中國病理生理學(xué)會第十屆全國代表大會暨學(xué)術(shù)會議論文摘要

·心血管·

中國病理生理學(xué)會第十屆全國代表大會暨學(xué)術(shù)會議論文摘要

In this study，the mice pretreated with trimetazidine (TMZ) were challenged with LPS and the cardiac function was evaluated.The levels of macrophage infiltration，macrophage inflammatory response and cardiomyocyte apoptosis were examined by immunohistochemical staining，ELISA，RT-PCR，Western blotting，TUNEL and flow cytometry.The results showed that TMZ protected against LPS-induced myocardial dysfunction and apoptosis through inhibition of macrophage pro-inflammatory response.

AIM: To investigate the effect of macrophage migration inhibitory factor (MIF) on fibrosis-associated gene expression in cardiac fibroblasts.METHODS: Cardiac fibroblasts were isolated from 1～3-day-old C57BL/6 mice.The expression of MIF，Col1a1，Col3a1 and α-SMA in mouse cardiac fibroblasts was detected by real-time PCR and Western blotting.Mature miR-29b expression in mouse cardiac fibroblasts was determined by real-time PCR.RESULTS: MIF inhibited fibrosis-associated Col1a1，Col3a1 and α-SMA expression at both mRNA and protein levels in cardiac fibroblasts.MIF inhibitor ISO-1 enhanced Col1a1，Col3a1 and α-SMA expression.The result of DCFH-DA staining revealed that MIF efficiently decreased ROS level in high glucose-induced cardiac fibroblasts.The anti-oxidant related genes，including HO-1，e-NOS，SOD1，SOD2 and Trx2，were does-dependently up-regulated in MIF-treated mouse cardiac fibroblasts.Additionally，Smad3 activation was inhibited，but miR-29b was up-regulated in MIF-treated cardiac fibroblasts.miR-29b significantly suppressed Col1a1，Col3a1，and α-SMA expression in cardiac fibroblasts.CONCLUSION: MIF possesses anti-fibrosis effect by inactivating Smad3 and up-regulating miR-29b expression i n cardiac fibroblasts.

*［Foundation item］Supported by National Natural Science Foundation of China (No.81270222; No.81470439) and Natural Science Foundation of Guangdong (No.2014A030313635)

△Corresponding author E-mail: zhixinshan@aliyun.com

AIM: To investigate whether anti-inflammation of apelin in amelioration of hypoxic pulmonary artery hypertension (HPAH) was through an inhibition of nuclear factor-κB (NF-κB) pathway.METHODS: The mice were exposed in a normobaric hypoxic chamber with a fraction of inspired oxygen (FiO2) of～10%，or hypoxia combined with apelin application，23 h/d，continued for 2 weeks.Mean right ventricular pressure (mRVP) was measured by pulmonary artery catheterization.Right ventricle hypertrophy (RVH) was assessed by the ratio of right ventricle/left ventricle plus septum［RV/(LV + S)］.Pulmonary vascular remodeling，inflammatory response，and nucleus translocation of NF-κB were also examined.RESULTS: Hypoxia increased mRVP and RVH as well as TNF-α and IL-1β levels in the lung tissues，which were blocked by apelin application.Hypoxia-increased NF-κB translocation into the nucleus was suppressed by apelin pretreatment，suggesting ameliorative effect of apelin on HPAH in the mice was through anti-inflammation by a robust inhibition of the NF-κB pathway.Utilizing the mice with NF-κB deletion (p50－/－)，no obvious mRVP change，RVH or inflammation response after 2-week hypoxia exposure was observed，further confirming NF-κB activation was involved in the development HPAH and RVH.CONCLUSION: Our data highlights the potential role of apelin/NF-κB axis as a novel regulatory pathway involved in anti-inflammation and amelioratio n of HPAH and RVH.

*［Foundation item］Supported by Natural Science Foundation of Zhejiang Province of China (No.LY12H01004; No.Y2091033)

