CD38 promotes angiotensin II‐induced cardiac hypertrophy

Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and regulated by various signalling pathways. Recently, we observed that mouse embryonic fibroblasts from CD38 knockout mice were significantly resistant to oxidative stress such as H₂O₂‐induced injury and hypoxia/reoxygenation‐induced injury. In addition, we also found that CD38 knockout mice protected heart from ischaemia reperfusion injury through activating SIRT1/FOXOs‐mediated antioxidative stress pathway. However, the role of CD38 in cardiac hypertrophy is not explored. Here, we investigated the roles and mechanisms of CD38 in angiotensin II (Ang‐II)‐induced cardiac hypertrophy. Following 14 days of Ang‐II infusion with osmotic mini‐pumps, a comparable hypertension was generated in both of CD38 knockout and wild‐type mice. However, the cardiac hypertrophy and fibrosis were much more severe in wild‐type mice compared with CD38 knockout mice. Consistently, RNAi‐induced knockdown of CD38 decreased the gene expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and reactive oxygen species generation in Ang‐II‐stimulated H9c2 cells. In addition, the expression of SIRT3 was elevated in CD38 knockdown H9c2 cells, in which SIRT3 may further activate the FOXO3 antioxidant pathway. The intracellular Ca²⁺ release induced by Ang‐II markedly decreased in CD38 knockdown H9c2 cells, which might be associated with the decrease of nuclear translocation of NFATc4 and inhibition of ERK/AKT phosphorylation. We concluded that CD38 plays an essential role in cardiac hypertrophy probably via inhibition of SIRT3 expression and activation of Ca²⁺‐NFAT signalling pathway. Thus, CD38 may be a novel target for treating cardiac hypertrophy.     

Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II

Cardiac hypertrophy is an important risk factor for heart failure. Epidermal growth factor receptor (EGFR) has been found to play a role in the pathogenesis of various cardiovascular diseases. The aim of this current study was to examine the role of EGFR in angiotensin II (Ang II)‐induced cardiac hypertrophy and identify the underlying molecular mechanisms. In this study, we observed that both Ang II and EGF could increase the phospohorylation of EGFR and protein kinase B (AKT)/extracellular signal‐regulated kinase (ERK), and then induce cell hypertrophy in H9c2 cells. Both pharmacological inhibitors and genetic silencing significantly reduced Ang II‐induced EGFR signalling pathway activation, hypertrophic marker overexpression, and cell hypertrophy. In addition, our results showed that Ang II‐induced EGFR activation is mediated by c‐Src phosphorylation. In vivo, Ang II treatment significantly led to cardiac remodelling including cardiac hypertrophy, disorganization and fibrosis, accompanied by the activation of EGFR signalling pathway in the heart tissues, while all these molecular and pathological alterations were attenuated by the oral administration with EGFR inhibitors. In conclusion, the c‐Src‐dependent EGFR activation may play an important role in Ang II‐induced cardiac hypertrophy, and inhibition of EGFR by specific molecules may be an effective strategy for the treatment of Ang II‐associated cardiac diseases.     

Sophocarpine ameliorates cardiac hypertrophy through activation of autophagic responses

ABSTRACT

Mounting evidences indicate that autophagy is an essential homeostatic mechanism to maintain the global cardiac structure function. Sophocarpine (SOP), a major bioactive compound derived from the natural plant Sophora flavescens. However, the role of SOP in cardiac hypertrophy remain to be fully elucidated. In the present study, we tested the hypothesis that SOP protects against Ang II–induced cardiac hypertrophy by mediating the regulation of autophagy. The results demonstrated that SOP attenuated the Ang II–induced cardiac hypertrophy, as assessed by measurements of echocardiography parameters, the ratios of heart weight/body weight and left ventricle weight/body weight, histopathological staining, cross-sectional cardiomyocyte area, and the expression levels of cardiac hypertrophic markers. The anti-hypertrophic effect of SOP was mediated by activating autophagy-related pathway, as revealed by reversal of the increased autophagy marker protein expression. These findings reveal a novel mechanism of SOP attenuating cardiac hypertrophy via activating autophagy-related signaling pathways.     

