Factor de crecimiento análogo a insulina-1 y cardiotrofina-1 inducido por ejercicio y su relación con hipertrofia miocárdica en maratonistas

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 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.

Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy

BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake­via AMP-activated protein kinase (AMPK)­after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.

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 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.

Role of FAK signaling in chagasic cardiac hypertrophy

Abstract Cardiac hypertrophy and dysfunction are a significant complication of chronic Chagas disease, with heart failure, stroke, and sudden death related to disease progression. Thus, understanding the signaling pathways involved in the chagasic cardiac hypertrophy may provide potential targets for pharmacological therapy. Herein, we investigated the implication of focal adhesion kinase (FAK) signaling pathway in triggering hypertrophic phenotype during acute and chronic T. cruzi infection. C57BL/6 mice infected with T. cruzi (Brazil strain) were evaluated for electrocardiographic (ECG) changes, plasma levels of endothelin-1 (ET-1) and activation of signaling pathways involved in cardiac hypertrophy, including FAK and ERK1/2, as well as expression of hypertrophy marker and components of the extracellular matrix in the different stages of T. cruzi infection (60-210 dpi). Heart dysfunction, evidenced by prolonged PR interval and decrease in heart rates in ECG tracing, was associated with high plasma ET-1 level, extracellular matrix remodeling and FAK signaling activation. Upregulation of both FAK tyrosine 397 (FAK-Y397) and serine 910 (FAK-S910) residues phosphorylation as well as ERK1/2 activation, lead to an enhancement of atrial natriuretic peptide gene expression in chronic infection. Our findings highlight FAK-ERK1/2 signaling as a regulator of cardiac hypertrophy in Trypanosoma cruzi infection. Both mechanical stress, induced by cardiac extracellular matrix (ECM) augment and cardiac overload, and ET-1 stimuli orchestrated FAK signaling activation with subsequent activation of the fetal cardiac gene program in the chronic phase of infection, highlighting FAK as an attractive target for Chagas disease therapy.

Formononetin alleviates diabetic cardiomyopathy by inhibiting oxidative stress and upregulating SIRT1 in rats

Objective: To evaluate the effect of formononetin on type 2 diabetic cardiomyopathy. Methods: Diabetes was induced by feeding high-fat diet for 2 weeks and administration of 35 mg/kg of streptozotocin in rats. Formononetin was administered at 10, 20 and 40 mg/kg for 16 weeks once a day. Plasma glucose, lipid parameters, and cardiac markers in blood samples were measured. Body weight and relative heart weight were recorded. Hemodynamic parameters, oxidative stress parameters and silence information regulator 1 (SIRT1) expression in cardiac tissue were estimated. Histopathological changes in cardiac tissue were also observed. Results: Formononetin significantly reduced the levels of glucose, triglycerides, cholesterol, low density lipoprotein, creatine kinase-MB, lactate dehydrogenase and aspartate aminotransferase. In addition, formononetin significantly improved hemodynamic parameters, alleviated oxidative stress and increased SIRT1 expression. Conclusions: The study indicates that formononetin can improve hyperglycemia and hyperlipemia, reduce oxidative stress and increase SIRT1 expression. It can be a potential therapeutic agent for diabetic cardiomyopathy.

Aliskiren attenuates cardiac dysfunction by modulation of the mTOR and apoptosis pathways

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.

Finasteride promotes worsening of the cardiac deleterious effects of nandrolone decanoate and protects against genotoxic and cytotoxic damage

Metabolism of anabolic androgenic steroids is important for its physiological effects. The aim was to investigate the effects of finasteride (a 5α-reductase inhibitor - 5αR) on cardiac and mutagenic effects promoted by ND. Male Wistar rats were separated into three groups: CONT, received the vehicles of ND and finasteride (Peanut oil+Saline); DECA group, received ND (20 mg.kg.week-1, i.m.), and DECAF received ND and finasteride (100 µg.kg-1, i.p.), for four weeks. After, hypertrophy, cytokines and Angiotensin Converting Enzyme (ACE) activity was determined in heart. Bone marrow was used for micronucleus evaluation. Treatment with ND promotes increase in cardiac hypertrophy, ACE activity and disbalance among pro- and anti-inflammatory cytokines, and combination with finasteride worsened those effects. Association with finasteride ameliorates the toxic effects of ND on bone marrow cells, as was observed by a normalization of the number of micronucleate polychromatic erythrocytes and the mitotic index. Our data demonstrates that deleterious effects promoted by ND are depend, at least in part, of its metabolization. Also, inhibition of 5αR by finasteride present variated effects dependent on organ studied. It can promote increase on cardiac damage and a reduction on mutagenic effects of ND, which demonstrated that dehydronandrolone has diverse role on ND effects..