△Corresponding author E-mail: fxb@wmu.edu.cn

AIM: To examine the effect of chronic intermittent hypoxia (IH) on endogenous catecholamine system activation in rats，and to address whether catestatin (CST) was involved in IH-induced hypertension in rats.METHODS: The rats were randomly divided into control，IH，and IH + CST groups.The circle time of IH model was 120 s (60 s +60 s，the lower oxygen concentration was 6. 0%± 0. 5%，and the upper was 21. 0%±0. 5%)，8 h/d，continued for 3 weeks.Mean pressure (MP)，systolic pressure (SP)，diastolic pressure (DP)，maximum dp/dt，and minimum dp/dt were measured by left heart catheterization.Right ventricle hypertrophy (RVH) was assessed by the ratio of right ventricle/left ventricle plus septum［RV/(LV + S)］.The levels of CST，NE，E，and His in the plasma were detected by ELISA.The expression of chromogranin A (CHGA) in the cerebrum，cerebellum，medulla oblongata，left ventricle，and lung tissue were detected by Western blotting.RESULTS: Compared with control group，the rats in IH group exhibited a significant increase in blood pressure after IH treatment for 10 d，which was markedly decreased with CST application.As compared with control group，MP，SP，and DP in IH group were significantly increased，which were greatly decreased with CST application.IH treatment induced the left ventricular hypertrophy as showed by a significant increase in the ratio of RV/LV + S，as compared with control group.IH treatment increased dp/dtmaxand dp/dtmin，while IH + CST decreased dp/dtmax.IH treatment decreased CST and His but increased NE and E levels in arteriovenous plasma，which were reversed by CST treatment.As compared with control group，CHGA levels in left ventricle and lung tissue as well as in central systemin IH group were decreased，which were restored by CST treatment.CONCLUSION: Decreased CST and increased NE and E levels in plasma may be involved in IH-induced hypertension in rats.CST treatment ameliorates hypertension induced by IH in rats.

*［Foundation item］Supported by Natural Science Foundation of Zhejiang Province of China (No.81200039)，Natural Science Foundation of Zhejiang Province of China (No.LY12H01004) and the Foundation of Zhejiang Educational Committee (No.Y201326833)

△Corresponding author E-mail: fxb@wmu.edu.cn

AIM: To evaluated the regulation of soluble epoxide hydrolase (sEH) in vascualr smooth muscle cells (VSMCs) and role of sEH in patients with atherosclerosis.METHODS: sEH expression in human atherosclerotic plaque was determined by immunohistochemistry.In cultured rat and human VSMCs，the phenotypic switching marker and sEH expression induced by platelet-derived growth factor-BB (PDGF-BB) were examined by Western blotting.Carotid-artery balloon injury was performed after adenovirus-mediated overexpression of sEH or oral administration of the sEH inhibitor 1-(1-methanesulfonyl-piperidin-4-yl) -3-(4-trifluoro-methoxy-phenyl) -urea (TUPS) in the male SD rats.RESULTS: sEH was highly expressed in the VSMCs of the intima and media within human atherosclerotic plaque.In vitro，PDGF-BB up-regulated the sEH expression in VSMCs post-transcriptionally and promoted cell proliferation and migration.The latter effect was largely attenuated by the treatment with TUPS.Adenovirus-mediated overexpression of sEH mimiced the effect of PDGF-BB，and induced VSMC proliferation and migration.In vivo，TUPS significantly decreased the injury-induced neointima formation in a rat carotid-artery injury model.CONCLUSION: These data establish the impact of sEH expression on atheroprogression and vascular remodeling after injury，thus identifying a novel integrative role of sEH in VSMC phenotypic modulation and migration.Blocking sEH activity may be a potential therapeutic approach for ameliorating vascular oc clusive disease.

△Corresponding author AI Ding E-mail: edin2000cn@gmail.com; ZHU Yi E-mail: zhuyi@tmu.edu.cn

▲These authors contribute equally to this work

AIM: To investigate the role of hydrogen sulfide (H2S) in the recovery of ischemic post-conditioning (PC) -induced cardioprotection in the aging hearts.METHODS: The male Wistar young rats (3-month-old，200～250 g) and the aging rats (24-month-old，450～500 g) were used for this study.Isolated rat hearts were subjected to 40 min of ischemia followed by 60 min of reperfusion.The hearts were post-conditioned after 40 min of ischemia by 6 cycles of 10 s of reperfusion and 10 s of re-ischemia applied before the 60 min of reperfusion.The apoptosis was assessed by TUNEL staining.The gene expression was analyzed by Western blotting and realtime PCR.The level of reactive oxygen species (ROS) was examined with dihydrodichlorofluorescein diacetate (H2DCFH-DA) staining.Myocardial infarct size was observed via triphenyltetrazolium chloride (TTC) staining.H2S production rate was detected by methylene blue methods.RESULTS: Ischemia/reperfusion (I/R) decreased H2S production rate and cystathionine gamma-lyase (CSE) expression，aggravated cardiomyocyte damage，apoptosis and myocardial infarct size，reduced cardiac function，increased the mRNA levels of Bcl-2，caspase-3 and caspase-9，and enhanced oxidative stress in isolated young and aging rat hearts.I/R also increased the release of cytochrome C and down-regulated the phosphorylation of PI3K，Akt and GSK-3β in the aging rat hearts.PC in-creased H2S production rate and CSE expression，and protected young hearts from I/R-induced cardiomyocyte damage，all of which disappeared in the aging hearts.Supply of NaHS not only increased PC-induced cardioprotection in the young hearts，but also attenuated I/R induced-myocardial damage and significantly recovered the cardioprotective role of PC against I/R-induced myocardial damage in the aging hearts.LY294002 (a PI3K inhibitor) abolished but N-acetylcysteine (NAC，an inhibitor of ROS) further enhanced the protective role of H2S against I/R-induced myocardial damage in the aging hearts.CONCLUSION: Exogenous H2S recovers PC-induced cardioprotection via inhibition of oxidative stress and up-regulation of PI3K-Akt-GSK-3β pathway in the aging rat hearts，suggesting that H2S might be a novel target for the treatment of aging cardiovascular diseases.