Crosstalk between AMPK activation and angiotensin II‐induced hypertrophy in cardiomyocytes: the role of mitochondria

AMP‐kinase (AMPK) activation reduces cardiac hypertrophy, although underlying molecular mechanisms remain unclear. In this study, we elucidated the anti‐hypertrophic action of metformin, specifically, the role of the AMPK/eNOS/p53 pathway. H9c2 rat cardiomyocytes were treated with angiotensin II (AngII) for 24 hrs in the presence or absence of metformin (AMPK agonist), losartan [AngII type 1 receptor (AT1R) blocker], Nω‐nitro‐L‐arginine methyl ester (L‐NAME, pan‐NOS inhibitor), splitomicin (SIRT1 inhibitor) or pifithrin‐α (p53 inhibitor). Results showed that treatment with metformin significantly attenuated AngII‐induced cell hypertrophy and death. Metformin attenuated AngII‐induced activation (cleavage) of caspase 3, Bcl‐2 down‐regulation and p53 up‐regulation. It also reduced AngII‐induced AT1R up‐regulation by 30% (P < 0.05) and enhanced AMPK phosphorylation by 99% (P < 0.01) and P‐eNOS levels by 3.3‐fold (P < 0.01). Likewise, losartan reduced AT1R up‐regulation and enhanced AMPK phosphorylation by 54% (P < 0.05). The AMPK inhibitor, compound C, prevented AT1R down‐regulation, indicating that metformin mediated its effects via AMPK activation. Beneficial effects of metformin and losartan converged on mitochondria that demonstrated high membrane potential (Δψ_m) and low permeability transition pore opening. Thus, this study demonstrates that the anti‐hypertrophic effects of metformin are associated with AMPK‐induced AT1R down‐regulation and prevention of mitochondrial dysfunction through the SIRT1/eNOS/p53 pathway.     

FKBP12.6 protects heart from AngII‐induced hypertrophy through inhibiting Ca2+/calmodulin‐mediated signalling pathways in vivo and in vitro

We previously observed that disruption of FK506‐binding protein 12.6 (FKBP12.6) gene resulted in cardiac hypertrophy in male mice. Studies showed that overexpression of FKBP12.6 attenuated thoracic aortic constriction (TAC)‐induced cardiac hypertrophy in mice, whereas the adenovirus‐mediated overexpression of FKBP12.6 induced hypertrophy and apoptosis in cultured neonatal cardiomyocytes, indicating that the role of FKBP12.6 in cardiac hypertrophy is still controversial. In this study, we aimed to investigate the roles and mechanisms of FKBP12.6 in angiotensin II (AngII)‐induced cardiac hypertrophy using various transgenic mouse models in vivo and in vitro. FKBP12.6 knockout (FKBP12.6^?/?) mice and cardiac‐specific FKBP12.6 overexpressing (FKBP12.6 TG) mice were infused with AngII (1500 ng/kg/min) for 14 days subcutaneously by implantation of an osmotic mini‐pump. The results showed that FKBP12.6 deficiency aggravated AngII‐induced cardiac hypertrophy, while cardiac‐specific overexpression of FKBP12.6 prevented hearts from the hypertrophic response to AngII stimulation in mice. Consistent with the results in vivo, overexpression of FKBP12.6 in H9c2 cells significantly repressed the AngII‐induced cardiomyocyte hypertrophy, seen as reductions in the cell sizes and the expressions of hypertrophic genes. Furthermore, we demonstrated that the protection of FKBP12.6 on AngII‐induced cardiac hypertrophy was involved in reducing the concentration of intracellular Ca²⁺ ([Ca²⁺]i), in which the protein significantly inhibited the key Ca²⁺/calmodulin‐dependent signalling pathways such as calcineurin/cardiac form of nuclear factor of activated T cells 4 (NFATc4), calmodulin kinaseII (CaMKII)/MEF‐2, AKT/Glycogen synthase kinase 3β (GSK3β)/NFATc4 and AKT/mTOR signalling pathways. Our study demonstrated that FKBP12.6 protects heart from AngII‐induced cardiac hypertrophy through inhibiting Ca²⁺/calmodulin‐mediated signalling pathways.     

