Research progress on the roles of angiopoietin-like protein 8 in the pathogenesis of cardiovascular diseases / 基础医学与临床

Angiopoietin-like protein 8(ANGPTL8)secreted by liver and adipose tissue,is a glycoprotein exerting paramount effects on facilitation of vascular remodeling and regulation of inflammatory response;ANGPTL8 is in-volved in the initiation and progression of cardiovascular diseases including coronary artery disease,hypertension,aortic aneurysm and pathological cardiac hypertrophy,and holds promise for being a new target for the prevention and treatment of cardiovascular diseases.

miR-20a regulates pressure overload-induced cardiac hypertrophy / 中国组织工程研究

BACKGROUND:Cardiac hypertrophy is an adaptive response of the heart to physiological and pathological stimuli such as pressure overload.It is of compensatory significance in the early stage,but if the stimulation continues,it can cause cardiomyopathy leading to heart failure.MicroRNAs are involved in the regulation of cardiac hypertrophy.However,the role of miR-20a in pressure overload-induced cardiac hypertrophy has not been reported. OBJECTIVE:To investigate the role of miR-20a in pressure overload-induced cardiac hypertrophy and the underlying mechanisms. METHODS:Transverse aortic constriction was used to induce cardiac hypertrophy in vivo and angiotensin Ⅱ was used to induce H9c2 cell models of cardiac hypertrophy in vitro.MiR-20a was overexpressed in vivo by intramyocardial injection of miR-20a overexpressing adenovirus and in vitro by transfecting miR-20a mimic into H9c2 cells.Cardiac hypertrophy was assessed by measuring heart weight/body weight ratio,cell surface area,and myocardial fibrosis.The expression levels of atrial natriuretic peptide,brain natriuretic peptide,β-myosin heavy chain and miR-20a were detected by real-time fluorescence quantitative PCR.Mitochondrial fission was detected by MitoTracker.The downstream target genes of miR-20a were predicted by RNAhybrid software. RESULTS AND CONCLUSION:(1)The expression level of miR-20a was significantly decreased in both hypertrophic cardiomyocytes and hearts(P<0.05).(2)At the animal level,overexpression of miR-20a significantly inhibited transverse aortic constriction-induced cardiac hypertrophy,including decreasing the upregulated expression level of hypertrophic marker genes(P<0.05),reduced the enlarged heart volume,reducing the increased heart weight/body weight ratio(P<0.01),reducing the increased myocardial cross-sectional area(P<0.05),and attenuating fibrosis(P<0.01).(3)At the cellular level,overexpression of miR-20a significantly inhibited angiotensin Ⅱ-induced cardiomyocyte hypertrophy,including decreasing the upregulated expression levels of atrial natriuretic peptide(P<0.05),brain natriuretic peptide(P<0.01)and β-myosin heavy chain(P<0.05),reducing the increased protein/DNA ratio(P<0.01),and suppressing the increased cell surface area(P<0.05).(4)Overexpression of miR-20a significantly inhibited angiotensin Ⅱ-induced mitochondrial fission(P<0.05).(5)The results of RNAhybrid software analysis showed that miR-20a and the mRNA 3'untranslated region of cAMP-dependent protein kinase inhibitor alpha were well complementary and the predicted binding sites were highly conserved.(6)In conclusion,miR-20a is significantly down-regulated in pressure overload-induced cardiac hypertrophy.Overexpression of miR-20a inhibits cardiac hypertrophy at both the cellular level and animal level and attenuates angiotensin Ⅱ-induced mitochondrial fission.

Regulation of N6-methyladenosine on non-coding RNAs in pathological cardiac remodeling / 中国组织工程研究

BACKGROUND:N6-methyladenosine(m6A)is a hot research topic in the mechanism of pathological cardiac remodeling and plays an important role in the development of cardiovascular diseases. OBJECTIVE:To summarize the possible mechanism by which m6A modification in non-coding RNAs regulates the main processes of pathological cardiac remodeling,such as pathological cardiac hypertrophy,cardiomyocyte death,myocardial fibrosis and vascular remodeling. METHODS:"m6A,non-coding RNA,pathological cardiac hypertrophy,cardiomyocyte apoptosis,cardiomyocyte pyroptosis,cardiomyocyte ferroptosis,myocardial fibrosis,vascular remodeling"were used as search terms in Chinese and English.Relevant literature from CNKI,PubMed and Web of Science databases published from January 1974 to April 2023 was retrieved,and finally 86 eligible articles were reviewed. RESULTS AND CONCLUSION:m6A modification is a highly dynamic and reversible modification.Pathological cardiac remodeling mainly involves pathological cardiac hypertrophy,cardiomyocyte apoptosis,cardiomyocyte pyroptosis,cardiomyocyte ferroptosis,myocardial fibrosis and vascular remodeling.m6A-related enzymes can regulate pathological cardiac remodeling processes through various non-coding RNAs and different signaling pathways,which can be used as a new potential intervention for cardiovascular diseases.In pathological cardiac remodeling,research on the regulatory relationship between m6A modification and non-coding RNAs is still in its infancy.With the development of epigenetics,m6A modification in non-coding RNAs is expected to have a new development in the regulation of pathological cardiac remodeling.

