practice
The late imperial Chinese state engaged its subjects by stressing shared beliefs
and interests. This general orientation differs from those adopted by early modernEuropean states and other empires and continues to affect the ways in which theChinese state since 1949 has grappled with the competing interests and diversebeliefs of people under its rule.
Professeur, Osaka University Medical School (Japon)
The Role of Apoptosis-Regulating Kinase-1 on Cardiac and Vascular Remodeling (June 5th, 2005)
Apoptosis signal-regulating kinase 1 (ASK1) has recently identified as one of
mitogen-activated protein kinase kinase kinases. ASK1 is activated by various
extracellular stimuli such as growth factors, vasoactive peptides, cytokines, che-mokines and stress, and is involved in a variety of cellular function. Manyevidences show that angiotensin 11 (Ang II) induces not only hypertension butalso directly contributes to cardiac diseases. Therefore, we examined the effectsof Ang II on the role of ASK1 in cardiac and vascular remodeling.
In Cardiac Remodeling ; (1) By using mice deficient in ASK1 (ASK1-/- mice),
we investigated the role of ASK1 in cardiac hypertrophy and remodeling inducedby Ang II. Left ventricular ASK1 was activated by Ang 11 infusion in wild-type mice, which was mediated by angiotensin 11 type I receptor and superoxide. Although Ang II-induced hypertensive effect was comparable to wild-type andASK1-/- mice, left ventricular ASK1 activation by Ang 11 was not detectable inASK1-/- mice, and p38 and c-Jun N-terminal kinase (JNK) activation was lesserin ASK-/- mice than in wild-type mice. Elevation of blood pressure by continuousAng 11 infusion was comparable between ASK1-/- and wild-type mice. However,Ang II-induced cardiac hypertrophy and remodeling, including cardiomyocytehypertrophy, cardiac natriuretic peptides mRNA upregulation, cardiomyocyteapoptosis, interstitial fibrosis, coronary arterial remodeling, and collagen geneupregulation, was significantly attenuated in ASK1-/- mice compared with wild-type mice. These results showed that ASK1 is the critical signaling molecule forAng II-induced cardiac hypertrophy and remodeling in vivo. (2) On the otherexperiments, Ang II-induced MCP-1 gene expression was investigated in thecardiac fibroblasts. MCP-1 mRNA was increased in cardiac fibroblasts by AngII treatment, whereas MCP-1 mRNA in cardiomyocytes was unchanged. Ang IIactivated JNK, p38MAPK, and NF-κB in cardiac fibroblasts. MCP-1 mRNAexpression by Ang II was inhibited by dominant-nagative mutant of p38MAPK(DN-p38) and ERK inhibitor (PD98059), whereas DN-JNK did not in cardiacfibroblasts. In wild type ASK1 transfected cardiac fibroblasts, MCP-1 and NF-κBgene expressions were increased, and this increases were inhibited by the treat-ment of DN-ASK1, and ND-p38. The Ang II-induced activation of ASK1 follo-wed by p38MAP kinase and NF-κB signaling in cardiac fibroblast is partiallyinvolved in myocardial MCP-1 expression.
In Vascular Remodeling ; (1) We used rat balloon injury model and cultured
vascular smooth muscle cells (VSMCs). Arterial ASK1 activity was rapidly anddramatically increased after balloon injury. To specifically inhibit endogenousASK1 activation, DN-ASK1 was transfected into rat carotid artery prior to bal-loon injury. Gene transfer of DN-ASK1 significantly prevented neointimal forma-tion at 14 days after injury. Bromodeoxyuridine labeling index at 7 days afterinjury showed that DN-ASK1 remarkably suppressed VSMCs proliferation inboth the intima and the media. We also examined the role of ASK1 in culturedrat VSMCs. Infection with DN-ASK1 significantly attenuated serum-inducedVSMCs proliferation and migration. (2) We compared in neointimal formationafter cuff placement around the femoral artery between mice deficient in ASK1(ASK1-/- mice) and wild type (WT) mice. Neointimal formation at 28 days after
cuff injury in ASK1-/- mice was significantly attenuated compared with WT mice. Furthermore, we compared between VSMCs isolated from ASK1-/- mice and WTmice in proliferation and migration. Both proliferation and migration of VSMCsfrom ASK1-/- mice were significantly attenuated compared with VSMCs from WTmice.
ASK1 activation plays the key role in cardiac hypertrophy and vascular intimal
hyperplasia. Thus, ASK1 is proposed to be a potential therapeutic target for cardiacdiseases. The Role of MAP Kinases on Cardiac and Vascular Remodeling
Angiotensin II (Ang II) is the central product of the renin-angiotensin system.