High-intensity interval training for treating pathological cardiac hypertrophy in spontaneously hypertensive rats: Effects and mechanisms / 中国组织工程研究

BACKGROUND: Regular exercise training possesses health promotion effect. Low-to-moderate intensity continuous aerobic exercise has been an important strategy for primary and secondary prevention of chronic diseases such as hypertension; however, the effect of high-intensity interval training is still debated. OBJECTIVE: To explore the effects of high-intensity interval training on pathological cardiac hypertrophy and investigate the possible mechanism in spontaneously hypertensive rats. METHODS: Thirty male spontaneously hypertensive rats were randomly assigned into a control group and a training group. Fifteen Wistar-Kyoto rats were used as normotensive group. Rats in the normotensive and control group were housed at rest, while those in the training group were subjected to a high-intensity interval training lasting for 8 weeks. After experiment, blood pressure was detected using a non-invasive blood pressure tester, and cardiac structure and function were measured by echocardiogram. Histopathological detection was performed by hematoxylin-eosin and Masson staining to determine myocardial cross-sectional area. mRNA expression of fetal genes including atrial natriuretic peptide and brain natriuretic peptide were detected by RT-PCR. Protein expression of PI3-K, Akt, CnAβ and NFATc3 was detected using western blot assay. RESULTS AND CONCLUSION: Compared with the normotensive group, the blood pressure level was significantly elevated (P 0.05) in the control group. Compared with the control group, the blood systolic pressure was lowered (P 0.05). Therefore, the 8-week high-intensity interval training can induce the transfer from pathological hypertrophy to physiological hypertrophy and enhance heart function in spontaneously hypertensive rats via the activation of PI3-K/Akt signal transduction pathway; however, the Cn/NFAT pathway cannot be inhibited.

Effects of cistanche phenylethanol glycosides on the cardiac hypertrophy and PI3K/PKB signaling pathway in rats with pressure overload / 中国药理学通报

Aim To investigate the inhibitory effect of cistanche phenylethanol glycosides (CPhGs) on cardiac hypertrophy in rats caused by pressure overload and its related mechanism. Methods Male SD rats(n =70) were randomly divided into control group (Con), sham operation group (Sham), model group (Mod), positive control group (Vst), and different CPhGs dosage (125, 250, 500 mg • kg-1) groups. Cardiac ultrasound indexes, heart-weight to body-weight index (HWI), cardiac histopathological changes, and the area of myocardical cells (AMC) were detected. Plasma ET-1 and BNP levels were detected by Elisa, and protein expressions of phosphorylated PI3K(p-PI3K), PI3K, phosphorylated PKB (p-pKB) and PKB were detected by Western blot. Results Compared with Mod group, LVPWT, HWI, plasma ET-1, BNP and AMC decreased to different degrees. LVEDD, LVEF, LVFS, the protein expressions of myocardial tissues pPI3K and p-PKB increased to different degrees in CPhGs groups. Moreover, the indexes of CPhGs 250 and 500 mg • kg-1 groups were significantly improved compared to those of Mod group (P < 0. 05 or 0. 01). Compared with Vst group, there were no significant difference in CPhGs 500 mg • kg-1 group. Conclusions CPhGs could inhibit cardiac hypertrophy in rats induced by pressure overload, which might be related to the activation of PI3K/PKB signaling pathway.