circMYO9A_006 inhibits expression of cardiac hypertrophy-related pro-teins in cardiomyocytes by translating protein MYO9A-208aa / 中国病理生理杂志

AIM:To investigate the effect of circular RNA MYO9A-006(circMYO9A_006)on hypertrophic phenotype of cardiomyocytes and the underlying mechanism.METHODS:The effect of adenovirus-mediated overexpres-sion of circMYO9A_006 on the expression of hypertrophy-related proteins,including β-myosin heavy chain(β-MHC),skeletal muscle actin alpha 1(ACTA1)and atrial natriuretic peptide(ANP),was evaluated in neonatal mouse ventricular cardiomyocytes(NMVCs).Moreover,a neonatal rat ventricular cardiomyocyte(NRVC)model of phenylephrine(PE)-in-duced hypertrophy was established.The effect of circMYO9A_006 overexpression on NRVC size was ascertained using Phalloidin-iFluor 647 staining method.Dual-luciferase reporter assay was employed to measure the activity of potential in-ternal ribosome entry sites(IRES)in circMYO9A_006.The translation and intracellular location of the circMYO9A_006-translated protein,MYO9A-208aa,were verified using Western blot.To investigate the role of MYO9A-208aa in the ef-fect of circMYO9A_006 on the cardiomyocyte hypertrophic phenotype,we prepared and used the following adenoviruses:the recombinant circMYO9A_006-ORF adenovirus to express MYO9A-208aa,the recombinant circMYO9A_006-ATG-mut adenovirus that does not express MYO9A-208aa,the recombinant circMYO9A_006 adenovirus,and the adenovirus vector control.These were then employed to infect NRVCs.RESULTS:Successful adenovirus-mediated overexpression of circMYO9A_006 was observed in NMVCs.The increased expression of circMYO9A_006 notably reduced the expres-sion of hypertrophy-related proteins in NMVCs(P<0.01).Concurrently,overexpression of circMYO9A_006 substantially reduced the expression of hypertrophy-associated proteins and diminished the size of PE-induced NRVCs(P<0.05).Dual-luciferase reporter assay identified the activity of 2 IRES in circMYO9A_006.Western blot results indicated that circ-MYO9A_006 could produce the MYO9A-208aa protein with an anticipated molecular weight of 28 kD in NRVCs,primari-ly found in the cytoplasm.Elevated expression of both circMYO9A_006 and MYO9A-208aa consistently reduced the ex-pression of hypertrophy-associated proteins(P<0.01),and counteracted the enlarged size of PE-induced NRVCs(P<0.05).However,increased expression of circMYO9A_006-ATG-mut did not counteract the PE-induced hypertrophic phe-notype of NRVCs.CONCLUSION:circMYO9A_006 attenuates the hypertrophic phenotype of cardiomyocytes by synthe-sizing the MYO9A-208aa protein.

Spermidine alleviates pressure overload-induced heart failure in mice via improving cardiac mitochondrial energy metabolism / 中国病理生理杂志