Effect of angiotensin coverting enzyme inhibitor on regression in cardiac hypertrophy

Cardiac hypertrophy in rats was produced by aortic banding for 6 weeks and regression of hypertrophy in these experimental animals was induced by administration of angiotensin converting enzyme inhibitor, enalapril (10 mg/kg/ day) for 6 weeks. The left ventricular muscle mass and systolic pressure were decrease upon treating the hypertrophied rats with enalapril. This drug also decreased the number of 1-adrenoceptors in hypertrophyied myocardium without any changes in -adrenoceptors. The regression of cardiac hypertrophy in spontaneously hypertensive rats by enalapril for 10 weeks was not associated with any alterations in 1-adrenoceptors in hypertrophied myocardium, but was decreased in -adrenoceptors. Effects of enalapril on extracellular matrix in the myocardium was also observed in regression of hypertrophy in which the type III collagen mRNA expression and collagen contents were reduced in comparison with those of hypertrophied myocardium. These results indicate that regression of cardiac hypertrophy is not alway associated with a decrease in the number of 1-adrenergic receptors and that the beneficial effects of enalapril in the hypertrophied heart in aortic banding animals may be of some specific nature.     

Reduction of cardiac hypertrophy in TGR(mREN2)27 by angiotensin II receptor blockade

TGR(mREN2)27 is a transgenic rat harboring the murine Ren-2 gene and exhibit fulminant hypertension and marked heart hypertrophy. In order to study the role of angiotensin II in the increase of cardiac mass, these animals were treated with anti-hypertensive and non-antihypertensive doses of the angiotensin II receptor AT₁ antagonist Telmisartan for 9 weeks. All doses led to significant reductions of heart hypertrophy detected by the evaluation of the diameter of cardiac muscle bundles. We conclude from this study that cardiac hypertrophy in TGR(mREN2)27 is characterized by an increased volume of cardiomyocytes and an unchanged amount of fibrous tissue and that angiotensin II plays an important role in the mechanisms leading to this phenotype.     

High‐density lipoprotein inhibits mechanical stress‐induced cardiomyocyte autophagy and cardiac hypertrophy through angiotensin II type 1 receptor‐mediated PI3K/Akt pathway

Mechanical stress triggers cardiac hypertrophy and autophagy through an angiotensin II (Ang II) type 1 (AT1) receptor‐dependent mechanism. Low level of high density lipoprotein (HDL) is an independent risk factor for cardiac hypertrophy. This study was designed to evaluate the effect of HDL on mechanical stress‐induced cardiac hypertrophy and autophagy. A 48‐hr mechanical stretch and a 4‐week transverse aortic constriction were employed to induce cardiomyocyte hypertrophy in vitro and in vivo, respectively, prior to the assessment of myocardial autophagy using LC3b‐II and beclin‐1. Our results indicated that HDL significantly reduced mechanical stretch‐induced rise in autophagy as demonstrated by LC3b‐II and beclin‐1. In addition, mechanical stress up‐regulated AT1 receptor expression in both cultured cardiomyocytes and in mouse hearts, whereas HDL significantly suppressed the AT1 receptor. Furthermore, the role of Akt phosphorylation in HDL‐mediated action was assessed using MK‐2206, a selective inhibitor for Akt phosphorylation. Our data further revealed that MK‐2206 mitigated HDL‐induced beneficial responses on cardiac remodelling and autophagy. Taken together, our data revealed that HDL inhibited mechanical stress‐induced cardiac hypertrophy and autophagy through downregulation of AT1 receptor, and HDL ameliorated cardiac hypertrophy and autophagy via Akt‐dependent mechanism.     

Sodium butyrate attenuates angiotensin II‐induced cardiac hypertrophy by inhibiting COX2/PGE2 pathway via a HDAC5/HDAC6‐dependent mechanism

Sodium butyrate (NaBu) is reported to play important roles in a number of chronic diseases. The present work is aimed to investigate the effect of NaBu on angiotensin II (Ang II)‐induced cardiac hypertrophy and the underlying mechanism in in vivo and in vitro models. Sprague Dawley rats were infused with vehicle or Ang II (200 ng/kg/min) and orally administrated with or without NaBu (1 g/kg/d) for two weeks. Cardiac hypertrophy parameters and COX2/PGE2 pathway were analysed by real‐time PCR, ELISA, immunostaining and Western blot. The cardiomyocytes H9C2 cells were used as in vitro model to investigate the role of NaBu (2 mmol/L) in inhibition of Ang II‐induced cardiac hypertrophy. NaBu significantly attenuated Ang II‐induced increase in the mean arterial pressure. Ang II treatment remarkably increased cardiac hypertrophy as indicated by increased ratio of heart weight/body weight and enlarged cardiomyocyte size, extensive fibrosis and inflammation, as well as enhanced expression of hypertrophic markers, whereas hearts from NaBu‐treated rats exhibited a significant reduction in these hypertrophic responses. Mechanistically, NaBu inhibited the expression of COX2/PGE2 along with production of ANP and phosphorylated ERK (pERK) stimulated by Ang II in in vivo and in vitro, which was accompanied by the suppression of HDAC5 and HDAC6 activities. Additionally, knocking down the expression of HDAC5 and HDAC6 via gene‐editing strategy dramatically blocked Ang II‐induced hypertrophic responses through COX2/PGE2 pathway. These results provide solid evidence that NaBu attenuates Ang II‐induced cardiac hypertrophy by inhibiting the activation of COX2/PGE2 pathway in a HDAC5/HDAC6‐dependent manner.     

