Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3β signaling

The lysosomal cysteine peptidase cathepsin L (CTSL) is an important lysosomal proteinase involved in a variety of cellular functions including intracellular protein turnover, epidermal homeostasis, and hair development. Deficiency of CTSL in mice results in a progressive dilated cardiomyopathy. In the present study, we tested the hypothesis that cardiac overexpression of human CTSL in the murine heart would protect against cardiac hypertrophy in vivo. The effects of constitutive human CTSL expression on cardiac hypertrophy were investigated using in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding (AB) in CTSL transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by two-dimensional and M-mode echocardiography as well as by molecular and pathological analyses of heart samples. Constitutive overexpression of human CTSL in the murine heart attenuated the hypertrophic response, markedly reduced apoptosis, and fibrosis. Cardiac function was also preserved in hearts with increased CTSL levels in response to hypertrophic stimuli. These beneficial effects were associated with attenuation of the Akt/GSK3β signaling cascade. Our in vitro studies further confirmed that CTSL expression in cardiomyocytes blunts cardiac hypertrophy through blocking of Akt/GSK3β signaling. The study indicates that CTSL improves cardiac function and inhibits cardiac hypertrophy, inflammation, and fibrosis through blocking Akt/GSK3β signaling. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Qizhu Tang, Jun Cai and Wei Wang contributed equally to this work.     

The Wnt/Frizzled pathway as a therapeutic target for cardiac hypertrophy: where do we stand?

Cardiac hypertrophy is an enlargement of the heart muscle in response to wall stress. This hypertrophic response often leads to heart failure. In recent years, several studies have shown the involvement of Wnt signalling in hypertrophic growth. In this review, the role of Wnt signalling and the possibilities for therapeutic interventions are discussed. In healthy adult heart tissue, Wnt signalling is very low. However, under pathological condition such as hypertension, Wnt signalling is activated. In recent years, it has become clear that both β-catenin-dependent signalling and β-catenin-independent signalling are involved in hypertrophic growth. Several studies, both in vitro and in vivo, have shown that genetic interventions in Wnt signalling at different levels resulted in an attenuated or diminished hypertrophic response. Therefore, inhibition of Wnt signalling could provide a new therapeutic strategy for cardiac hypertrophy, but further research on the Wnts and Frizzleds involved in the different forms of cardiac hypertrophy will be needed to achieve this goal.     

Cinnamaldehyde attenuates pressure overload-induced cardiac hypertrophy

Background: Cinnamaldehyde is a major bioactive compound isolated from the leaves of Cinnamomum osmophloeum. Studies have demonstrated that cinnamaldehyde has anti-bacterial activity, anti-tumorigenic effect, immunomodulatory effect, anti-fungal activity, anti-oxidative effect, anti-inflammatory and anti-diabetic effect. It has been proven that Cinnamaldehyde improves ischemia/reperfusion injury of pre-treatment. However, little is known about the effect of cinnamaldehyde on cardiac hypertrophy. Methods: Aortic banding (AB) was performed to induce cardiac hypertrophy in mice. Cinnamaldehyde premixed in diets was administered to mice after one week of AB. Echocardiography and catheter-based measurements of hemodynamic parameters were performed at week 7 after starting cinnamaldehyde (8 weeks after surgery). The extent of cardiac hypertrophy was evaluated by pathological and molecular analyses of heart samples. Meanwhile, the effect of cinnamaldehyde on myocardial hypertrophy, fibrosis and dysfunction induced by AB was investigated, as was assessed by heart weigh/body weight, lung weight/body weight, heart weight/tibia length, echocardiographic and haemodynamic parameters, histological analysis, and gene expression of hypertrophic and fibrotic markers. Results: Our data demonstrated that echocardiography and catheter-based measurements of hemodynamic parameters at week 7 revealed the amelioration of systolic and diastolic abnormalities by cinnamaldehyde intervention. Cardiac fibrosis in AB mice was also decreased by cinnamaldehyde. Moreover, the beneficial effect of cinnamaldehyde was associated with the normalization in gene expression of hypertrophic and fibrotic markers. Further studies showed that pressure overload significantly induced the activation of extracellular signal-regulated kinase (ERK) signaling pathway, which was blocked by cinnamaldehyde. Conclusion: Cinnamaldehyde may be able to retard the progression of cardiac hypertrophy and fibrosis, probably via blocking ERK signaling pathway.     