AIM:To investigate the effect of spermidine(SPD)on pressure overload-induced cardiac hyper-trophy and heart failure model in mice and its underlying mechanisms.METHODS:(1)Eight-week-old male C57BL/6J mice were randomly divided into 4 groups:sham group,sham+SPD group,transverse aortic constriction(TAC)group,and TAC+SPD group.After TAC,the mice in sham+SPD group and TAC+SPD group were fed with 3 mmol/L SPD via drinking water,and the mice in other groups were fed with normal water.Western blot was used to detect the protein ex-pression levels of silent information regulator 6(SIRT6),peroxisome proliferator-activated receptor γ coactivator-1(PGC-1)and mitofusin 2(MFN2).Adult mouse cardiomyocytes were isolated to detect cell length and width.Wheat germ agglu-tinin staining was used to detect the cardiac cell size.Masson staining was used to detect the extent of fibrosis.Echocar-diography was used to detect cardiac function and myocardial hypertrophy.Transmission electron microscopy was used to analyze mitochondrial morphology.Oxygraph-2k high-resolution respirometer was used to detect cardiac mitochondrial oxy-gen consumption.(2)In vitro,primary rat ventricular cardiomyocytes were cultured and treated with angiotensin II(Ang II;1 μmol/L)to construct a hypertrophy model of cardiomyocytes.These cardiomyocytes were divided into control(Con)group,Con+SPD(1 mmol/L)group,Ang II group,Ang II+SPD group and Ang II+SPD+SIRT6 siRNA(siSIRT6)group.Confocal microscopy was used to detect cardiomyocytes area and mitochondrial.RESULTS:(1)Compared with sham group,cardiac function of the mice in TAC group was significantly decreased(P＜0.05),the degree of myocardial hyper-trophy was significantly increased(P＜0.05),and the expression levels of SIRT6,PGC-1 and MFN2 in the myocardial tis-sue were significantly decreased(P＜0.05).Compared with TAC group,the expression levels of SIRT6,PGC-1 and MFN2 in mouse myocardial tissues of TAC+SPD group were significantly increased(P＜0.05),pathological myocardial hy-pertrophy was reduced(P＜0.05),the numbers of mitochondria and mitochondrial cristae were increased(P＜0.05),mito-chondrial function was restored(P＜0.05),myocardial fibrosis was alleviated(P＜0.05),and cardiac function was im-proved(P＜0.05).(2)In vitro,compared with Con group,the expression levels of SIRT6,PGC-1 and MFN2 in cardio-myocytes of Ang II group were decreased(P＜0.05),and the degree of cardiomyocyte hypertrophy was significantly in-creased(P＜0.05).Treatment with SPD increased the expression levels of SIRT6,PGC-1 and MFN2 in cardiomyocytes of Ang II group(P＜0.05),reversed myocardial hypertrophy and improved mitochondrial dynamics(P＜0.05).Compared with Ang II group,the expression levels of SIRT6,PGC-1 and MFN2 in Ang II+SPD+siSIRT6 group showed no significant changes,and the degree of cardiomyocyte hypertrophy and mitochondrial dynamics also had no statistically significant changes.CONCLUSION:Spermidine promotes the expression of SIRT6,PGC-1 and MFN2,thus improving mitochon-drial function,reducing myocardial hypertrophy and alleviating heart failure in mice with pressure overload.

Function of Cortactin/N-cadherin signal axis in pathological myocardial hypertrophy / 中国药理学通报

Aim To investigate the regulatory effect of Cortaetin on pathological myocardial hypertrophy induced by isoprenaline (ISO) and the underlying mechanism. Methods ISO was used to stimulate neonatal rat cardiomyocytes for 24 h, and myocardial hypertrophy model was established at the cellular level. C57BL/6 mice were injected subcutaneously with ISO for one week to establish myocardial hypertrophy model at animal level. RT-qPCR was used to detect the changes of mRNA and Western blot was used to detect the changes of relative protein content. Immunofluorescence was used to measure the subcellular location of Cortaetin and the change of its expression. The overex-pression of Cortaetin by adenovirus infection and the knockdown of Cortaetin by transfection of small interfering RNA were studied. Results On the cellular and animal levels, ISO-induced myocardial hypertrophy models were successfully established, and it was observed that ISO caused the decrease of Cortaetin and N-cadherin protein levels. Overexpression of Cortaetin could reverse the decrease of N-cadherin protein level and myocardial hypertrophy caused by ISO. Knockdown of Cortaetin showed the opposite effect. Conclusion Cortaetin, in combination with N-cadherin, may play a role in combating myocardial hypertrophy by enhancing the connections between cardiomyocytes.

Factor de crecimiento análogo a insulina-1 y cardiotrofina-1 inducido por ejercicio y su relación con hipertrofia miocárdica en maratonistas / Cardiotrophin-1 and Insulin like growth factor induced by exercise are associated to cardiac hypertrophy in marathon runners

Antecedentes: El ejercicio de alta intensidad induce hipertrofia miocárdica necesaria para adaptar al corazón a la mayor demanda de trabajo. Se desconoce si correr una maratón induce de forma aguda factores humorales asociados al desarrollo de hipertrofia miocárdica en atletas. Objetivo: Evaluar cardiotrofina-1 (CT1) y el factor de crecimiento análogo a insulina-1 (IGF-1), conocidos inductores de hipertrofia, en maratonistas previo y justo después de correr una maratón y su relación con hipertrofia cardíaca. Métodos: Estudio prospectivo ciego simple de atletas hombres que corrieron la maratón de Santiago. Se incluyó un grupo control sedentario. En todos los sujetos se realizó un ecocardiograma transtorácico estándar. Los niveles de CT1 e IGF-1 se determinaron en plasma obtenidos antes (basal) y justo después de haber terminado (antes de 15 minutos) la maratón, usando test de ELISA. Resultados: Los atletas tenían frecuencias cardíacas menores que los controles, asociado con una mayor hipertrofia miocárdica, determinado por el grosor del septo y pared posterior del corazón, y volúmenes del ventrículo y aurícula izquierda. Los niveles basales de CT1 e IGF-1 fueron similares entre atletas y controles sedentarios. El correr la maratón aumentó los niveles de estas dos hormonas en un subgrupo de atletas. Solo los atletas que incrementaron los niveles de IGF-1, pero no de CT1, tenían volúmenes de ventrículo izquierdo y derecho más grandes que los otros atletas. Conclusiones: IGF-1 que se incrementa de forma aguda por el ejercicio, pero no CT1, estaría asociado con el aumento de los volúmenes ventriculares observado en los atletas.

