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ABSTRACT: The small GTPase RhoA and its downstream effector, Rho kinase (ROCK), appear to mediate numerous pathophysiological signals, including smooth muscle cell contraction, actin cytoskeleton organization, cell adhesion and motility, proliferation, differentiation and the expression of several genes. Clinical interest in the RhoA/ROCK pathway has increased, due to emerging evidence that this signaling pathway is involved in the pathogenesis of several diseases, including hypertension, coronary vasospasm, stroke, atherosclerosis, heart failure and diabetes; ROCK is considered an important future therapeutic target. Several pharmaceutical companies are already actively engaged in the development of ROCK inhibitors as the next generation of therapeutic agents for these diseases. This review discusses the relationship between diabetes and hyperglycemia-induced RhoA/ROCK activation, highlights recent findings on the roles of ROCK inhibitors from experimental models of diabetes and clinical studies in cardiovascular patients, and elucidates major challenges for developing more selective ROCK inhibitors. Accumulating evidence suggests the potential of ROCK inhibitors as therapeutic agents for diabetes and its complications.
Current pharmaceutical design 05/2012; 18(20):2964-73. · 4.41 Impact Factor
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ABSTRACT: To investigate whether activation of RhoA/Rho kinase (ROCK) is involved in myocardial fibrosis in diabetic hearts.
A rat model of type 2 diabetes was established using high fat diet combined with streptozotocin (30 mg/kg, ip). Animals were randomly divided into 3 groups: control rats, untreated diabetic rats that received vehicle and treated diabetic rats that received Rho-kinase inhibitor fasudil hydrochloride hydrate (10 mg·kg(-1)·d(-1), ip, for 14 weeks). Cardiac contractile function was evaluated in vivo. The morphological features of cardiac fibrosis were observed using immunohistochemistry and TEM. The mRNA expression of JNK, TGFβ1, type-I, and type-III procollagen was assessed with RT-PCR. The phosphorylation of MYPT1, JNK and Smad2/3, as well as the protein levels of TGFβ1 and c-Jun, were evaluated using Western blotting.
In untreated diabetic rats, myocardial fibrosis was developed and the heart contractility was significantly reduced as compared to the control rats. In the hearts of untreated diabetic rats, the mRNA expression level and activity of JNK were upregulated; the expression of TGFβ1 and phosphorylation of Smad2/3 were increased. In the hearts of treated diabetic rat, activation of JNK and TGFβ/Smad was significantly decreased, myocardial fibrosis was reduced, and cardiac contractile function improved.
The data suggest that fasudil hydrochloride hydrate ameliorates myocardial fibrosis in rats with type 2 diabetes at least in part through inhibiting the JNK and TGFβ/Smad pathways. Inhibition of RhoA/ROCK may be a novel therapeutic target for prevention of diabetic cardiomyopathy.
Acta Pharmacologica Sinica 08/2011; 32(8):999-1008. · 1.95 Impact Factor
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ABSTRACT: 1. Hyperglycaemia promotes the proliferation of cardiac fibroblasts (CFs) and collagen synthesis in CFs. The objectives of the present study were to determine the effects of fasudil hydrochloride hydrate, a Rho-kinase (ROCK) inhibitor, on high glucose (HG)-induced proliferation of CFs and collagen production in rat CFs and to investigate the molecular mechanism of action of fasudil. 2. Rat CFs were cultured in Dulbecco's modified Eagle's medium, supplemented with 5.5 or 25 mmol/L d-glucose or 5.5 mmol/L d-glucose + 19.5 mmol/L mannose, in the presence of absence of fasudil (50 or 100 μmol/L). Proliferation was measured by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, whereas the production of Type I collagen was evaluated using ELISA and the expression of ROCK1, c-Jun N-terminal kinase (JNK) and Type I procollagen mRNA was determined by reverse transcription-polymerase chain reaction. Intracellular Type I procollagen protein levels were evaluated using immunocytochemistry. Western blot analysis was used to evaluate the phosphorylation of myosin phosphatase target subunit 1 (MYPT1), JNK and Smad2/3, as well as c-jun protein levels. 3. Both concentrations of fasudil effectively inhibited HG (25 mmol/L d-glucose)-induced increases in the proliferation of CFs and collagen synthesis, concomitant with suppression of HG-induced upregulation of ROCK1 and JNK mRNA expression and c-jun protein levels, as well as the phosphorylation of MYPT1, JNK and Smad2/3. 4. These data suggest that ROCK activation is essential for the proliferation of CFs and collagen synthesis induced by HG. Fasudil suppressed HG-induced increases in the proliferation of CFs and collagen synthesis, which may be associated with inhibition of the JNK and transforming growth factor β/Smad pathways. The results of the present study indicate that inhibition of ROCK may be a novel therapeutic target for the prevention of diabetic cardiac fibrosis.