Angiotensin II-induced dilated cardiomyopathy in Balb/c but not C57BL/6J mice

Balb/c mice, which are T-helper lymphocyte 2 (Th2) responders, are highly susceptible to infectious and non-infectious heart diseases, whereas C57BL/6 mice (Th1 responders) are not. Angiotensin II (Ang II) is not only a vasopressor but also a pro-inflammatory factor that leads to cardiac hypertrophy, fibrosis and dysfunction. We hypothesized that Ang II exacerbates cardiac damage in Balb/c but not in C57BL/6 mice even though both strains have a similar level of hypertension. Twelve-week-old male C57BL/6J and Balb/c mice received either vehicle or Ang II (1.4 mg kg(-1) day(-1), s.c. via osmotic minipump) for 8 weeks. At baseline, Balb/c mice exhibited the following: (1) a lower heart rate; (2) an enlarged left ventricular chamber; (3) a lower ejection fraction and shortening fraction; and (4) twice the left ventricular collagen deposition of age-matched C57BL/6J mice. Angiotensin II raised systolic blood pressure (to ～150 mmHg) and induced cardiomyocyte hypertrophy in a similar manner in both strains. While C57BL/6J mice developed compensatory concentric hypertrophy and fibrosis in response to Ang II, Balb/c mice demonstrated severe left ventricular chamber dilatation, wall thinning and fibrosis, leading to congestive heart failure as evidenced by dramatically decreased ejection fraction and lung congestion (significant increase in lung weight), which are both characteristic of dilated cardiomyopathy. Our study suggests that the Th phenotype plays an active role in cardiac remodelling and function both in basal conditions and in hypertension. Angiotensin II-induced dilated cardiomyopathy in Balb/c mice is an ideal animal model for studying the impact of the adaptive immune system on cardiac remodelling and function and for testing strategies to prevent or treat hypertension-associated heart failure.     

大鼠肥厚心脏卸负荷后心室逆重塑相关的信号通路改变

目的： 研究肥厚心脏心室重塑及逆重塑过程中Akt/GSK3β、MAPKs和NF-κB信号通路的变化。方法：以Lewis大鼠行腹主动脉缩窄术,建立压力超负荷性心肌肥厚模型。将肥厚心脏移植到同源Lewis大鼠腹部,建立压力卸负荷模型。对各组心肌取材进行病理学评价。Western blotting法检测心肌组织中相关信号通路蛋白的表达。结果：在心肌肥厚大鼠心脏中Akt/GSK3β、MAPKs和NF-κB磷酸化水平均显著升高,移植卸负荷后除p38 MAPK和JNK外,其它蛋白磷酸化水平均显著降低。结论：肥厚心脏经异位移植卸负荷后产生逆重塑现象,Akt/GSK3β、ERK1/2和NF-κB信号通路的改变参与其中,该结果为临床心室逆重塑的研究提供了实验依据。     

G protein-coupled receptor signalling in in vivo cardiac overload.

Cardiac myocytes respond to biomechanical stress by initiating cellular processes that lead to hypertrophy. Although cardiac hypertrophy is a response to increased stress on the heart, it is associated with elevated plasma catecholamine levels and an increase in cardiac morbidity and mortality. Understanding the cellular signals that initiate the hypertrophic response will be of critical importance to identify pathways that mediate the maladaptive deterioration of the hypertrophic heart to one of cardiac failure. This review will focus on the role of G protein-coupled receptors in the activation of signalling pathways in the heart, such as the mitogen activated protein kinase and phosphoinositide-3 kinase pathways.     

Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes

Rat and sheep cardiac myocytes become binucleate as they complete the 'terminal differentiation' process soon after birth and are not able to divide thereafter. Angiotensin II (Ang II) is known to stimulate hypertrophic changes in rodent cardiomyocytes under both in vivo and in vitro conditions via the AT₁ receptor and intracellular extracellular regulated kinase (ERK) signalling cascade. We sought to develop culture methods for immature sheep cardiomyocytes in order to test the hypothesis that Ang II is a hypertrophic agent in the immature myocardium of the sheep. We isolated fetal sheep cardiomyocytes and cultured them for 96 h, added Ang II and phenylephrine (PE) for 48 h, and measured footprint area and proliferation (5-bromo-2'-deoxyuridine (BrdU) uptake) separately in mono- vs. binucleate myocytes. We found that neither Ang II nor PE changed the footprint area of mononucleated cells. PE stimulated an increase in footprint area of binucleate cells but Ang II did not. Ang II increased myocyte BrdU uptake compared to serum free conditions, but PE did not affect BrdU uptake. The MAP kinase kinase (MEK) inhibitor UO126 prevented BrdU uptake in Ang II-stimulated cells and prevented cell hypertrophy in PE-stimulated cells. This paper establishes culture methods for immature sheep cardiomyocytes and reports that: (1) Ang II is not a hypertrophic agent; (2) Ang II stimulates hyperplastic growth among mononucleate myocytes; (3) PE is a hypertrophic agent in binucleate myocytes; and (4) the ERK cascade is required for the proliferation effect of Ang II and the hypertrophic effect of PE.     

心脏糜酶活性改变在心肌肥厚患者心肌纤维化中的意义

目的： 观察心脏糜酶与心肌肥厚患者心肌组织胶原合成和心肌纤维化的关系。方法: 应用病理检查、放射免疫、计算机分析和逆转录-聚合酶链式反应等方法，检测心肌肥厚患者（心肌肥厚组）和正常人（对照组）心脏糜酶活性、心肌局部血管紧张素II（Ang II）水平、心肌胶原容积分数（CVF）、心肌血管周围胶原面积比（PVCA）及心肌组织I型和III型胶原mRNA表达。心脏糜酶活性和心肌局部Ang II水平与CVF及PVCA之间的关系采用相关分析。结果: 心肌肥厚组心脏糜酶活性为(0.27±0.06) kU/g蛋白，对照组为(0.12±0.06) kU/g蛋白，心肌肥厚组心脏糜酶活性明显高于对照组（P<0.01）。心肌肥厚组心肌组织匀浆液Ang II水平为(179.3±36.1) ng/g心肌组织，对照组心肌组织匀浆液Ang II水平为(103.2±13.6) ng/g心肌组织，心肌肥厚组心肌组织Ang II水平明显高于对照组（P<0.01）。心肌肥厚组CVF为39.5%±9.8%，对照组为20.9%±8.2%，心肌肥厚组明显高于对照组（P<0.01）；心肌肥厚组PVCA为1.98±1.05，对照组为0.41±0.12，心肌肥厚组也明显高于对照组（P<0.01）。心肌肥厚患者心肌组织I型胶原及III型胶原mRNA表达相对含量均明显高于正常人（均P<0.01）。心脏糜酶活性与CVF及PVCA呈明显正相关（相关系数分别为0.52和0.69，P<0.05和P<0.01）。心肌局部Ang II水平也与CVF及PVCA呈明显正相关（相关系数分别为0.49和0.58，均P<0.05）。结论: 心脏糜酶可增加胶原的合成，参与细胞外基质的形成和降解，促进心肌纤维化。     

Neuropeptide Y mediates cardiac hypertrophy through microRNA-216b/FoxO4 signaling pathway