Background: High intensity exercise induces the development of myocardial hypertrophy necessary to adapt the heart to the increased work demand. Whether running a marathon is associated with acutely induced humoral factors responsible for the development of myocardial hypertrophy observed in athletes is not known. Objective: To evaluate the levels of cardiotrophin-1 (CT1) and insulin-like growth factor-1 (IGF-1), known hypertrophy inducers, in marathon runners before and just after running a marathon and their relationship with cardiac hypertrophy. Methodology: Single-blind prospective study of male athletes who ran the Santiago's marathon. A sedentary control group was included. All subjects underwent a standard transthoracic echocardiogram. CT1 and IGF-1 levels were determined in plasma obtained before (basal) and just after finishing (within 15 min) the marathon using ELISA assays. Results: Athletes had lower heart rates than controls, associated with greater myocardial hypertrophy, as determined by thickness of the heart's septum and posterior wall, and left atrial and ventricular volumes. Basal CT1 and IGF-1 levels were similar between athletes and sedentary controls. Marathon running increased the levels of these two hormones in a subgroup of athletes. Only the athletes who increased IGF-1 levels, but not CT1, had larger left and right ventricular volumes. Conclusion: IGF-1 acutely increased by exercise, but not CT1, was associated with the augmented ventricular volumes observed in athletes.

Effect of histone methylase EZH2 on proliferation and apoptosis of hypertrophic myocardial cells of AC16 / 国际生物医学工程杂志

Objective:To explore the molecular mechanism of the effect of the histone methylase zeste gene enhancer homolog 2 (EZH2) on the proliferation and apoptosis of human hypertrophic cardiomyocytes AC16.Methods:The AC16 hypertrophic cardiomyocyte model was constructed by adding angiotensin Ⅱ to the AC16 cell culture medium. The cells were divided into four groups, including the blank control group, the angiotensin Ⅱ group, the empty vector + angiotensin Ⅱ group, and the EZH2 overexpression + angiotensin Ⅱ group. The expression levels of EZH2 and brain natriuretic peptide ( BNP) genes were measured using fluorescent quantitative PCR. The EZH2, trimethylation of lysine at position 27 of histone H3 (H3K27me3), and BNP proteins expression were detected by Western Blot. The MTS method was used to detect the proliferation of AC16 cell. The Annexin V-FITC/PI double staining method was used to detect the apoptosis of AC16 cell. Results:Compared with the blank control group, the expression levels of EZH2 and H3K27me3 in the angiotensin Ⅱ group were decreased, the expression level of BNP was increased, cell proliferation was decreased, and apoptosis was increased (all P < 0.001). Compared with the empty vector + angiotensin Ⅱ group, the expression levels of EZH2 and H3K27me3 in the EZH2 overexpression + angiotensin Ⅱ group were increased, the expression level of BNP was decreased, the cell proliferation level was increased, and the apoptosis level was decreased (all P < 0.001). There was no significant difference between the angiotensin Ⅱ group and the empty vector + angiotensin Ⅱ group (all P > 0.05). Conclusions:Histone methylase EZH2 has an effect on the proliferation and apoptosis of AC16 cell, providing a reference for the treatment of myocardial hypertrophy and revealing the exact pathogenesis of myocardial hypertrophy.

Effect of hyperoside on transverse aortic constriction-induced cardiac hypertrophy / 安徽医科大学学报