*［Foundation item］Supported by National Natural Science Foundation of China (No.81270273; No.81000059; No.81270311) and Natural Science Foundation of Heilongjiang (No.LC201430)

△Corresponding author Tel: 0451-86674548; E-mail: hongzhuli61@163.com

AIM: To investigate the expression of fibrosis-related genes and microRNAs in TGF-β1-induced H9c2 cells.METHODS: The expression of fibrosis-associated genes，including Col3a1，α-SMA，F(xiàn)N1，CTGF and TSP-1，and miR-16，-21a and -29b was detected in TGF-β1-induced H9c2 cells by quantitative real-time PCR.The activations of Smad3 and NF-κB signaling in TGF-β1-treated H9c2 cells were studied by dual-luciferase assay.The expression of Col3a1，α-SMA，F(xiàn)N1，CTGF and TSP-1 were also detected in H9c2 cells with adenovirus-mediated overexpression of miR-21a.RESULTS: The mRNA expression of α-SMA，F(xiàn)N1，CTGF and TSP-1，but not Col3a1，was up-regulated in TGF-β1-induced H9c2 cells.FIHC result also revealed that α-SMA was increased in TGF-β1-treated H9c2 cells.Consistently，dual-luciferase assay showed that Smad3 and NF-κB signalings were activated in TGF-β1-treated H9c2 cells.miR-21a，but not miR-16 and -29b，was significantly up-regulated in TGF-β1-treated H9c2 cells.Additionally，overexpression of miR-21a significantly increased mRNA expression of α-SMA，F(xiàn)N1，CTGF and TSP-1 in H9c2 cells.CONCLUSION: miR-21a was up-regulated in TGF-β1-induced H9c2 cells，and miR-21a may contribute to the expression of fibrosis-associated genes in TGF-β1-induced H9c2 myoblasts.

*［Foundation item］Supported by National Natural Science Foundation of China (No.81270222; No.81470439) and Natural Science Foundation of Guangdong (No.2014A030313635).

△Corresponding author E-mail: zhixinshan@aliyun.com

AIM: To detect miR-199a/214 cluster expression in hypertrophic myocardium and hypertrophic cardiomyocytes.METHODS: An animal model of hypertrophy was established in a mouse with transverse aortic constriction (TAC) or in a mouse with subcutaneous injection of phenylephrine (PE).A cell model of hypertrophy was achieved based on Ang II-promoted neonatal mouse ventricular cardiomyocytes (NMVCs).The expression of miR-199a and -214 was determined by qPCR.The expression of ANP，BNP and β-MHC was detected in NMVCs with enforced expression of miR-199a or -214.RESULTS: ANP，BNP and β-MHC were significantly up-reg-ulated in the mouse myocardial model after TAC surgery or after subcutaneous injection of PE，and in Ang II-induced NMVCs.miR-199a and miR-214 were consistently up-regulated in mouse hypertrophic myocardium and hypertrophic cardiomyocytes.The results of qPCR and Western blotting showed that ANP，BNP and β-MHC were consistently increased in NMVCs with overexpression of miR-199a or -214.CONCLUSION: miR-199a/214 cluster is up-regulated in hypertrophic myocardium.miR-199a and miR-214 enhances ANP，BNP and β-MHC expression in cardiomyocytes.

*［Foundation item］Supported by National Natural Science Foundation of China (No.81270222; No.81470439) and Natural Science Foundation of Guangdong (No.2014A030313635)

△Corresponding author E-mail: zhixinshan@aliyun.com

AIM: To study the association between cytomegalovirus (CMV) infection and hypertension in Kazakh and Han populations from Xinjiang province，China.METHODS: The data of 800 Kazakhs (467 hypertension patients and 333 healthy control participants) and 800 Hans (482 hypertension patients and 318 healthy participants) aged 18～84 years old were analyzed.ELISA and real-time PCR coupled with restriction fragment length polymorphism analysis were applied for determining CMV infection and glycoprotein B (gB) genotypes，respectively.RESULTS: Serologic evidence of CMV infection was obtained in 95.4% and 90.1% of the Kazakhs and Hans，respectively.The CMV seroprevalence rates among the Kazakh and Han participants with hypertension were 96.8% and 89.8%，respectively.Multiple logistic regression analysis revealed statistically significant independent associations between CMV seropositivity and hypertension in Kazakh males and between CMV antibody titers and hypertension in Hans.Significant relationships also existed between CMV antibody titers and blood pressure in Hans.In Kazakhs，3 CMV gB genotypes gB2，gB1 + gB2 and gB2 + gB3 were identified.In Hans，4 CMV gB genotypesg B1，gB2，gB1 + gB2，and gB2 + gB3 were identified.Of the 4 studied genotypes，gB2 + gB3 showed a significant independent association with hypertension in Kazakh females.CONCLUSION: CMV infection is associated with essential hypertension in Kazakh males and Hans in Xinjiang.CMV seropositivity is associated with hypertension in Kazakh males，and CMV antibody titers are associated with blood pressure and hypertension in Han males and females.Moreover，the CMV gB2 + gB3 genotype mixture is associated independently with essential hypertension in Kaza kh females.

