陈兰英
中国医学科学院阜外医院 群体遗传研究室
JAK2/STAT3 is a cardio-protective, pro-inflammation pathway, the function of which in cardiomyopathy caused by diabetic (DCM) is currently unknown. Here we explore the role of the JAK2/STAT3 pathway in DCM employing different time courses and a type 2 DM (T2DM) rat model. We examined the interactions of metformin and sitagliptin treatment with the JAK2/STAT3 pathway and cardiac remodeling. A T2DM rat model was induced by high fat diet/streptozotocin (HFD/STZ) and treated with metformin, sitagliptin (10 mg/d or 20 mg/d) or a placebo. Cell inflammation markers, cardiac remodeling and cardiomyocyte apoptosis were evaluated. We observed an activated inflammation reaction as well as activation of the JAK2/STAT3 thought-out the experiment in the simple HFD group only in the early stage of the disease (until week 9). JAK2/STAT3 activity showed a phasic peculiarity as increased inflammation was observed in prolongation of the DCM accompanied with an accelerated cardiac dysfunction but reduced phosphorylation of myocardial STAT3. Moreover, in the metformin but not the sitagliptin treated group, JAK2/STAT3 activation was associated with having better improved cardiac remolding and reduced myocardial apoptosis. In vitro studies further validated that metformin could activate JAK2/STAT3 pathway and alleviate apoptosis of NRCMs under hyperglycemia incubation. The phasic feature of JAK2/STAT3 pathway activation may participate in the pathophysiological development of DCM. The superior cardio-protective effect of metformin over sitagliptin treatment may partly account for the differences we observed in JAK2/STAT3 activation, indicating that measuring JAK2/STAT3 pathway coupled with metformin treatment may give insight into a more promising DM treatment.
American journal of translational research 2019
We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases and 5,019 controls followed by replication studies in 15,460 cases and 11,472 controls, all of Chinese Han ancestry. We identify four new loci for coronary artery disease that reached the threshold of genome-wide significance (P < 5 × 10(-8)). These loci mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (in or near PHACTR1, TCF21, CDKN2A-CDKN2B and C12orf51). These findings provide new insights into pathways contributing to the susceptibility for coronary artery disease in the Chinese Han population.
Nature genetics 2012
OBJECTIVE:To search new clues to reveal the action mechanism of inhaled anesthetics.METHODS:Three kinds of Drosophila melanogaster were used as studied models: the wild type strain (H), the sevoflurane-sensitive strain (S), and the sevoflurane-resistant strain (R). Differential display reverse transcriptional-polymerase chain reaction method was performed to examine the differentially expressed fragments between Drosophila induced with and without sevoflurane. Rapid amplification of cDNA ends (RACE) method was used to clone the full length cDNA from positive differentially expressed fragments.RESULTS:Thirty-one differentially expressed fragments were found between the two groups. Three fragments were identified as the positive differentially expressed fragments by Northern blot analysis. Two full-length cDNAs were cloned by RACE method, among which one was a 1.0 kb Drosophila calmodulin (CaM), located on Chr.2; the other was a 4.1 kb gene with unknown function (No.45), located on Chr.3.CONCLUSION:The two full-length cDNAs belong to the genes that related to anesthetic action pathway, which might participate in the regulation of cellular functions and signal transduction pathways. The two genes that we found should provide a novel way to study the mechanism of inhaled anesthetic action.
Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 2004
Heart remodeling is associated with the loss of cardiomyocytes and increase of fibrous tissue owing to abnormal mechanical load in a number of heart disease conditions. In present study, a well-described in vitro sustained stretch model was employed to study mechanical stretch-induced responses in both neonatal cardiomyocytes and cardiac fibroblasts. Cardiomyocytes, but not cardiac fibroblasts, underwent mitochondria-dependent apoptosis as evidenced by cytochrome c (cyto c) and Smac/DIABLO release from mitochondria into cytosol accompanied by mitochondrial membrane potential (Deltapsi(m)) reduction, indicative of mitochondrial permeability transition pore (PTP) opening. Cyclosporin A, an inhibitor of PTP, inhibited stretch-induced cyto c release, Deltapsi(m) reduction and apoptosis, suggesting an important role of mitochondrial PTP in stretch-induced apoptosis. The stretch also resulted in increased expression of the pro-apoptotic Bcl-2 family proteins, including Bax and Bad, in cardiomyocytes, but not in fibroblasts. Bax was accumulated in mitochondria following stretch. Cell permeable Bid-BH3 peptide could induce and facilitate stretch-induced apoptosis and Deltapsi(m) reduction in cardiomyocytes. These results suggest that Bcl-2 family proteins play an important role in coupling stretch signaling to mitochondrial death machinery, probably by targeting to PTP. Interestingly, the levels of p53 were increased at 12 h after stretch although we observed that Bax upregulation and apoptosis occurred as early as 1 h. Adenovirus delivered dominant negative p53 blocked Bax upregulation in cardiomyocytes but showed partial effect on preventing stretch-induced apoptosis, suggesting that p53 was only partially involved in mediating stretch-induced apoptosis. Furthermore, we showed that p21 was upregulated and cyclin B1 was downregulated only in cardiac fibroblasts, which may be associated with G2/M accumulation in response to mechanical stretch.