Objective To investigate the protective effect of hyperoside(Hyp)on transverse aortic constriction-in-duced cardiac hypertrophy and its possible mechanism.Methods Forty 8-week-old male C57BL/6J mice were randomly divided into four groups:Sham group,TAC group,Hyp+TAC group and Hyp+ML385+TAC group.Four weeks after operation,cardiac function including left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS)and left ventricular end-diastolic posterior wall thickness(LVPWd)were measured with echocardiography.HE staining was used to evaluate the myocyte cross-sectional area.Masson staining was used to determine myocardial fibrosis.The ratio of heart weight/body weight was calculated.DHE staining was used to assess reactive oxygen species(ROS)production.The mRNA levels of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP)and β-myosin heavy chain(β-MHC)were detected by qRT-PCR.The protein levels of NF-E2-related factor 2(Nrf2),heme oxygenase-1(HO-1),superoxide dismutase2(SOD2)and NAD-PH-Oxidase 2(gp91phox)were detected by Western blot.Differences among groups were compared by one-way a-nalysis of variance,and LSD-t test was used for comparison between the two groups.Results Compared with the Sham group,the values of LVEF and LVFS in the TAC group decreased(P＜0.01).The value of LVPWd,the cross-sectional area,fibrosis and the ratio of HW/BW increased(P＜0.01).The mRNA levels of ANP,BNP andβ-MHC were upregulated(P＜0.01).The ROS production and gp91phox protein level were elevated in the TAC group(P＜0.01),while the protein levels of Nrf2,HO-1 and SOD2 decreased(P＜0.01).Compared with the TAC group,the values of LVEF and LVFS in the Hyp+TAC group increased(P＜0.01).The value of LVPWd,the cross-sectional area,fibrosis and the ratio of HW/BW decreased(P＜0.01).The mRNA levels of ANP,BNP and β-MHC were downregulated(P＜0.01).The ROS production and gp91 phox protein levels were reduced in the Hyp+TAC group(P＜0.01),while the protein levels of Nrf2,HO-1 and SOD2 increased(P＜0.01).However,ML385 could partially reverse the protective effects of Hyp on TAC-induced cardiac hypertrophy.Conclusion Hyp alleviates pressure overload-induced cardiac hypertrophy by inhibiting oxidative stress and fibrosis,and its mechanism may be related to Nrf2/HO-1 signaling.

Protective effect of dexmedetomidine on pathological cardiomyocyte hypertrophy / 中国医科大学学报

Objective The purpose of this study was to investigate the protective effect of dexmedetomidine(DEX)on pathological car-diomyocyte hypertrophy.Methods An in vitro cell population was established in neonatal rats.The rats were divided into six groups:control group(C)without serum for 24 h,model group(A)with angiotensin Ⅱ(Ang Ⅱ)for 24 h,dexmedetomidine group(AD)with Ang Ⅱ+DEX(5μmol/L)for 24 h,C'group with serum-free culture for 48 h,A'group with Ang Ⅱfor 24 h,and AD'group with DEX+Ang Ⅱfor 24 h.The morphological changes of cells were observed by immunofluorescence.The protein expressions of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),and myosin heavy chain(β-MHC)were detected by western blot,and the cell activity was detected by CCK-8.Results Compared with group C,the size of cells in group A was larger,and that in group AD was even more significant.Simi-lar observations were found for hypertrophy related proteins.Compared with group C,the expression of ANP,BNP,and βMHC increased in group A,although the increase in AD group was more obvious.CCK-8 detection showed that compared with group C,the activity of group A decreased and that of group AD increased significantly.Compared with the C'group,the expression of hypertrophy-related pro-tein in the A'group was significantly increased,but the expression of ANP and BNP protein in the AD'group was significantly lower than that in the A'group.The differences were statistically significant(P<0.05).Conclusion Dexmedetomidine can alleviate the occur-rence of pathological hypertrophy through compensatory mechanisms similar to physiological myocardial hypertrophy,and may play a role in myocardial protection.

Study on the role of indole sulfate in inducing myocardial hypertrophy and fibrosis through organic anion transporter-3 and oxidative stress / 中国医师杂志

Objective:To investigate the role of indoxyl sulfate (IS) in myocardial hypertrophy and fibrosis through organic anion transporter-3 (OAT-3) and oxidative stress in H9C2 cells.Methods:Rat myocardial cells (H9C2) were cultured and divided into four groups: Control group, IS group, siRNA negative control group (siOAT-3), and siOAT-3+ IS group. The control group was cultured routinely without IS stimulation. The IS group was stimulated with 250 μmol IS. The siRNA negative control group was transfected with 20 nmol/L OAT-3 siRNA, and the siOAT-3+ IS group was transfected with OAT-3 siRNA 48 hours later, then stimulated with IS for 24 hours. Real-time polymerase chain reaction (RT-PCR) was used to detect and analyze the mRNA expression levels of OAT-3, NADPH oxidase-4 (Nox-4), antioxidant proteins [nuclear factor E2 related factor 2 (Nrf-2), heme oxygenase 1 (HO-1)], myocardial hypertrophy markers [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-myosin heavy chain gene (β-MHC)], and fibrosis markers [transforming growth factor β1 (TGF-β1), Smad homologous protein 3 (Smad-3), collagen type Ⅰ (Collagen Ⅰ)] in each group. H9C2 cells were further divided into three groups: Control group, IS group, and N-acetylcysteine (NAC) group. The NAC group was pre-treated with the antioxidant NAC before stimulation with 250 μmol IS for 24 hours. RT-PCR was used to detect the mRNA expression levels of the above indicators.Results:The mRNA expression level of OAT-3 in the IS group was significantly higher than that in the control group, while the mRNA expression levels of OAT-3 in the siOAT-3 group and the siOAT-3+ IS group were significantly lower than those in the IS group (all P<0.001). Compared with the Control group, the mRNA relative expression levels of Nox-4, ANP, BNP, β-MHC, TGF-β1, Smad-3, and Collagen Ⅰ in H9C2 cells of the IS group were significantly increased (all P<0.001), while the mRNA expression levels of Nrf-2 and HO-1 were significantly decreased (all P<0.001). Compared with the IS group, the mRNA relative expression levels of Nox-4, ANP, BNP, β-MHC, TGF-β1, Smad-3, and Collagen Ⅰ in H9C2 cells of the siOAT-3 group and the siOAT-3+ IS group were significantly lower (all P<0.001), while the mRNA expression levels of Nrf-2 and HO-1 were significantly increased (all P<0.001). Pre-treatment with NAC significantly inhibited the high expression of Nox-4, ANP, BNP, β-MHC, TGF-β1, Smad-3, and Collagen Ⅰ mRNA induced by IS (all P<0.001), while significantly increasing the mRNA expression levels of Nrf-2 and HO-1 (all P<0.01). Conclusions:IS promotes myocardial hypertrophy and fibrotic factor overexpression in H9C2 cells through OAT-3 and oxidative stress.