*［Foundation item］Supported by the Joint Funds of the National Natural Science Foundation of China (No.U1403123)

△Corresponding author E-mail: FangF2002shz@126.com

We aimed to explore the mechanism of ERS inhibition-induced cardioprotection against I/R injury，focusing on the role of Zn2 +and the mitochondrial permeability transition pore (mPTP).Exposure of H9c2 cells to 800 μmol/L H2O2for 20 min increased the expression of GRP78 and GRP94，suggesting that H2O2induced ERS.The cells treated with H2O2showed a significant decrease in TMRE fluorescence compared normal group，indicating that H2O2induced the mPTP opening.In contrast，ERS inhibitor TUDCA prevented the loss of TMRE fluorescence，implying that inhibition of ERS prevented the mPTP opening.This effect of TUDCA was blocked by zinc chelator TPEN，indicating a role of Zn2 +in the action of TUDCA on the mPTP opening.In support，TUDCA increased intracellular free zinc，as indicated by a marked increase in Newport Green DCF fluorescence intensity.In isolated rat hearts，GRP78 expressionwas not altered after 10 min of reperfusion，but was markedly increased 30 and 60 min after the onset of reperfusion.Hearts treated with TUDCA showed a significant reduction of GRP78 expression，and this effect was reversed by TPEN.The immunofluorescence study also showed that the effect of TUDCA on GRP78 expression was reversed by TPEN.The results of transmission electron microscopy and hematoxylin-eosin staining revealed that TUDCA prevented endoplasmic reticulum and mitochondrial damages at reperfusion，which was blocked by TPEN.In conclusion，inhibition of ERS protects the heart from reperfusion injury through prevention of the mPTP opening.Increased intracellular free Zn2 +accounts for the cardioprotective effect of E RS inhibition.

*［Foundation item］Supported by China Postdoctoral Science Foundation (No.CPSF 2014M560190)，Research Project of Education Department of Hebei Province (No.ZD 2014006; No.QN2014092)，North China University of Science and Technology Foundation for Outstanding Young Scholars (No.JP 201302) and Project of Hebei Administration of Traditional Chinese Medicine (No.2014196)

△Corresponding author E-mail: jinkunxi@126.com

We aimed to determine whether NECA，an adenosine receptor agonist，induces cardioprotection against myocardial ischemia/ reperfusion (I/R) injury by modulation of endoplasmic reticulum stress (ERS) through inhibiting the mitochondrial permeability transition pore (mPTP) opening via inactivating glycogen synthase kinase 3β(GSK-3β).Heart tissue-derived H9c2 cells exposed to 800 μmol/L H2O2for 20 min showed reduced TMRE fluorescence.In contrast，NECA at different concentrations suggested an obvious inhibition of TMRE fluorescence intensity weakening，indicating that NECA inhibited the mPTP opening caused by oxidative stress.H2O2reduced GSK-3β phosphorylation at Ser9 but increased GRP94 expression，and this effect was prevented by NECA.NECA enhanced GSK-3β phosphorylation but reduced GRP94 expression，which were prevented by the ERS inductor 2-DG.NECA increased GSK-3β (Ser9) and VASP (Ser239) phosphorylation，which were blocked by the PKG inhibitor KT5823，suggesting that NECA may induce cardioprotection though inactivating GSK-3β via ERS and cGMP/PKG signaling pathway.In isolated rat heart，both NECA and ERS inhibitor TUDCA decreased myocardial infarction，increased GSK-3β phosphorylation，and reversed GRP94 expression at reperfusion compared to the control，suggesting that NECA protected the heart by inhibiting GSK-3β and ERS.Transmission electron microscopy analysis showed that NECA and TUDCA reduced mitochondrial swelling and the endoplasmic reticulum expansion，further supporting that NECA protected the heart by preventing the mPTP opening through modulation of ERS.In conclusion，NECA protects the heart from reperfusion injury by preventing the mPTP opening through inactivation of GSK-3β via ER stress inhibition.The cGMP/PKG signaling pathway is responsible for GSK-3βinactivation by NECA.