Role and mechanism of platelet-derived growth factor/AKT pathway in pressure overload-induced ventricular remodeling / 中国临床药理学与治疗学

AIM: To analyze the role and mechanism of PDGF/AKT pathway in pressure overload-induced ventricular remodeling. METHODS: A total of 55 C57BL/6 female mice were selected to establish aortic arch narrowing model. Forty-five models were successfully modeled. The randomized digital table method was used to divide the models into sham operation group, DMSO group and experimental group. The sham operation group was opened after chest operation. The suture was performed without aortic coarctation (TAC). After 24 hours of thoracotomy, 200 μL of PBS solution and 50 μL of DMSO were administered. The DMSO group was given 200 μL of PBS solution and 50 μL of DMSO 24 h after operation. The experimental group was given PBS solution 200 μL plus AG1296 50 μL 24 h after TAC to observe the heart function and myocardial histopathology of mice. Lentiviral infection was established to identify and culture HUVEC cells with different expression of PDGF gene. According to different treatments, the cells were divided into control group, PDGF group, shRNA group and PDGF+IMA group to detect the expression of p-AKT and t-AKT protein in HUVEC cells. RESULTS:LVESV, LVEDV, LVESD and LVEDD were increased in DMSO group as compared with sham operation group, while EF and FS of DMSO group were lower than those in sham operation group. LVESV, LVEDV, LVESD and LVEDD were lower in experimental group than those in DMSO group, while EF and FS in experimental group were higher than those in DMSO group. The difference was statistically significant (P<0.05). The sham operation group had neatly arranged myocardial tissue and normal interstitial; the DMSO group had irregular morphology, inflammatory cell infiltration, cell gap was enlarged, and the nucleus was deeply stained. The number of expanded or necrotic cells in experimental group decreased, the gap became smaller, and the inflammatory infiltration decreased. The cross-sectional area of myocardial cells in DMSO group was higher than that in sham operation group. The cross-sectional area of the myocardial cells in experimental group was lower than that in DMSO group (P<0.05). The expression of p-AKT and t-AKT protein in PDGF+IMA group was significantly higher than that in PDGF group and shRNA group, the difference was statistically significant (P<0.05). CONCLUSION:PDGF can accelerate ventricular remodeling induced by pressure overload and promote the formation of myocardial fibrosis, while inhibiting PDGF/AKT pathway can improve myocardial cell hypertrophy.

Formononetin alleviates diabetic cardiomyopathy by inhibiting oxidative stress and upregulating SIRT1 in rats

Objective: To evaluate the effect of formononetin on type 2 diabetic cardiomyopathy.Methods: Diabetes was induced by feeding high-fat diet for 2 weeks and administration of 35 mg/kg of streptozotocin in rats. Formononetin was administered at 10, 20 and 40 mg/kg for 16 weeks once a day. Plasma glucose, lipid parameters, and cardiac markers in blood samples were measured. Body weight and relative heart weight were recorded. Hemodynamic parameters, oxidative stress parameters and silence information regulator 1 (SIRT1) expression in cardiac tissue were estimated. Histopathological changes in cardiac tissue were also observed. Results: Formononetin significantly reduced the levels of glucose, triglycerides, cholesterol, low density lipoprotein, creatine kinase-MB, lactate dehydrogenase and aspartate aminotransferase. In addition, formononetin significantly improved hemodynamic parameters, alleviated oxidative stress and increased SIRT1 expression. Conclusions: The study indicates that formononetin can improve hyperglycemia and hyperlipemia, reduce oxidative stress and increase SIRT1 expression. It can be a potential therapeutic agent for diabetic cardiomyopathy.

Effects of difluoromethylalanine on cardiac hypertrophy and endoplasmic reticulum stress in type 2 diabetic rats / 中国药理学通报

Aim: To investigate the protective effects of difluoromethylornithine (DFMO) on cardiac hypertrophy and to explore its influence on the protein expression of GRP78 and CHOP in type 2 diabetic rats. Methods: The type 2 diabetic mellitus (T2DM) rat model was induced by 4 weeks' high sucrose-high fat diet feeding and one-time intraperitoneal injection of streptozotocin. Rats were randomly divided into three groups:control group, T2DM model group and DFMO treatment group. Rats of treatment group were treated with 2% DFMO drinking for 12 weeks. The changes in blood glucose and cardiac index were calculated. Myocardium superoxide dismutase (SOD), malondialdehyde (MDA) and the total antioxidant capacity (T- A0C) were determined. The morphological changes were observed by Masson staining, and the protein expressions of GRP78 and CHOP were measured by Western blot. Results: Compared with T2DM model group, the blood glucose, cardiac index and the degree of myocardial fibrosis significantly decreased (P < 0. 05), the content of MDA decreased and the activity of SOD and T-AOC increased. Meanwhile, the protein expressions of GRP78 and CHOP were down-regulated in treatment group (P < 0. 05). Conclusions: DFMO exerts protective effects on cardiac hypertrophy in T2DM rats, which may be related to its function of the down-regulation of protein expression of GRP78 and CHOP and inhibition of endoplasmic reticulum stress.