Prdx1 overexpression inhibits oxidative stress through Nrf2 / HO-1 signaling pathway and reduces myocardial hypertrophy and fibrosis in spontaneously hypertensive rats / 安徽医科大学学报

Objective@#To investigate the effect of peroxide reductase 1 (Prdx1) on myocardial hypertrophy and fibrosis in spontaneously hypertensive rats，and to analyze its mechanism．@*Methods@#Forty five SHR rats were randomly divided into model group (SHR group) ，AAV9-NC group and AAV9-Prdx1 group．There were 15 WKY rats in each group，and the other 15 Wistar Kyoto rats were set as the control group．The rats in each group were administered continuously for 8 weeks，and the indexes of cardiac function were detected by echocardiography ; The mean blood pressure and myocardial hypertrophy were measured ; HE staining and Masson staining were used to observe the histomorphology and fibrosis of rat myocardium ; The indexes of oxidative stress in rat serum were detected by ELISA ; The expression level of Prdx1 mRNA in rat myocardium was detected by qRT-PCR ; Western blot was used to detect the expression of Prdx1 protein and nuclear factor E2 related factor 2 (Nrf2) / heme oxygenase-1 (HO-1) signaling pathway related proteins in rat myocardium. @*Results@# Compared with the Control group，the expression of Prdx1 mRNA and protein ，left ventricular ejection fraction ( EF) and left ventricular shortening rate ( FS) decreased in SHR group (P＜0. 05) ，the mean blood pressure，heart mass index ( HMI) and left ventricular mass index (LVMI) of rats increased (P＜0. 05) ，and there were obvious pathological damage and collagen fiber deposition in myocardial tissue．The activities of superoxide dismutase (SOD) and glutathione peroxidase ( GSH-Px) in rat serum decreased，and the content of malondialdehyde (MDA) increased (P＜0. 05) ; The expression of Nrf2， HO-1 and quinone oxidoreductase 1 (NQO1) protein decreased in myocardial tissue (P＜0. 05) ．Compared with SHR group，the expression of Prdx1 mRNA and protein，EF and FS in myocardial tissue of AAV9-Prdx1 group increased (P＜0. 05) ，the mean blood pressure，HMI and LVMI of rats decreased (P＜0. 05) ，and myocardial tissue injury and myocardial fibrosis improved ; The activities of SOD and GSH-Px in rat serum increased，while the content of MDA decreased (P＜0. 05) ; The expression of Nrf2，HO-1 and NQO1 protein increased in myocardial tissue (P＜0. 05) ．@*Conclusion@# Overexpression of Prdx1 can reduce myocardial hypertrophy and fibrosis and improve cardiac function in SHR rats．Its mechanism may be related to activating Nrf2 / HO-1 signaling pathway and inhibiting oxidative stress response.