*［Foundation item］Supported by China Postdoctoral Science Foundation (No.CPSF 2014M560190)，Research Project of Education Department of Hebei Province (No.ZD 2014006; No.QN2014092)，North China University of Science and Technology Foundation for Outstanding Young Scholars (No.JP 201302) and Project of Hebei Administration of Traditional Chinese Medicine (No.2014196)

△Corresponding author E-mail: zxu@tijmu.edu.cn

AIM: To investigate the role of 15-hydroxyeicosatetraenoic acid (15-HETE) on MMP-2 expression and the role of MMP-2 in pul-monary arterial endothelial cell (PAEC) proliferation and vascular angiogenesis，and to determine whether hypoxia-induced 15-HETE may affect the expression of tissue inhibitor of metalloproteinase-2 (TIMP-2).METHODS: The expression of MMP-2 in hypoxic PAECs was detected by Western blotting，immunofluorescence and RT-PCR.The roles and the relationship of MMP-2 and 15-HETE in hypoxia PAECs were analyzed by observing cell viability，BrdU cell proliferation assay and flow cytometry.RESULTS: After exposure to hypoxia for 24 h，the protein content and activity of MMP-2 in PAECs increased and TIMP-2 decreased significantly compared to normoxic group.MMP-2 was observed to distribute in the nucleus by immunofluorescence.15-HETE is a product of arachidonic acid catalyzed by 15-lipoxygenase (15-LO).After interfering endogenous 15-HETE，the activity of MMP-2 decreased significantly.In contrary，after adding exogenous 15-HETE，the activity of MMP-2 increased significantly.MMP-2 was also capable of stimulating the cell cycle progression and promoting the cell cycle-related protein expression under normoxic and hypoxia condition via MMP-2 inhibition，GM6001 and MMP-2 small interfering RNA.The same results were achieved by cell viability，BrdU cell proliferation assay and flow cytometry analysis.CONCLUSION: Hypoxia-induced 15-HETE decreases the expression of TIMP-2，and increases the expression of MMP-2 at the same time，suggesting that MMP-2 promotes PAEC proliferation via an relationship between 15-LO/15-HETE and MMP-2.

△Corresponding author E-mail: 642727434@qq.com

AIM: To investigate the pathological process of abnormal pulmonary arterial smooth muscle cell (PASMC) proliferation in the hypoxic pulmonary arterial hypertension (PAH) and the underlying molecular mechanism.METHODS: The methods of animal models，cell biology and molecular biology were used to detect the mitochondrial fusion protein 1 (Mfn1) in hypo-xia-induced proliferation of PASMCs.The key miRNA was determined by bioinformatics.The cell cycle profiles and the expression of cyclins were determined after overexpression or knockdown of miRNAs.RESULTS: Mfn1 was increased in hypoxia-induced pulmonary vascular remodeling.Hypoxia-induced smooth muscle cell proliferation was in an Mfn1-dependent manner.Furthermore，bioinformatic analysis showed that Mfn1 was mediated by miR-125 and miR-351.Subsequently，the functions of these miRNAs in PASMC apoptosis under hypoxic conditions were examined.The promotive effect of Mfn1 was weakened in the presence of miR-125 and miR-351 mimics.CONCLUSION: In the present study，we determined the role of miRNAs in regulating Mfn1 expression in hypoxia by bioinformatics for the first time.These results provide a theoretical basis for the prevention and treatment of pulmonary vascular remodeling.

△Corresponding author E-mail: woshiaiwenhe@163.com

AIM: To verify the mechanism of endothelial-to-mesenchymal transition (EndoMT) involved in pulmonary artery remodeling (PAR)，and to investigate whether EndoMT in pulmonary artery hypertension (PAH) could be inhibited.METHODS: The methods of multiple immunofluorescence staining，morphologic analysis，Western blotting and coimmunoprecipitation were applied to identify the role of EndoMT in the PAR and the molecular mechanisms participating EndoMT.RESULTS: EndoMT occurred in the pathologicalprocess of PAR in hypoxia and MCT induced PAH，which was inhibited by a PDGF receptor antagonist imatinib.Platelet-derived growth factor-B (PDGF-B)，platelet-derived growth factor-A (PDGF-A) and transforming growth factor-β1 (TGF-β1) signaling pathways were involved in EndoMT of pulmonary artery endothelial cells (PAECs).More importantly，a reciprocal regulation between PDGF-BB and TGF-β1，but not between PDGF-AA and TGF-β1，was observed.Mechanically，the reciprocal regulation between PDGF-BB and TGF-β1 resulted from the down-regulation of neprilysin (NEP) induced by hypoxia in PAECs.CONCLUSION: EndoMT is mediated by NEP，PDGF-BB and TGF-β1 singling pathway.In addition，attenuating EndoMT in arteries endothelium by imatinib，a PDGF receptor antagonist，and subsequent relieving PAR provides theoretical support for imatinib as a new candidate for PAH treatment.