Cardiac hypertrophy (CH) is a major risk factor for heart failure accompanied by maladaptive cardiac remodeling. The role and potential mechanism of neuropeptide Y (NPY) in CH are still unclear. We will explore the role and the mechanism of NPY inactivation (NPY-I) in CH caused by pressure overload. Abdominal aortic constriction (AAC) was used to induce CH model in rats. NPY or angiotensin II (Ang II) was used to trigger CH model in vitro in neonatal rat ventricular myocytes (NRVMs). We found that NPY was increased in the heart and plasma of hypertrophic rats. However, Ang II did not increase NPY expression in cardiomyocytes. NPY-I attenuated CH as decreasing CH-related markers (ANP, BNP and β-MHC mRNA) level, reducing cell surface area, and restoring cardiac function. NPY inactivation increased miR-216b and decreased FoxO4 expression in CH heart. Moreover, NPY decreased miR-216b and increased FoxO4 expression in NRVMs which were reversed by NPY type 1 receptor (NPY1R) antagonist BIBO3304. MiR-216b mimic and FoxO4 siRNA (small interfering RNA) inhibited NPY/Ang II-induced myocardial hypertrophy in vitro. Meanwhile, BIBO3304 reversed the pro-hypertrophy effect of NPY in vitro. Collectively, NPY deficiency attenuated CH by NPY1R-miR-216b-FoxO4 axis. These findings suggested that NPY would be a potential therapeutic target for the prevention and treatment of cardiac hypertrophy.     

高血压与2型糖尿病协同作用导致小鼠心功能障碍和心肌重塑

目的:研究高血压与2型糖尿病联合作用是否能导致小鼠心功能障碍和心肌重塑。方法:将14周龄的2型糖尿病和非糖尿病小鼠经血管紧张素Ⅱ(Ang Ⅱ)给药4周诱导小鼠形成轻度高血压。运用超声波心动描记术和多巴酚丁胺负荷试验评价小鼠左心室功能;HE染色分析左心室心肌细胞的肥大作用;Western blotting测定心肌组织中磷酸化腺苷酸活化蛋白激酶(p-AMPK)的表达水平。结果:与非糖尿病小鼠比较,糖尿病小鼠(DM组)的心脏功能和心肌结构无明显变化;Ang Ⅱ给药不影响2型糖尿病小鼠和非糖尿病小鼠的体重和血糖含量,但血压明显增高;左心室重量和心肌细胞表面积结果分析显示,Ang Ⅱ诱导2型糖尿病小鼠的左心室肥大程度显著大于Ang Ⅱ组;Ang Ⅱ给药的2型糖尿病小鼠左心室的缩短分数和射血分数显著降低,而Ang Ⅱ组小鼠无明显变化;Western blotting结果显示Ang Ⅱ组、DM组和DM+Ang Ⅱ组小鼠左心室组织中p-AMPK的表达量显著降低。结论:2型糖尿病小鼠心脏功能和心肌结构无明显变化,当高血压存在时2型糖尿病小鼠容易发生心脏功能障碍和心肌重塑,提示高血压是2型糖尿病小鼠心脏功能障碍和心肌重塑的关键因子。     

miR-133a-3p attenuates cardiomyocyte hypertrophy through inhibiting pyroptosis activation by targeting IKKε

ObjectiveCardiac hypertrophy is an adaptive response to physiological and pathological stimuli, the latter of which frequently progresses to valvulopathy, heart failure and sudden death. Recent reports revealed that pyroptosis is involved in regulating multiple cardiovascular diseases progression, including cardiac hypertrophy. However, the underlying mechanisms remain poorly understood. This study aims to extensively investigate the regulation of miR-133a-3p on pyroptosis in angiotensin II (Ang II)-induced cardiac hypertrophyin vitro.MethodsThe in vitro model of cardiac hypertrophy was induced by Ang II, which was validated by qPCR combined with measurement of cell surface area by immunofluorescence assay. CCK-8 assay and Hochest33342/PI staining was performed to assess pyroptosis. Dual luciferase reporter system was used to verify the direct interaction between miR-133a-3p and IKKε. The effects of miR-133a-3p/IKKε on pyroptosis activation and cardiac hypertrophy markers (Caspase-1, NLRP3, IL-1β, IL-18, GSDMD, ASC, ANP, BNP and β-MHC) were evaluated by western blot, ELISA and qPCR.ResultsAng II treatment could induce cardiomyocyte hypertrophy and pyroptosis. The expression of miR-133a-3p was repressed in Ang II-treated HCM cells, and its overexpression could attenuate both pyroptosis and cardiac hypertrophyin vitro. Additionally, IKKε expression was significantly up-regulated in Ang II-induced HCM cells. Dual luciferase reporter system and qPCR validated that miR-133a-3p directly targeted the 3’-UTR of IKKε and suppressed its expression. Moreover, IKKε overexpression impaired the protective function of miR-133a-3p in cardiomyocyte hypertrophy.ConclusionCollectively, miR-133a-3p attenuates Ang II induced cardiomyocyte hypertrophy via inhibition of pyroptosis by targeting IKKε. Therefore, miR-133a-3p up-regulation may be a promising strategy for cardiac hypertrophy treatment.     