Effect and mechanism of leonurine on pressure overload-induced cardiac hypertrophy in rats / 中国中药杂志

To investigate the effects of leonurine(Leo) on abdominal aortic constriction(AAC)-induced cardiac hypertrophy in rats and its mechanism. A rat model of pressure overload-induced cardiac hypertrophy was established by AAC method. After 27-d intervention with high-dose(30 mg·kg~(-1)) and low-dose(15 mg·kg~(-1)) Leo or positive control drug losartan(5 mg·kg~(-1)), the cardiac function was evaluated by hemodynamic method, followed by the recording of left ventricular systolic pressure(LVSP), left ventricular end-diastolic pressure(LVESP), as well as the maximum rate of increase and decrease in left ventricular pressure(±dp/dt_(max)). The degree of left ventricular hypertrophy was assessed based on heart weight index(HWI) and left ventricular mass index(LVWI). Myocardial tissue changes and the myocardial cell diameter(MD) were measured after hematoxylin-eosin(HE) staining. The contents of angiotensin Ⅱ(AngⅡ) and angiotensin Ⅱ type 1 receptor(AT1 R) in myocardial tissue were detected by ELISA. The level of Ca~(2+) in myocardial tissue was determined by colorimetry. The protein expression levels of phospholipase C(PLC), inositol triphosphate(IP3), AngⅡ, and AT1 R were assayed by Western blot. Real-time quantitative PCR(qRT-PCR) was employed to determine the mRNA expression levels of β-myosin heavy chain(β-MHC), atrial natriuretic factor(ANF), AngⅡ, and AT1 R. Compared with the model group, Leo decreased the LVSP, LVEDP, HWI, LVWI and MD values, but increased ±dp/dt_(max) of the left ventricle. Meanwhile, it improved the pathological morphology of myocardial tissue, reduced cardiac hypertrophy, edema, and inflammatory cell infiltration, decreased the protein expression levels of PLC, IP3, AngⅡ, AT1 R, as well as the mRNA expression levels of β-MHC, ANF, AngⅡ, AT1 R, c-fos, and c-Myc in myocardial tissue. Leo inhibited AAC-induced cardiac hypertrophy possibly by influencing the RAS system.

Inhibition of activated K-opioid receptor to myocardical hypertrophy induced by ET-1 in neonatal rats by extracellular signal-regulated kinase pathway / 中国药理学通报

Aim To investigate the inhibitory effect of kappa-opioid receptor(κ-OR)stimulation on extracellular signal-regulated kinase pathway on ET-1-induced cardiomyocyte hypertrophy in vitro cultured myocardial cells from neonatal rats.Methods Myocardial cells of neonatal rats were cultured in vitro.The hypertrophic myocytes were induced by ET-1(10 nmol·L-1)before κ-OR agonist U50488H(1 μmol·L-1)was administered.The antihypertrophic effect of κ-OR stimulation was observed in the presence of U0126(1μmol·L-1), Ro-31-8220(50 nmol·L-1)and PTX(5 mg·L-1).The cardiomyocytes volume was measured by computer photographalysis system.The relative expression of ERK1/2 was determined by Western blot.The morphological changes in cardiomyocytes were observed under an inverted phase contrast microscope.The expression of mRNA of atrial natriuretic peptide(ANP)was determined by RT-PCR.Results Compared with normal control group, ET-1 could induced cardiomyocyte hypertrophy.Compared with ET-1 model group, U50488H(1 μmol·L-1)could obviously inhibit ET-1-induced increase of the cardiomyocytes volume, expression of ANPmRNA and expression of ERK1/2, which was similar to U0126(1 μmol·L-1)and Ro-31-8220(50 nmol·L-1); however, the inhibitory effects of U50488H were partly lost when preincubated with U0126(1 μmol·L-1)and Ro-31-8220(50 nmol·L-1); the inhibitory effects of U50488H, U0126(1 μmol·L-1)and Ro-31-8220(50 nmol·L-1)were lost when preincubated with NOR-BNI.Conclusion The stimulation of kappa-opiod can inhibit myocardial hypertrophy induced by ET-1, which is possibly via attenuating ERK1/2.

Analysis on mechanism of frankincense volatile oil in prevention and treatment of cardiac hypertrophy based on in vitro cell experiment and network pharmacology / 中国临床药理学与治疗学