Clinical and Experimental Pharmacology and Physiology 04/2011; 38(6):387-94. · 1.85 Impact Factor
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ABSTRACT: To investigate whether telmisartan (Telm) pretreatment attenuates isoproterenol (Iso)-induced postinfarction remodeling (PIR) in rats, and whether the effect of Telm is associated with cardiac expression of adiponectin.
PIR was induced in male Wistar rats with two consecutive injections of Iso (80 mg/kg, sc) at an interval of 24 h. Primary culture of ventricular myocytes from neonatal rats was prepared. Iso-induced cardiomyocyte injury was assessed based on cell growth and lactate dehydrogenase (LDH) activity. Cardiac adiponectin expression was measured using qRT-PCR and immunoblot analysis.
In the rats with PIR, Telm (10 mg·kg(-1)·d(-1), po for 65 d) suppressed Iso-induced increases in gravimetric parameters, cardiomyocyte diameter and collagen volume fraction, but had no effect on Iso-induced myocardial hypertrophy and interstitial fibrosis. The protective effect of Telm was associated with enhanced protein expression of cardiac adiponectin. In cultured cardiomyocytes, Telm (5-20 μmol/L) inhibited the cell death and LDH release induced by Iso (10 μmol/L), and reversed Iso-induced reduction in adiponectin protein expression. In cardiomyocytes exposed to Iso (20 μmol/L), GW9662 (30 μmol/L), a selective antagonist of PPAR-γ, blocked the effects of Telm pretreatment on adiponectin protein expression, as well as the protective effects of Telm on Iso-induced cell injury.
Telm attenuates Iso-induced cardiac remodeling and cell injury, which is associated with induction of cardiac adiponectin expression.
Acta Pharmacologica Sinica 03/2011; 32(4):449-55. · 1.95 Impact Factor
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ABSTRACT: Left ventricular diverticulum is a rare congenital anomaly of which the incidence was reported to be 0.26%. Diverticula are usually localized near the apex and most often involve the inferior or anterior parietal walls of the left ventricle. In this report, we describe a rare case of congenital isolated left ventricular apical diverticulum, which was tako-tsubo-like in systole, "dumbbell-like" the whole left ventricle, diagnosed by angiography and magnetic resonance imaging.
Chinese medical journal 01/2011; 124(2):315-7. · 0.86 Impact Factor
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ABSTRACT: To reveal the roles of Rho kinase (ROCK) in the mechanisms of complications in diabetes by reviewing the correlations between ROCK and related complications in diabetes.
The data used in the present article were mainly from PubMed with relevant English articles published from 1998 to 2010. The search terms were "ROCK" and "diabetes".
Original articles including the roles of ROCK or its inhibitors in diabetic complications and review articles about the biological character of ROCK were selected.
The activity and expression of ROCK were up-regulated in the models of type 1 or type 2 diabetes animals and the cultured cells with concentrations of high glucose, ROCK activation was associated with the development or progression of complications in diabetes. Inhibition of RhoA/ROCK pathway prevented or ameliorated the pathologic changes of diabetic complications, and ROCK has been regarded as a key target for treatment of these complications.
RhoA/ROCK signaling plays important roles in the pathogenesis of long-term complications in diabetes and ROCK inhibitors are becoming a promising solution to treatments of complications in diabetes.
Chinese medical journal 09/2010; 123(17):2461-6. · 0.86 Impact Factor
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ABSTRACT: To quantitatively observe the effect of long-term use of Gingko biloba Tablet (GBT) on left ventricular systolic and diastolic function in patients with chronic heart failure (CHF) by tissue Doppler imaging (TDI).
Eighty-four CHF patients were randomly assigned to two groups, the treatment group and the control group. All were treated with furosemide, spironolactone, and perindopril, but additional medication of GBT was given to the treatment group. The treatment lasted for 24 weeks. TDI measurement was performed at three time points, i. e. before treatment (T0), 12 weeks and 24 weeks after treatment (T1 and T2), by which, the peak velocity on 6 mitral annulus sites at systolic, early and late diastolic phase (V(S), V(E), V(A), V(E)/V(A)) was measured, and the average velocity on the 6 sites at the 3 phases (V(MS), V(ME), V(ME)/V(MA)) was calculated and analyzed.