*［Foundation item］Supported by National Natural Science Foundation of China (No.31471095; No.81270113; No.81400353)，Key Research Plan of National Natural Science Foundation of China (No.91339107)，Natural Science Foundation of Heilongjiang Province (No.SCX-2012-9; No.QC2014C096)，Wu Liande Youth Science Foundation (No.WLD-QN1410) and Postdoctoral Foundation of Heilongjiang Province (No.LBH-Z14133)

△Corresponding author Tel: 011-86-459-8153555; E-mail: dalingz@yahoo.com

AIM: To evaluate the influence of bone morphogenetic protein-7 (BMP-7) on endothelial-to-mesenchymal transition (EndoMT) in pulmonary artery endothelial cells (PAECs) and further explore how it regulates EndoMT.METHODS＆RESULTS: The expression of BMP-7 was recognized in hypoxic rat model and cultured PAECs by immunofluorescence and Western blotting.Under the condition of hypoxia，the expression of BMP-7 was decreased both in vivo and in vitro.In order to determine the role of BMP7 in PAECs，the cells were transfected with small interfering RNA targeting BMP-7 under normoxia，and the exogenous rh-BMP7 was added to the cells under hypoxia.EndoMT was assessed by immunofluorescence for α-smooth muscle actin (α-SMA) and CD31，and by Western blotting for α-SMA，VE-cadherin，vimentin and fibronectin.Cell migration was detected by cell scratch experiment.Under the condition of normoxia，BMP-7 deficiency induced spontaneous EndoMT and significant migration.The hypoxia-induced EndoMT and cell migration were markedly attenuated after pretreatment with rh-BMP7.Moreover，m-TOR phosphorylation was involved in EndoMT，and BMP-7 suppressed hypoxia-induced m-TOR phosphorylation in PAECs.CONCLUSION: BMP-7 attenuates the hypoxia-induced EndoMT and cell migration by suppressing m-TOR signaling pathway.Our study revealed a novel mechanism underlying hypoxia-induced EndoMT in pulmonary arterial endothelium cells and suggested a new therapeutic strategy targeting EndoMT in the treatment of pulmonary arterial hypertension.

△Corresponding author E-mail: 624394182@qq.com

The present study aimed to investigate the expression and potential target of microRNA-1 (miR-1) in the myocardium of a rat model of ischemia/reperfusion (I/R).The apoptosis of cardiomyocytes in the ischemic rat myocardium increased on day 1，and then decreased on post-I/R day 3 and day 7.While miR-1 was decreased，the reduced heat shock protein 90 (Hsp90) aa1 protein，not Hsp90aa1 mRNA，was reversed on post-I/R day 3 and day 7.Repression of miR-1 in cultured neonatal rat ventricular cells (NRVCs) led to an increase in Bcl-2 and decreases in Bax and activated caspase-3.Dual-luciferase reporter assays revealed that miR-1 interacted with the 310～315 nt site at the 3'UTR of Hsp90aa1，and miR-1 was verified to inhibit Hsp90aa1 expression at the post-transcriptional level.Additionally，miR-1 mimic，in parallel to Hsp90aa1 siRNA，enhanced oxygen-glucose deprivation (OGD) -induced apoptosis ofNRVCs.Together，our results reveal that Hsp90aa1 is a novel target of miR-1，and repression of miR-1 may contribute to the recovery of Hsp90aa1 during myocardial I/R.

*［Foundation item］Supported by National Natural Science Foundation of China (No.81270222; No.81470439) and Natural Science Foundation of Guangdong (No.2014A030313635)

△Corresponding author E-mail: zhixinshan@aliyun.com

AIM: To detect the expression and potential role of miR-214 in diabetic myocardial fibrosis.METHODS: The expression of Col1a1，Col3a1，α-SMA and miR-214 at mRNA and protein levels was detected in diabetic mouse myocardium and 33 mmol/L glucose-stimulated C75BL/6 mouse cardiac fibroblasts.Dual-luciferase reporter gene assay was performed to verify whether EZH2 was a target gene of miR-214.The expression of EZH2，Col1a1，Col3a1 and α-SMA at mRNA and protein levels was detected in mouse cardiac fibroblasts after transfection with miR-214 mimic or inhibitor.RESULTS: Col1a1，Col3a1 and α-SMA were up-regulated and the level of phosphorylated Smad3 was increased significantly in the 18-week-old db/db mouse myocardium.miR-214 was up-regulated in mouse diabetic myocardium and high glucose-promoted cardiac fibroblasts.Dual-luciferase reporter gene assay revealed that EZH2 was a target gene of miR-214.EZH2 was post-transcriptionly modulated by miR-214.Additionally，miR-214 mimic increased，but miR-214 inhibitor inhibited Col1a1，Col3a1 and α-SMA expression in the cardiac fibroblasts.CONCLUSION: miR-214 enhances fibrosisassociated gene expression through suppress ing EZH2 in cardiac fibroblasts.