To explore the potential mechanism of frankincense volatile oil in the prevention and treatment of cardiac hypertrophy based on in vitro cell experiment and network pharmacology. METHODS: The anti-hypertrophic effect of frankincense volatile oil was investigated by isoproterenol induced H9c2 cardiomyocytes hypertrophy model. The active chemical components and targets of frankincense volatile oil and targets associated with cardiac hypertrophy were obtained by CNKI, Pubmed, Pubchem databases, etc. String database and Cytoscape 3.8.0 software were used to construct protein-protein interaction network (PPI) and a network of "drug-active component-key target-disease" of frankincense volatile oil in order to screen the key targets of frankincense volatile oil against cardiac hypertrophy. The fluorescent quantitative PCR experiments were performed to verify those key targets. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation analysis of key target genes were performed using David online analysis tool. RESULTS: In vitro cell experiments showed that frankincense volatile oil significantly inhibited the isoproterenol induced increases in cardiomyocytes surface area and protein synthesis, and upregulations of ANP and β-MHC mRNA. A total of 87 active components and 36 ingredient-disease targets of frankincense volatile oil were screened. Network analysis showed that ESR1, NOS3, PTGS2, TNF, MAPK14, and PPARG were key targets. Fluorescence quantitative PCR experiments results indicated that frankincense volatile oil inhibited isoproterenol induced upregulations of ESR1, PTGS2, TNF, and MAPK14 mRNA levels, and downregulations of NOS3, PPARG mRNA levels, respectively. In addition, the GO functional enrichment analysis showed that its biological pathways mainly included lipopolysaccharide-mediated signaling pathway, positive regulation of nitric oxide biosynthetic process, caveola, enzyme binding, etc. The KEGG pathway enrichment analysis included 22 KEGG pathways, which were closely related to VEGF signaling pathway, TNF signaling pathway, sphingolipid signaling pathway and others. CONCLUSION: The active components of frankincense volatile oil may regulate VEGF signaling pathway, TNF signaling pathway, Sphingolipid signaling pathway by acting on ESR1, NOS3, PTGS2, TNF, MAPK14 and PPARG targets, thereby affecting the regulation of lipopolysaccharide-mediated signaling pathway, positive regulation of nitric oxide biosynthetic process, caveola, and enzyme binding, and improving cardiac hypertrophy.

Research progress of miroRNA in the mechanism of cardiac hypertrophy and its role as new drug targets / 国际生物医学工程杂志

Cardiac hypertrophy is a common physiological or pathological process, and pathological cardiac hypertrophy can lead to heart failure, sudden death, etc. The role of microRNA (miRNA or MIR) in myocardial hypertrophy has gradually attracted public attention. miR-1 plays a certain protective role in the occurrence of cardiac hypertrophy. miR-133 is a key factor in the establishment of mast gene program, which is very important for the development of myocardial hypertrophy. Carvedilol and other drugs can regulate the expression of miR-133. miR-208a plays an important physiological role in the cardiovascular system, and its expression level changes dynamically in a variety of cardiovascular diseases such as cardiac hypertrophy, which is closely related to the progression and prognosis of the disease. The expression of miR-199a is up-regulated in pressure-overload cardiac hypertrophy, and it is found that miR-199a can inhibit autophagy of cardiomyocytes and induce the occurrence of cardiac hypertrophy. miR-200c can protect cardiomyocytes through a variety of pathways. miRNA may become an important biomarker or drug therapeutic target for cardiac hypertrophy. With the deepening of the research on non-coding RNAs including miRNA, its regulation on the occurrence of cardiac hypertrophy and the pathological process of heart failure will be further revealed.

Advances in the anti-ageing effects of GDF11 in blood / 中国输血杂志

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β superfamily, is widely expressed in multiple species such as human, mouse, rat, horse and sheep. Moreover, GDF11 is implicated in diverse biological functions and plays an important role in regulating anterior/posterior patterning, skeletal muscle regeneration, bone formation, vascular remodeling and neurogenesis. Recent studies have revealed that GDF11 in blood reverses age-related cardiac hypertrophy, skeletal muscle dysfunction and age-related cognitive decline, suggesting the potential value of GDF11 on anti-ageing. However, some other studies questioned the effects of GDF11 on anti-ageing. Herein, we highlighted structural characteristics of GDF11, advances in effects of GDF11 on anti-ageing, and the controversies of GDF11, to provide new insights for future studies on anti-ageing.

Research on role of Nampt in regulating ERK1/2 in pathological myocardial hypertrophy / 中国药理学通报

Aim To investigate the role of Nampt in regulating ERK1/2 in cardiac hypertrophy and its mechanisms. Methods The primary neonatal rat cardiomyocytes were stimulated by phenylephrine (PE) (100 μmol · L

Screening and identification the hub genes of cardiac hypertrophy in mice / 解剖学报

Objective To screen and identify the hub genes closely related to cardiac hypertrophy by using bioinformaticsmethod and biological experiments. Methods The chip data related to cardiac hypertrophy in mice were downloaded from the Gene Expression Omnibus (GEO) database, and the GE02R online tool was adopted to screen for differentially expressed genes; DAVID 6.7, String 11.0 and Cytoscape 3.7. 0 softwares were used to analyze differentially expressed genes; Kunming mice were randomly divided into a normal saline group (n = 6) and an angiotensin II (Ang II) group (n = 6) to establish a cardiac hypertrophy model, the expression of hub gene in Kunming mouse model of cardiac hypertrophy induced by Ang II was detected by Real-time PCR method. Results A total of 202 common differentially expressed genes and 12 hub genes were selected; the Real-time PCR result demonstrated that decorin(Dcn), HADHA and heat shock protein (HSP) 90αA 1 were significantly down-regulated in the Angli group. Conclusion The selected hub genes can influence the development of cardiac hypertrophy in Kunming mice through extracellular matrix and transforming growth factor β(TGF-β).