The alteration of protein prenylation induces cardiomyocyte hypertrophy through Rheb–mTORC1 signalling and leads to chronic heart failure

G protein‐regulated cell function is crucial for cardiomyocytes, and any deregulation of its gene expression or protein modification can lead to pathological cardiac hypertrophy. Herein, we report that protein prenylation, a lipidic modification of G proteins that facilitates their association with the cell membrane, might control the process of cardiomyocyte hypertrophy. We found that geranylgeranyl diphosphate synthase (GGPPS), a key enzyme involved in protein prenylation, played a critical role in postnatal heart growth by regulating cardiomyocyte size. Cardiac‐specific knockout of GGPPS in mice led to spontaneous cardiac hypertrophy, beginning from week 4, accompanied by the persistent enlargement of cardiomyocytes. This hypertrophic effect occurred by altered prenylation of G proteins. Evaluation of the prenylation, membrane association and hydrophobicity showed that Rheb was hyperactivated and increased mTORC1 signalling pathway after GGPPS deletion. Protein farnesylation or mTORC1 inhibition blocked GGPPS knockdown‐induced mTORC1 activation and suppressed the larger neonatal rat ventricle myocyte size and cardiomyocyte hypertrophy in vivo, demonstrating a central role of the FPP–Rheb–mTORC1 axis for GGPPS deficiency‐induced cardiomyocyte hypertrophy. The sustained cardiomyocyte hypertrophy progressively provoked cardiac decompensation and dysfunction, ultimately causing heart failure and adult death. Importantly, GGPPS was down‐regulated in the hypertrophic hearts of mice subjected to transverse aortic constriction (TAC) and in failing human hearts. Moreover, HPLC–MS/MS detection revealed that the myocardial farnesyl diphosphate (FPP):geranylgeranyl diphosphate (GGPP) ratio was enhanced after pressure overload. Our observations conclude that the alteration of protein prenylation promotes cardiomyocyte hypertrophic growth, which acts as a potential cause for pathogenesis of heart failure and may provide a new molecular target for hypertrophic heart disease clinical therapy. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Effects of different angiotensin Ⅱ type 1 receptor blockers on regulation of ACE-Ang Ⅱ-AT1 and ACE2-Ang( 1-7)-Mas axes in pressure overload-induced cardiac remodeling in male mice