Effect of endostatin overexpression on angiotensin II-induced cardiac hypertrophy in rats / 中华医学杂志(英文版)

Background@#Endostatin, a biologically active fragment of collagen XVIII, has been observed in patients with ischemic heart disease. The aim of the present study was to investigate whether endostatin overexpression could attenuate cardiac hypertrophy by inhibiting the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling pathway.@*Methods@#This study was examined in vivo in rats and in vitro in primary neonatal rat cardiomyocytes treated with angiotensin (Ang) II to model cardiac hypertrophy. Twenty-four male Sprague-Dawley rats were randomized into adenovirus (Ad)-green fluorescent protein, Ang II, Ad-endostatin, and Ang II + Ad-endostatin groups (n = 6 in each group). Four weeks later, all the rats were weighed and sacrificed after transthoracic echocardiography. Cardiac function was evaluated by transthoracic echocardiography, cardiomyocyte size was evaluated by hematoxylin-eosin staining. Levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were evaluated by quantitative reverse-transcription polymerase chain reaction or Western blotting, PKA level was evaluated by Western blotting, and cAMP level was evaluated by enzyme-linked immunosorbent assay. Statistical significance among multiple groups was evaluated by one-way analysis of variance.@*Results@#Endostatin overexpression reduced the increases in left ventricle (LV) mass (P = 0.0063), LV mass/body weight (BW) (P = 0.0013), interventricular septal thickness (IVS) in diastole (P = 0.0013), IVS in systole (P = 0.0056), left ventricular posterior wall thickness (LVPW) in diastole (P = 0.0291), LVPW in systole (P = 0.0080), heart weight (HW) (P = 0.0138), HW/BW (P = 0.0001), and HW/tibial length (P = 0.0372) in Ang II-treated rats. In addition, endostatin overexpression reduced cardiomyocyte cross-sectional area expansion, and reduced the levels of ANP and BNP in Ang II-treated rats (P = 0.0251 and 0.0477 for messenger RNA [mRNA]), and primary neonatal rat cardiomyocytes (P = 0.0188 and P = 0.0024 for mRNA; P = 0.0023 and 0.0013 for protein, respectively). Additionally, endostatin overexpression reduced the increase of cAMP (P = 0.0054) and PKA (P = 0.0328) levels in cardiomyocytes treated with Ang II. Treatment with cAMP reversed the effects of endostatin overexpression on ANP (P = 0.0263) and BNP (P = 0.0322) levels in cardiomyocytes induced by Ang II.@*Conclusion@#Endostatin overexpression could alleviate cardiac hypertrophy by inhibiting the cAMP-PKA signaling pathway.

MicroRNA-199a-3p Enhances Cardiomyocyte Hypertrophy through Targeting Retinoblastoma Transcriptional Corespressor 1 / 中山大学学报(医学科学版)