*［Foundation item］Supported by National Natural Science Foundation of China (No.81270222; No.81470439) and Natural Science Foundation of Guangdong (No.2014A030313635)

△Corresponding author E-mail: zhixinshan@aliyun.com

Angiotensin-converting enzyme 2 (ACE2) was recently identified as a multifunctional monocarboxypeptidase responsible for the conversion of angiotensin (Ang) II to Ang-(1-7).The role of ACE2/Ang-(1-7) signaling is involved in the processes related to proliferation，inflammation，vascular fibrosis and remodeling.The aim of present study was to provide proof of principle for the potential use of ACE2 as a novel therapeutics for the treatment of hypertension and other vascular diseases.Using bioinformatic approach，a number of candidate potential activators of ACE2 were identified.Human umbilical vein endothelial cells (HUVECs) and human lung adenocarcinoma A549 cells were treated with 6 drugs (SB-202190，benzamil，fenspiride，acetylsalicylic acid，rosiglitazone and diazoxide) for 3 h.The mRNA expression of ACE2 was quantified by real-time PCR.Our findings suggest that acetylsalicylic acid and diazoxide affected the mRNA expression of ACE2 in HUVECs and human lung adenocarcinoma A549 cells.Using bioinformatic analysis might be a rational approach for discovery of potential activators of ACE2.

△Corresponding author CUI Qing-hua E-mail: cuiqinghua@bjmu.edu.cn; ZHU Yi E-mail: zhuyi@bjmu.edu.cn

Trimetazidine prevents macrophage-mediated septic myocardial dysfunction via Sirt1

WANG Dao-wen
(Department of Internal Medicine and Gene Therapy Center，Tongji Medical College of Huazhong University of Science and Technology，Wuhan 430030，China.E-mail: chenchen@tjh.tjmu.edu.cn)

Macrophage migration inhibitory factor suppresses fibrosisassociated gene expression through scavenging ROS and up-regulating miR-29b expression in cardiac fibroblasts*

ZOU Xiao，ZHU Jie-ning，LIN Qiu-xiong，ZHU Wen-si，DENG Chun-yu，F(xiàn)U Yong-heng，TAN Hong-hong，SHAN Zhi-xin△
(Medical Research Center of Guangdong General Hospital，Guangdong Provincial Cardiovascular Institute，Guangdong Academy of Medical Sciences，Guangzhou 510080，China)

Anti-inflammation of apelin in ameliorating hypoxic pulmonary artery hypertension is through an inhibition of NF-κB pathway*

DING Lu，LI Yang，ZHENG Qing-qing，XIA Dong-mei，LIU Hui，F(xiàn)AN Jun-ming，MAO Sun-zhong，F(xiàn)AN Xiao-fang，GONG Yong-sheng△
(Institute of Hypoxia Medicine，Wenzhou Medical University，Wenzhou 325035，China)

Role of catestatin in chronic intermittent hypoxia-induced hypertension in rats*

ZHENG Qing-qing，XING Xue-ping，CHEN Ran，DING Lu，ZHAO Ru，GONG Yong-sheng，F(xiàn)AN Xiao-fang△
(Institute of Hypoxia Medicine，Wenzhou Medical University，Wenzhou 325035，China)

Soluble epoxide hydrolase is involved in development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration

WANG Qing-jie1▲，HUO Lei-jun1，2▲，HE Jin-long4，ZHANG Xu4，DING Wen-shang1，SU Hang1，TIAN Dong-ping1，Carrie Welch5，Bruce D.HAMMOCK3，AI Ding4△，ZHU Yi4△
(1Department of Pathology，Shantou University Medical College，Shantou 515063，China;2Department of Pathology，Guangdong Women and Children’s Hospital，Guangzhou Medical College，Guangzhou 510000，China;3Department of Entomology and UC Davis Comprehensive Cancer Center，University of California at Davis，Davis，CA 95616，USA;4Department of Physiology and Pathophysiology，Collaborative Innovation Center of Tianjin for Medical Epigenetics，Tianjin Medical University，Tianjin 300070，China;5Division of Molecular Medicine，Department of Medicine，Columbia University，New York，NY 10032，USA)

Mediation of exogenous hydrogen sulfide in recovery of ischemic postconditioning-induced cardioprotection via down-regulating oxidative stress and up-regulating PI3K/Akt/GSK-3β pathway in isolated aging rat hearts*

LI Hong-zhu1△，WANG Yue-hong1，WEI Can1，BAI Shu-zhi1，ZHAO Ya-jun1，LI Hong-xia1，WU Bo1，WANG Rui2，WU Ling-yun3，XU Chang-qing1
(1Department of Pathophysiology，Harbin Medical University，Harbin 150081，China;2Department of Biology，3Department of Health Science，Lakehead University，Thunder Bay，ON P7B5E1，Canada)

MicroRNA-21a enhances fibrosis-associated gene
expression in TGF-β1-induced rat H9c2 myoblasts*

LIN Qiu-xiong，ZHU Wen-si，ZHU Jie-ning，TANG Chun-mei，DENG Chun-yu，F(xiàn)U Yong-heng，TAN Hong-hong，YANG Min，YU Xi-yong，SHAN Zhi-xin△
(Guangdong Cardiovascular Institute，Guangdong General Hospital，Guangdong Academy of Medical Sciences，Guangzhou 510080，China)