AIM: To examine and compare the effects of several ARBs that are widely used in clinics,on the ACE-Ang II-AT1 receptor and the ACE2-Ang(1-7)-Mas axis during the development of cardiac remodeling after pressure overload. METHODS: All of the mice used in the study underwent transverse aortic constriction( TAC) or sham operation for 2 or 4 weeks. A solution of either ARBs or saline was administered through a stomach tube 3 days before the operation. Meanwhile,to eliminate the influence of Ang II,a recombinant adenovirus expressing small interfering RNAs targeting angiotensinogen( Ad-ATG si RNA) was injected via the tail vein. The surgery was then performed and the drug was administered as mentioned above. Cardiac function and remodeling were evaluated by echocardiography,hemodynamic measurements and cardiac histology. Western blotting was used to determine the protein expression levels.Meanwhile,we performed similar experiments using ARBs with or without ATG si RNA in cardiomyocytes induced by mechanical stretch. RESULTS: Although all of the six ARBs,none of which repressed the elevation of left ventricular pressure after TAC,attenuated the development of cardiac hypertrophy and heart failure in the wild-type mice,the degree of attenuation by Olmesartan,Candesartan and Losartan tended to be larger than that of the other three drugs tested. Additionally,the degree of downregulation of the ACEAng II-AT1 axis and upregulation of the ACE2-Ang(1-7)-Mas axis was higher in response to Olmesartan,Candesartan and Losartan administration in vivo and in vitro. Additionally,Olmesartan had a larger influence when administered long term. However,the expression of ACE was not influenced by the administration of ARBs in vivo and in vitro. Moreover,in angiotensinogen-knockdown mice,TAC-induced cardiac hypertrophy and heart failure were inhibited by Olmesartan,Candesartan and Losartan but not by Telmisartan,Valsartan and Irbesartan administration. Furthermore,only Olmesartan and Candesartan could downregulate the ACE-Ang II-AT1 axis and upregulate the ACE2-Ang(1-7)-Mas axis in vitro. CONCLUSION: Olmesartan,Candesartan and Losartan could effectively inhibit pressure overload-induced cardiac remodeling even when with knockdown of Ang II,possibly through upregulation of the expression of the ACE2-Ang(1-7)-Mas axis and downregulation of the expression of the ACE-Ang II-AT1 axis. In contrast,Telmisartan,Valsartan and Irbesartan only played a role in the presence of Ang II,and Losartan had no effect in the presence of Ang II in vitro.     

Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart

Angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin-converting enzyme (ACE), converts angiotensin (Ang) I to Ang(1-9) and Ang II to Ang(1-7), but does not directly process Ang I to Ang II. Cardiac function is compromised in ACE2 null mice; however, the importance of ACE2 in the processing of angiotensin peptides within the murine heart is not known. We determined the metabolism of angiotensins in wild-type (WT), ACE (ACE(-/-)) and ACE2 null mice (ACE2(-/-)). Angiotensin II was converted almost exclusively to Ang(1-7) in the cardiac membranes of WT and ACE(-/-) strains, although generation of Ang(1-7) was greater in the ACE(-/-) mice (27.4 +/- 4.1 versus 17.5 +/- 3.2 nmol(-1) mg h(-1) for WT). The ACE2 inhibitor MLN4760 significantly attenuated Ang II metabolism and the subsequent formation of Ang(1-7) in both strains. In the ACE2(-/-) hearts, Ang II metabolism and the generation of Ang(1-7) were significantly attenuated; however, the ACE2 inhibitor reduced the residual Ang(1-7)-forming activity in this strain. Angiotensin I was primarily converted to Ang(1-9) (WT, 28.9 +/- 3.1 nmol(-1) mg h(-1); ACE(-/-), 49.8 +/- 5.3 nmol(-1) mg h(-1); and ACE2(-/-), 35.9 +/- 5.4 nmol(-1) mg h(-1)) and to smaller quantities of Ang(1-7) and Ang II. Although the ACE2 inhibitor had no effect on Ang(1-9) formation, the carboxypeptidase A inhibitor benzylsuccinate essentially abolished the formation of Ang(1-9) and increased the levels of Ang I in cardiac membranes. In conclusion, our studies in the murine heart suggest that ACE2 is the primary pathway for the metabolism of Ang II and the subsequent formation of Ang(1-7), a peptide that, in contrast to Ang II, exhibits both antifibrotic and antiproliferative actions.     