Cell research 2004
OBJECTIVES:The cellular repressor of E1A-stimulated genes (CREG), a mannose-6-phosphate-containing secreted glycoprotein, enhances differentiation and inhibits proliferation. In this study, our aim was to understand the role of CREG in cardiac hypertrophy.METHODS:Two models of cardiac hypertrophy were used: the in vivo pressure-overloaded rat cardiac hypertrophy and the in vitro stretched neonatal rat cardiomyocyte hypertrophy. CREG's function in cardiac cells was investigated after over-expression or antisense inhibition of CREG.RESULTS:We found reduced CREG expression in rat hearts after the in vivo overload, as shown by Northern blot analysis. CREG over-expression inhibited cardiac cell growth, as demonstrated by reduced protein content, cell area and ERK1/2 level in cultured neonatal rat cardiomyocytes, and by the reduced proliferation of cultured neonatal rat cardiac fibroblasts. Additionally, over-expression of CREG dampened the stretched cardiomyocyte hypertrophy through ERK1/2. On the other hand, the opposite effects were observed when CREG expression was decreased using antisense. This modulation of CREG expression resulted in no changes in the cardiomyocyte expressions of the hypertrophic or apoptotic signaling molecules such as protein kinase C (PKC) epsilon, PKC beta1, PKC alpha, PKC beta2, PKC delta, JNK1/2, p38, p53, Bax, Bcl2 and Fas.CONCLUSIONS:CREG was found to inhibit cardiac cell growth as a novel regulator of ERK1/2 and might participate in the development of cardiac hypertrophy under pressure overload. The insight that CREG inhibited the growth in rat hearts in vivo and in cardiac cells in vitro provides new clues for further investigation of the mechanism of heart remodeling.
Journal of hypertension 2004
OBJECTIVES:To study the function of chymase on heart remodeling by overexpression of human chymase in the heart of transgenic mice.METHODS:Transgenic mice were produced by microinjection. The chymase mRNA levels in the heart and other tissues were assessed by competitive reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of collagen I/III genes was analyzed by Northern blot hybridization. Chymase and angiotensin-converting enzyme (ACE) activities, and angiotensin II (Ang II) content in the heart were determined by radioimmunoassay (RIA). The matrix metalloprotease-9 (MMP-9) in protein and activity levels were measured by Western blot and zymogram, respectively.RESULTS:A model of transgenic mice with selective overexpression of a rat myosin light chain 2 promoter-human heart chymase (MLC(2-)-hChymase) fusion gene was produced. In MLC(2)-hChymase transgenic mice (the F(6) line), the human heart chymase gene was expressed at a high level in heart and at lower levels in skeletal muscle and kidney, while no expression was detected in the liver or lung. The heart chymase activity increased markedly in the F(6) transgenic mice versus non-transgenic mice (0.274 +/- 0.071 U/mg versus 0.152 +/- 0.021 U/mg) ( P < 0.05), with no difference in ACE activity. Heart Ang II level in the F(6) transgenic mice increased nearly threefold (1984 +/- 184 versus 568 +/- 88 pg/g protein) ( P < 0.05) but was unchanged in plasma. MMP-9 activity increased significantly in the cardiac tissue of F(6) transgenic mice ( P < 0.05), while both collagen I and the ratio of collagen I : III mRNA levels decreased significantly (both P < 0.05). The F(6) transgenic mice showed no significant changes in cardiac parameters.CONCLUSIONS:We have demonstrated selective overexpression of human chymase gene in the heart of transgenic mice, and the results support the hypothesis of a dual Ang II-forming pathway from chymase and ACE in the cardiac tissue in vivo. The results also suggest that chymase may play a role in heart remodeling by increasing Ang II formation and activating MMP-9, and the regulation of collagen I gene expression.
Journal of hypertension 2002
The role of a dual angiotensin (Ang) II-forming pathway from the local renin angiotensin system (RAS) of the cardiac tissue was determined in a hamster model of cardiac hypertrophy. Time-dependent expressions of chymase and angiotensin converting enzyme (ACE) genes and their enzymes activities, and Ang II levels were measured in the hamster heart at 3 days, and at 4 and 8 weeks after pressure overload. Cardiac hypertrophy was induced by an operation to constrict the abdominal aorta. Compared to the sham-operated group, the cardiomyocyte diameters of hamster hearts at 3 days after overload underwent no obvious changes, while those at 4 and 8 weeks after overload increased markedly (p<0.01), and both transcriptional expressions of chymase and ACE genes gradually increased in the hamster hearts at 3 days, and at 4 and 8 weeks after overload, but the transcriptional expressions of angiotensin II type 1 receptor (AT1R) gene gradually decreased. Chymase and ACE activities (U/mg) (0.441+/-0.040 vs. 0.175+/-0.014, 0.446+/-0.036 vs. 0.160+/-0.016 and 0.522+/-0.014 vs. 0.148+/-0.038) (p<0.01) and (0.142+/-0.023 vs. 0.056+/-0.038, 0.317+/-0.017 vs. 0.079+/-0.016 and 0.466+/-0.010 vs. 0.098+/-0.003) (p<0.01), respectively and Ang II levels (pg/g) (98.7+/-4.5 vs. 71.2+/-4.9, 134.4+/-7.8 vs. 71.9+/-12.8 and 151.6+/-10.1 vs. 80.7+/-3.0) gradually increased in the hamster hearts, vs. sham treatment, respectively, at 3 days, and at 4 and 8 weeks after overload. However, the increases in chymase and ACE activities were much higher than those in their respective mRNA levels, and the levels of chymase activities were also higher than those of ACE activities during the development of cardiac hypertrophy. The results suggested that the increase in Ang II levels via the dual pathway of Ang II formation by chymase and ACE plays an important role in the cardiac hypertrophy of hamsters caused by the overloaded state. Importantly, in the non-hypertrophied hamster heart in the early stage after overload (at 3 days), chymase could be activated by mechanical stress in advance of an increase in its mRNA, and the Ang II level increased significantly.
Hypertension research : official journal of the Japanese Society of Hypertension 2002