All measured data at T0 were not statistically different between the two groups (P > 0.05). As compared with the data measured at T0, V(MS), V(ME), V(ME)/V(MA) in the treatment group and V(ME) in the control group raised at T2, showing statistical significant differences (P < 0.05). Comparisons between groups showed that V(MS), V(ME) at T1 and V(MS), V(ME), V(MA), V(ME)/V(MA) at T2 were higher in the treatment group than in the control group respectively with statistical significance (P < 0.05 or P < 0.01).
Long-term administration of GBT can significantly improve the left ventricular function in CHF patients.
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine / Zhongguo Zhong xi yi jie he xue hui, Zhongguo Zhong yi yan jiu yuan zhu ban 05/2010; 30(5):478-81.
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ABSTRACT: To investigate the prognostic factors and influence of the number of lymph node metastases on survival and UICC-TNM classification in patients with thoracic esophageal cancer after curative resection.
From 1985 to 1990, 1224 patients were surgically treated for thoracic esophageal cancer. The patients who died within 30 days after operation were not included in this study. Fifteen factors possibly influencing survival of these patients were selected and analyzed. A multivariate analysis of these individual variables was performed by Cox proportional hazard model. According to the number of lymph node metastases (0, 1 and > or = 2), a new modification of the TNM classification was suggested: stage IIa (T2N0M0 and T3N0M0), stage IIb [T1N1M0 and T2N1(1)M0], stage IIIa [T2N1 (2)M0 and T3N1 (1) M0] and stage IIIb [T3N1 (2) M0 and T4N any M0].
According to multivariate analysis, lymph node metastases, depth of invasion, location of tumor, histological classification and length of the tumor were of prognostic significance (P < 0.01). There was obvious correlation between the rate of lymph node metastasis and the depth of invasion, length of tumor and grade of differentiation. The 5-year survival rate of the patients with 0, 1 and > or = 2 positive metastatic lymph nodes was 59.1%, 32.0% and 8. 9%, respectively. The 5-year survival rate of the patients with stage T2N1 M0 and stage T3N1 M0 was significantly higher in those with only one lymph node involved than in those with two or more lymph nodes involved (43.1% vs. 18.0% and 28.0% vs. 9.6%, P < 0.01). The 5-year survival rate of the modified stage IIa, IIb, IIIa and IIIb was 56.5%, 43.9%, 25.6% and 11.1%, respectively, with a statistically significant difference among different stages (P < 0.01).
The lymph node metastasis is the most important prognostic factor for thoracic esophageal cancer after resection. The major influencing factors of lymph node metastasis are the depth of invasion, length of tumor and grade of differentiation. Therefore, the lymphadenectomy along with esophagectomy and subsequently combined modality therapy against lymph node metastasis is necessary to improve the 5-year survival rate. Our proposed new classification based on number of lymph node metastases (0, 1, > or = 2 positive nodes) is more applicable because it can well reflect the correlation between lymph node metastasis and the survival, and provides evidence for the modification of the currently used UICC TNM staging system for surgically treated thoracic esophageal cancer.
Zhonghua zhong liu za zhi [Chinese journal of oncology] 07/2009; 31(7):541-5.
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ABSTRACT: This study was aimed to explore the apoptotic effect of Resveratrol (RES) on KG-1 cells and the expression of bcl-2/bax in vitro, and to clarify the possible mechanism of apoptotic effect of RES on leukemia cells. After treating with different concentrations of RES, the suppressive effect of RES on proliferation of KG-1 cells was analyzed by MTT method. Transmission electron microscope technique were used to detect the apoptosis status of KG-1 cells. The cell cycle and apoptosis percentage of KG-1 cells treated with RES were detected by flow cytometry. The expressions of bcl-2, bax mRNA and protein were assessed by semiquantitative RT-PCR and flow cytometry. The results showed that RES could obviously inhibit proliferation of KG-1 cells (p < 0.05). Compared with the control group, the cell number in S phase of KG-1 cells treated with RES increased (p < 0.05), the apoptosis rate enhanced significantly (p < 0.01) and the expression level was down-regulated, while expression level of bax was obviously up-regulated (p < 0.01). It is concluded that RES significantly induces apoptosis of KG-1 cells in vitro, which is probably related to the down-regulation of bcl-2 expression and up-regulation of bax expression.
Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology 10/2008; 16(5):1026-9.
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Ze-Jun Tian,
Wei Cui, Yong-Jun Li,
Yu-Ming Hao,
Jun Du,
Fan Liu,
Hui Zhang,
Xiu-Guang Zu,
Su-Yun Liu,
Li Chen,
Wei An
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ABSTRACT: To assess the contribution of signal transducer and activator of transcription 3 (JAK-STAT3) pathway, extracellular signal-regulated kinases1/2 (ERK1/2) pathway, and phosphatidylinositol 3-kinase (PI3-K) pathway to cardiomyocytes hypertrophy induced by cardiotrophin-1 (CT-1), a new member of interleukin-6 (IL-6) family of cytokines.
STAT3, ERK1/2, and PI3-K were assessed by Western blot analysis. Activity of ERK1/2 was also confirmed by in-gel kinase assay. Hypertrophy of cardiomyocyte was evaluated by [3H]leucine incorporation and cellular protein-to-DNA ratio.
CT-1 simultaneously activated phosphorylation of STAT3, ERK1/2, and PI3-K in rat cardiomyocytes. Parthenolide, an inhibitor of STAT, suppressed CT-1-induced [3H]leucine incorporation by 88.3 % and protein-to-DNA ratio by 75.0 %. U0126, an MEK1/2 inhibitor, increased CT-1-induced the phosphorylation of STAT3 in a dose-dependent manner and, consistently, augmented CT-1-induced increase in [3H]leucine incorporation and cellular protein-to-DNA ratio by 17.6 % and 16.3 %, respectively. Wortmannin, a PI3-K inhibitor, did not influence CT-1-induced [3H]leucine incorporation and cellular protein-to-DNA ratio.
The hypertrophic effect of CT-1 was essentially mediated by STAT3, independent of PI3-K, and negatively regulated by ERK1/2 via inhibiting the phosphorylation of STAT3. The interaction between STAT3 and ERK1/2 in CT-1-induced signaling contributes to development of cardiac hypertrophy.
Acta Pharmacologica Sinica 10/2004; 25(9):1157-64. · 1.95 Impact Factor
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Yong-Jun Li,
Wei Cui,
Ze-Jun Tian,
Yu-ming Hao,
Jun Du,
Fan Liu,
Hui Zhang,
Xiu-guang Zu,
Su-yun Liu,
Rui-qin Xie,
Xiao-hong Yang,
Yu-zhou Wu,
Li Chen,
Wei An
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ABSTRACT: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway and the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway are the two major independent signal transduction pathways. However, it has recently been found that STAT3 may be negatively regulated by ERK1/2 in gp130-dependent signaling. Cardiotrophin-1 (CT-1), a potent novel hypertrophic cytokine, depends on gp130 to induce signaling and depends on STAT3 to exert hypertrophic effect. In this study, we examined whether STAT3 activity was negatively regulated by ERK1/2 during CT-1-induced signaling in rat cardiomyocytes and, if so, whether such crosstalk interfered with the hypertrophic effect of CT-1 and, furthermore, whether the mechanism underlying the crosstalk involved phosphorylation of serine 727 (S727) in STAT3.
The activities of ERK1/2 and STAT3 were assessed by in-gel kinase assay and Western blot analysis, respectively. The role of S727 phosphorylation in the crosstalk between ERK1/2 and STAT3 was determined by a transient transfection study using a STAT3S727A mutant. Cardiomyocyte hypertrophy was evaluated by the cellular protein-to-DNA ratio and [(3)H]-leucine incorporation.
CT-1 simultaneously activated both ERK1/2 and STAT3 in rat cardiomyocytes. Inhibition of ERK1/2 by U0126 resulted in an increase of CT-1-induced tyrosine phosphorylation of STAT3 and, consequently, the protein-to-DNA ratio and [(3)H]-leucine incorporation. Transient transfection of the cells with STAT3S727A had no significant effect on CT-1-induced tyrosine phosphorylation of STAT3.
STAT3 is activated by CT-1 in rat cardiomyocytes, but full activation is mitigated by the simultaneous activation of ERK1/2. The inhibition of ERK1/2 increases the activity of STAT3, which, in turn, enhances the hypertrophic effect of CT-1. The crosstalk between ERK1/2 and STAT3 is independent of the phosphorylation of the S727 in STAT3. Such crosstalk may contribute to the development of adequate cardiac hypertrophy.
Chinese medical journal 09/2004; 117(8):1135-42. · 0.86 Impact Factor