Geniposide alleviates pressure overload in cardiac fibrosis with suppressed TGF-β1 pathway

BackgroundCardiac fibrosis is one of the main contributors to the pathogenesis of heart failure. Geniposide (GE), a major iridoid in gardenia fruit extract, has recently been reported to improve skeletal muscle fibrosis through the modulation of inflammation response. This investigation aimed to illuminate the cardio-protective effect and the potential mechanism of GE in cardiac fibrosis.Material and methodsA transverse aortic contraction (TAC) induction mice model was established and GE (0 mg/kg; 10 mg/kg; 20 mg/kg; 40 mg/kg) was administered by oral gavage daily for 4 weeks. Hemodynamic parameters, Masson’s trichrome stain, and hematoxylin-eosin (HE) staining were estimated and cardiomyocyte fibrosis, interstitial collagen levels, and hypertrophic markers were analyzed using qPCR and western blot. In vitro, H9C2 cells were exposed to the Ang II (1 μM) pretreated with GE (0.1 μM, 1 μM, and 10 μM). Cardiomyocyte apoptosis was detected. Moreover, the transforming growth factor β1 (TGF-β1)/Smad2 pathway was assessed in vivo and in vitro.ResultsGE significantly ameliorated TAC-induced cardiac hypertrophy, ventricular remodeling, myocardial fibrosis, and improved cardiac function in vivo, and it inhibited Ang II-induced cardiomyocyte apoptosis in vitro. We further observed that the inflammatory channel TGF-β1/Smad2 pathway was suppressed by GE both in vivo and in vitro.ConclusionThese results indicate that GE inhibited myocardial fibrosis and improved hypertrophic cardiomyocytes with attenuated the TGF-β1/Smad2 pathway and proposed to be an important therapeutic of cardiac fibrosis reduced by TAC.     

Distinct functions of junD in cardiac hypertrophy and heart failure

Cardiac hypertrophic stimuli induce both adaptive and maladaptive growth response pathways in heart. Here we show that mice lacking junD develop less adaptive hypertrophy in heart after mechanical pressure overload, while cardiomyocyte-specific expression of junD in mice results in spontaneous ventricular dilation and decreased contractility. In contrast, fra-1 conditional knock-out mice have a normal hypertrophic response, whereas hearts from fra-1 transgenic mice decompensate prematurely. Moreover, fra-1 transgenic mice simultaneously lacking junD reveal a spontaneous dilated cardiomyopathy associated with increased cardiomyocyte apoptosis and a primary mitochondrial defect. These data suggest that junD promotes both adaptive-protective and maladaptive hypertrophy in heart, depending on its expression levels.     

Regulator of G protein signalling 2 ameliorates angiotensin II-induced hypertension in mice

Angiotensin II (Ang II) activates signalling pathways predominantly through the G-protein-coupled Ang II type 1 receptor (AT(1)R). The regulator of G protein signalling 2 (RGS2) is a negative G protein regulator. We hypothesized that RGS2 deletion changes blood pressure regulation by increasing the response to Ang II. To address this issue, we infused Ang II (0.5 mg kg(-1) day(-1)) chronically into conscious RGS2-deleted (RGS2(-/-)) and wild-type (RGS2(+/+)) mice, measured mean arterial blood pressure and heart rate (HR) with telemetry and assessed vasoreactivity and gene expression of AT(1A), AT(1B) and AT(2) receptors. Angiotensin II infusion increased blood pressure more in RGS2(-/-) than in RGS2(+/+) mice, while HR was not different between the groups, indicating a resetting of the baroreceptor reflex. Urinary catecholamine excretion was similar in Ang II-infused RGS2(-/-) and RGS2(+/+) mice, indicating a minor role of sympathetic tone for blood pressure differences. Myogenic tone and vasoreactivity in response to Ang II, endothelin-1 and phenylephrine were increased in isolated renal interlobar arterioles of RGS2(-/-) mice compared with RGS2(+/+) mice. The AT(1A), AT(1B) and AT(2) receptor gene expression was not different between RGS2(-/-) and RGS2(+/+) mice. Our findings suggest that RGS2 deletion promotes Ang II-dependent hypertension primarily through an increase of myogenic tone and vasoreactivity, probably by sensitization of AT(1) receptors.