It plays an important role not only in the etiology of hypertension but also inthe pathophysiology of cardiovascular diseases. Resent studies elucidate that therole of Ang II in cardiovascular diseases at the molecular and cellular levels andthe pharmacological effects of angiotensin receptor antagonists in comparisonwith angiotensin-converting enzyme inhibitors. Ang II, via AT1 receptor, directlycauses cellular phenotypic changes and cell growth, regulates the gene expressionof various bioactive substances (vasoactive hormones, growth factors, extracellu-lar matrix components, cytokines, etc.), and activates multiple intracellular signa-ling cascades (mitogen-activated protein kinase cascades, tyrosine kinases, varioustranscription factors, etc.) in cardiac myocytes and fibroblasts, vascular endothelialand smooth muscle cells, and renal mesangial cells. These actions are supposedto participate in the pathophysiology of cardiac hypertrophy and remodeling,heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis. Fur-thermore, in vivo recent evidence suggests that the activation of mitogen-activatedprotein kinases and activator protein-1 by Ang II may play the key role in cardio-vascular and renal diseases. We investigated the role of MAP kinases on cardiacand vascular remodeling in various diseases model.
Ang II infusion in rats induces cardiac hypertrophy via AT1 receptor, indepen-
dent of its blood pressure-elevating effect. Ang II (200 ng/kg/min s.c.) infusionin rats caused a small and gradual increase in blood pressure with elevated leftventricular mRNAs for skeletal α-actin, β-MHC, ANF, and fibronectin, precedingan increase in left ventricular mass and elevated TGF-βl and types I and 111collagen mRNA levels. These increases were completely inhibited by candesartancilexetil (AT1 receptor antagonist) but not by hydralazine. Thus, Ang II in vivo,via AT1 receptor, directly induces cardiac myocyte hypertrophy and gene repro-gramming, and probably fibroblast proliferation and subsequent fibrosis as well,independent of the elevation of blood pressure, indicating the key role of AngII in the development of pathological cardiac hypertrophy. Recent work on theeffects of Ang II infusion in vivo in conscious rats showed that Ang II-inducedcardiac activation of JNK occurs in a more sensitive manner than that of ERK,
and JNK activation by Ang II without ERK activation is followed by activationof activator protein-1 (AP-1 ; composed of c-Fos and c-Jun proteins). Importantly,AP-1 regulates the expression of various genes by binding the AP-1 consensussequence present in their promoter regions. Fetal phenotypes of cardiac genessuch as skeletal α-actin and ANF, and cardiac fibrosis-associated genes such asTGF-βl and collagen type I have AP-1 responsive sequences in their promoterregions. Indeed, AP-1 activation has been demonstrated to lead to increasedpromoter activity of skeletal α-actin and TGF-βl. Therefore, it is intriguingto postulate that JNK activation may be implicated in Ang II-induced cardiachypertrophic response in vivo.
In spontaneously hypertensive rats and other hypertensive models, effects of
angiotensin blockade were investigated. Molecular phenotypes of pathologicalcardiac hypertrophy differ among various types of cardiac diseases. In sponta-neously hypertensive rats (SHR), left ventricular mRNAs for skeletal α-actin,ANF, and collagen types I and III were higher and α-MHC mRNA levels werelower than those in normotensive control Wistar-Kyoto rats. An AT1 receptorantagonist (SC-52458) or an ACE inhibitor (imidapril) with a mildly hypotensiveeffect attenuated the increases in cardiac ANF and collagen types I and IIImRNAs and significantly normalized the decreased α-MHC mRNA. On the otherhand, a calcium channel blocker or a α1-adrenergic blocker had no effect onthese mRNA expressions in SHR. Stroke-prone SHR (SHRSP) showed a differentcardiac molecular phenotype from SHR or TGR(mRen2)27, as shown by increa-sed expressions of β-MHC and TGF-βl mRNAs. Losartan induced regression ofleft ventricular hypertrophy in SHRSP and normalized the altered cardiac expres-sions of α-MHC, skeletal α-actin, ANF, TGF-βl, and collagen types I and III inSHRSP to a greater extent than amlodipine despite comparable hypotensive effects. Left ventricular ERK and JNK activities were chronically higher in SHRSP thanin WKY. Treatment of SHRSP with losartan significantly inhibited the increasein left ventricular JNK activity, along with the regression of left ventricularhypertrophy, and did not lower cardiac ERK activity. Furthermore, hydralazinetreatment, which completely normalized blood pressure, caused neither significantregression of cardiac hypertrophy nor decreased cardiac JNK or ERK activity. Thus, the increased cardiac JNK activity in SHRSP is at least in part directlymediated by AT1 receptor and JNK may contribute to pathological cardiac hyper-trophy in SHRSP.