@#【Objective】To investigate the role and the potential target of miR-199a-3p in mouse cardiac hypertrophy.【Methods】Neonatal mouse ventricular cardiomyocytes（NMVC）were isolated from the hearts of 0- 3- day- old newborn C57BL/6 mice. MiR-199a-3p mimic and retinoblastoma transcriptional corepressor 1（Rb-1）siRNA were transfected in? to NMVC to elevate the level of miR-199a-3p and inhibit Rb-1 expression，respectively. NMVC were stained with FITC- phalloidin solution to determine the size of NMVC. Dual luciferase reporter assay was performed to identify the interaction between miR- 199a- 3p and the 3’UTR of Rb- 1. mRNA and protein expression of cardiac hypertrophy associated genes were determined by RT-qPCR and Western blotting assay，respectively.【Results】（1）Over-expression of miR-199a-3pcould significantly enhance the expression of cardiac hypertrophy-related genes in NMVC ；（2）Dual-luciferase reporter assay results verified that miR- 199a-3p can interact with the 3’UTR of Rb-1. MiR-199a-3p could suppress Rb-1 ex? pression at the post-transcriptional level；（3）Functionally，miR-199a-3p mimic，consistent with Rb-1 siRNA，could increase cell size and the expression of Nppa，Acta1 and Myh7 in NMVC，and promote the nuclear translocation of E2f2 in NMVC.【Conclusions】MiR-199a-3p promotes the entry of E2f2 into the nucleus through inhibiting the expression of Rb-1，contributing to cardiomyocyte hypertrophy.

Effect of Dracocephalum Heterophyllum Benth Flavonoid on Myocardial Cell Hypertrophy Induced by Noradrenaline in Rats / 医药导报

Objective To probe into effect of Dracocephalum heterophyllum Benth flavonoids(DHBF) on noradrenaline (NE) -induced myocardial cell hypertrophy, and to study the mechanism. Methods SD neonatal rat myocardial cells were cultured in vitro. The experiment was divided into normal control group, model control group (NE 2 μmol·L-1) , prazosin group (prazosin 50 μmol·L-1) ,low-,medium-and high-dose DHBF group (DHBF 10,25,50 μmol·L-1) .Cardiomyocyte hypertrophy were induced by NE(2 μmol·L-1) . DHBF and prazosin were intervened respectively. CCK-8 method was used to observe the activity of myocardial cells. RT-PCR technique was used to detect the expression of mRNA of cardiac hypertrophy c-jun and brain natriuretic peptide (BNP) ,and Western blotting was used to detect the protein expression of CaN and NFAT-3 in myocardial cells. Confocal laser scanning was used to detect the surface area of myocardial cell. Results Compared with the normal control group, survival rate of cardiomyocytes was significantly decreased, expression of mRNA of c-jun and BNP significantly upregulated, protein expression of CaN and NFAT-3 decreased, and surface area increased in model control group (P<0.05) . Compared with the cell of model control group, low-,medium-and high-dose DHBF significantly reversed NE-induced decrease of the survival rate, increase of surface area, increase of c-jun and BNP mRNA, and increase of CaN and NFAT-3 protein expression (P<0.05) . Conclusion DHBF can improve the survival rate of cardiac hypertrophy patients, down-regulate c-jun and BNP mRNA expression, decrease CaN and NFAT-3 protein expression, and decrease NE-induced surface area of cardiomyocytes.

Aconitine ameliorates cardiomyocyte hypertrophy induced by angiotensin Ⅱ / 中国中药杂志

This paper was aimed to investigate the inhibitory effect of aconitine(AC) on angiotensin Ⅱ(Ang Ⅱ)-induced H9 c2 cell hypertrophy and explore its mechanism of action. The model of hypertrophy was induced by Ang Ⅱ(1×10-6 mol·L-1),and cardiomyocytes were incubated with different concentrations of AC. Western blot was used to quantify the protein expression levels of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),β-myosin heavy chain(β-MHC),and α-smooth muscle actin(α-SMA). Real-time quantitative PCR(qRT-PCR) was used to quantify the mRNA expression levels of cardiac hypertrophic markers ANP,BNP and β-MHC. In addition,the fluorescence intensity of the F-actin marker,an important component of myofibrils,was detected by using laser confocal microscope. AC could significantly reverse the increase of total protein content in H9 c2 cells induced by Ang Ⅱ; qRT-PCR results showed that AC could significantly inhibit the ANP,BNP and β-MHC mRNA up-regulation induced by AngⅡ. Western blot results showed that AC could significantly inhibit the ANP,BNP and β-MHC protein up-regulation induced by AngⅡ. In addition,F-actin expression induced by Ang Ⅱ could be inhibited by AC,and multiple indicators of cardiomyocyte hypertrophy induced by Ang Ⅱ could be down-regulated,indicating that AC may inhibit cardiac hypertrophy by inhibiting the expression of hypertrophic factors,providing new clues for exploring the cardiovascular protection of AC.