Expression of miR-199a/214 cluster in hypertrophic myocardium and hypertrophic cardiomyocytes*

TANG Chun-mei，ZHU Jie-ning，LIN Qiu-xiong，ZHU Wen-si，F(xiàn)U Yong-heng，QI Zhou-cuo，ZHANG Meng-zhen，TAN Hong-hong，SHAN Zhi-xin△
(Medical Research Center of Guangdong General Hospital，Guangdong Provincial Cardiovascular Institute，Guangdong Academy of Medical Sciences，Guangzhou 510080，China)

Human cytomegalovirus infection is associated with essential hypertension in the Kazakh and Han Chinese populations*

TANG Na，LI Jia-wei，LIU Yong-min，ZHONG Hua，WANG La-mei，HE Fang△
(Department of Pathophysiology/Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases，Medical College of Shihezi University，Shihezi 832002，China)

Role of Zn2 +in endoplasmic reticulum stress inhibition-induced cardioprotection against ischemia/reperfusion injury*

FEI Shuo1，HE Yong-gui1，ZHENG Huan1，LI Lu1，HE Yi-fei1，XU Zhe-long2，XI Jin-kun1，2△
(1Heart Institute，North China University of Science and Technology，Tangshan 063000，China;2Department of Physiology and Pathophysiology，Tianjin Medical University，Tianjin 300070，China)

Role of mPTP and ER stress in NECA-induced cardioprotection against ischemia/reperfusion injury*

XI Jin-kun1，HE Yong-gui2，F(xiàn)EI Shuo2，ZHENG Huan2，HE Yi-fei2，LI Lu2，XU Zhe-long1△
(1Department of Physiology and Pathophysiology，Tianjin Medical University，Tianjin 300070，China;2Heart Institute，North China University of Science and Technology，Tangshan 063000，China)

MMP-2 contributes to vascular angiogenesis induced by hypoxia/15-HETE in pulmonary arterial endothelial cells

LIU Ying，ZHANG Hong-yue，ZHU Da-ling△
(Department of Biopharmaceutical Sciences，College of Pharmacy，Harbin Medical University(Daqing)，Daqing 163319，China)

Key role of microRNAs in mitochondrial fusion protein 1-mediated pulmonary vascular remodeling

MA Cui，ZHU Da-ling△
［Department of Biopharmaceutical Sciences，College of Pharmacy，Harbin Medical University (Daqing)，Daqing 163319，China］

Down-regulating NEP induces endothelial-to-mesenchymal transition via reciprocal regulation of PDGF-BB and TGF-β1 during pulmonary artery remodeling*

SONG Sha-sha1，ZHANG Min1，YI Zhi1，ZHANG Hong-yue1，SHEN Ting-ting1，YU Xiu-feng1，ZHANG Chen1，ZHENG Xiao-dong1，YU Lie1，MA Cui1，SHI Heng-yuan1，CAO Wei-wei1，ZHU Da-ling1，2△
［1Department of Biopharmaceutical Sciences，College of Pharmacy，Harbin Medical University (Daqing)，Daqing 163319，China;2Biopharmaceutical Key Laboratory of Heilongjiang Province，Harbin 150081，China］

Bone morphogenetic protein-7 inhibits endothelial-to-mesenchymal transition in pulmonary artery endothelial cells

ZHANG Hong-yue，LIU Ying，ZHU Da-ling△
［Department of Biopharmaceutical Sciences，College of Pharmacy，Harbin Medical University (Daqing)，Daqing 163319，China］

Hsp90aa1: a novel target gene of miR-1 in cardiac ischemia/reperfusion injury*

ZHU Jie-ning，ZHU Wen-si，F(xiàn)U Yong-heng，LIN Qiu-xiong，GUO Wei，ZOU Xiao，LIANG Ye-you，TAN Ning，SHAN Zhi-xin△
(Guangdong Cardiovascular Institute，Guangdong General Hospital，Guangdong Academy of Medical Sciences，Guangzhou 510080，China)

miR-214 enhances fibrosis-associated gene expression through targeting EZH2 in cardiac fibroblasts*

ZHU Wen-si，ZHU Jie-ning，F(xiàn)U Yong-heng，LIN Qiu-xiong，QI Zhou-cuo，ZHANG Meng-zhen，TAN Hong-hong，SHAN Zhi-xin△
(Medical Research Center of Guangdong General Hospital，Guangdong Provincial Cardiovascular Institute，Guangdong Academy of Medical Sciences，Guangzhou，510080，China)

Candidate therapeutic ACE2 activator screening based on bioinformatic method

WANG Yu-chen，CUI Qing-hua△，ZHU Yi△
(Department of Physiology and Pathophysiology，Peking University School of Basic Medical Sciences，Beijing 100191，China)