In diabetes, hyperglycemia leads to increases in cardiac AT1 receptor density
and mRNA levels without altering plasma renin concentrations, suggesting possibleactivation of the cardiac renin-angiotensin system in diabetic rats. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a recently developed model of humanNIDDM, show a unique cardiac molecular phenotype. An AT1 receptor antagonist(E-4177) and an ACE inhibitor (cilazapril) similarly prevented left ventricularup-regulation of TGF-βl mRNA and down-regulation of α-MHC mRNA in OLETFrats, suggesting that AT1 receptor may be involved in these gene expressions. Renal Protective Effects of Angiotensin Receptor Antagonist
Glomerular diseases are mainly caused by glomerular hypertension, DM, or
inflammation and are commonly characterized by mesangial cell overgrowth andexcessive accumulation of ECM proteins. The development of such glomerularinjuries is largely responsible for glomerular capillary obliteration and decline inthe glomerular filtration rate (GFR), ultimately leading to renal failure. Glomerulardiseases are the most clinically important kidney diseases. Accumulating evidencesuggests that mesangial cells, which are a major determinant in regulation ofGFR, play a key role in progression from glomerular injury to glomerulosclerosis,due to their overgrowth and synthesis of excess ECM proteins. Therefore, we focuson the molecular effects of Ang II on glomerular mesangial cells. Interestingly,Ang II concentrations within the kidney are about 1000-fold higher than thosein circulating blood, suggesting the presence of an intrarenal renin-angiotensinsystem. Ang II plays a critical role not only in the regulation of GFR but also inthe development of glomerulosclerosis by increasing glomerular capillary pressurecaused by preferential constriction of efferent arterioles.
Acute i.v. infusion of Ang II (100 or 1000 ng/kg/min) in conscious rats rapidly
and transiently induced activation of glomerular ERK and JNK, followed by anincrease in glomerular AP-1 binding activity. Thus, as in cardiovascular diseases,the ERK and JNK signaling cascades, via activation of AP-1, may be implicatedin the development of Ang II-induced glomerular injury.
The beneficial effects of AT1 receptor antagonists were tested in a variety of
renal disease models. In deoxycorticosterone acetate (DOCA)-salt hypertensiverats or SHRSP, which prominently exhibit progressive glomerulosclerosis, renalTGF-βl and ECM protein mRNA levels are higher than those in normotensivecontrol rats. Treatment of DOCA-salt hypertensive rats with candesartan cilexetil(1 mg/kg/day) or enalapril (10 mg/kg/day), although not decreasing blood pressure,significantly reduced urinary protein and albumin excretion and induced histolo-gical improvement in renal lesions, in association with decreases in renal corticalmRNA levels for TGF-βl, fibronectin, laminin, and collagen types I, III, and IV. Also in SHRSP, candesartan cilexetil (0.1 mg/kg/day), without significantlydecreasing blood pressure, significantly reduced renal TGF-βl, fibronectin, lami-nin, and collagen types I, III, and IV mRNA levels. These findings provide invivo evidence implicating Ang II, via AT1 receptor, in renal injury in thesehypertensive models, due to enhanced renal TGF-βl and ECM expressions.
Nephropathy is a major cause of complications and death in DM. AT1 receptor
antagonists as well as ACE inhibitors has been shown to decrease proteinuriaand slow the progression of diabetic glomerular injury in streptozotocin-induceddiabetic rats and OLETF rats, an NIDDM model. Thus, it is possible that AT1receptor blockade may be effective for treating nephropathy in NIDDM patientsas well as in IDDM patients, although the molecular mechanism is unknown. In
rats with subtotal renal ablation (remnant kidney model), candesartan cilexetil(1 mg/kg/day) significantly reduced the expression of glomerular α-smooth muscleactin and desmin, while decreasing urinary albumin excretion and inducing histo-logical improvement of glomerulosclerosis. These findings suggest a contributionof the AT1 receptor to glomerular cell phenotypic changes in the remnant kidneymodel. Ang II may participate in glomerulosclerosis in the remnant kidney modelby enhancing glomerular TGF-βl expression. Assessment of hyper accumulation around the lesion by FDG PET in primate thromboembolic stroke (June 26th, 2005)
There were many reports about new neuroprotective drugs for acute ischemic
stroke using the animal model of primate. However many drugs were failed inclinical study and there are only few drugs in clinical trials. The objects of thisstudy are to develop the new animal model using primate, which is closed tohuman being, and to may establish the new assessment for new drug in ischemicstroke using positron emission tomography (PET) study. Thromboembolic StrokeModel was prepared. In briefly, under pentobarbital anesthesia, a catheter wasimplanted into the left internal carotid artery of male cynomolgus monkeys(4-6 kg). All animals were allowed to recover for 2 days before embolization. Thromboembolic stroke was accomplished via occlusion of the middle cerebralartery (MCA), obtained by injecting an autologus blood clot into the left internalcarotid artery. Neurologic deficits scores were assigned at a certain hours afterembolism using a scale adapted from the Japanese stroke scale. The animalsshowed long-lasting and profound extensor hypotonia of the contralateral upperand lower limbs, and drowsiness after embolization. The animals had severebrain injury in the basal ganglia, insular cortex and around the sulcus lateralis. In PET study, cerebral metabolic rate of glucose (FDG) increased in the parietaland temporal cortex, six hours after embolization. However, after 24 hours ofembolization, these regions resulted in the infarct area. These results demonstratedthat thromboembolic stroke model in primate relevant in evaluating neurologicdysfunction and histological brain damage in thromboembolic stroke model inhuman. Therefore, the evaluation cerebral metabolic rate of glucose of this modelmay be important to predict the risk in infarct area in acute stage.
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