缓激肽B1受体在卡托普利抑制心脏成纤维细胞增殖中的作用

目的：探讨缓激肽（BK）B1受体在ACEI类药物卡托普利（captopril）抑制血管紧张素Ⅱ（AngⅡ）诱导的新生大鼠心脏成纤维细胞（CR）增殖中的作用及其可能机制。方法：经差速贴壁法培养新生大鼠CFs,随机给予AngⅡ、captopfil、B2受体阻断剂icatibant和BJ受体阻断剂des-Arg^10,Leu^9-kallidin进行干预。采用四氮唑盐（MTT）比色法测细胞数目,流式细胞仪技术（FCM）检测细胞周期,硝酸还原酶法和放射免疫分析技术分别测定培养CR细胞上清液中NO含量和细胞内cGMP水平。结果：与空白对照组比较,AngⅡ10^-7mol／L孵育细胞48h后可显著升高CRS期细胞百分率和MTT比色法测定的CFs吸光度（A490nm）值（P〈0．01）;Captopril 10^-5mol／L可明显降低AngⅡ刺激的CFsS期细胞百分率和A490nm值升高（均P〈0．05）,显著促进CFsNO和cGMP生成,该作用可被icatibant（10^-6mol／L）部分阻断,同时阻断B1和B2受体可进一步减弱captopril的作用。结论：Captopril抑制AngⅡ诱导的CFs增殖作用部分是由BK经其B2受体介导的;同时阻断BK B1和B2受体可进一步减弱captopril抗CR增殖效应,B1受体在B2受体阻断情况下可能起部分代偿作用,抑制CFs生长,该作用与NO、cGMP生成有关。     

Increased mRNA expression of cardiac renin-angiotensin system and collagen synthesis in spontaneously hypertensive rats

Hypertensive cardiac hypertrophy is associated with the accumulation of collagen in the myocardial interstitium. Previous studies have demonstrated that this myocardial fibrosis accounts for impaired myocardial stiffness and ventricular dysfunction. Although cardiac fibroblasts are responsible for the synthesis of fibrillar collagen, the factors that regulate collagen synthesis in cardiac fibroblasts are not fully understood. We investigated the effects of angiotensin II on cardiac collagen synthesis in cardiac fibroblasts. Cardiac fibroblasts of 10 week old spontaneously hypertensive rats and age-matched Wistar-Kyoto rats were prepared and maintained in culture medium supplemented with 10% fetal calf serum. The expression of mRNA of the renin-angiotensin system (renin, angiotensinogen, angiotensin converting enzyme) was determined by using a ribonuclease protection assay. Basal collagen synthesis in cardiac fibroblasts from spontaneously hypertensive rats was 1.6 fold greater than that in the cell of Wistar-Kyoto rats. Angiotensin II stimulated collagen synthesis in cardiac fibroblasts in a dose-dependent manner. The responsiveness of collagen production to angiotensin II was significantly enhanced in cardiac fibroblasts from spontaneously hypertensive rats (100 nM angiotensin II resulted in 185 ± 18% increase above basal levels, 185 ± 18 versus 128 ± 19% in Wistar-Kyoto rats p < 0.01). This effect was receptor-specific, because it was blocked by the competitive inhibitor saralasin and MK 954. These results indicate that collagen production was enhanced in cardiac fibroblasts from spontaneously hypertensive rats, that angiotensin II had a stimulatory effect on collagen synthesis in cardiac fibroblasts, and that cardiac fibroblasts from spontaneously hypertensive rats were hyper-responsive to stimulation by angiotensin II.Level of angiotensin and renin mRNA expressed in ventricles, and angiotensinogen mRNA expressed in fibroblasts from SHR were higher than those from WKY.These findings suggest that the cardiac renin-angiotensin system may play an important role in collagen accumulation in hypertensive cardiac hypertrophy.     

Mechanical stress-evoked but angiotensin II-independent activation of angiotensin II type 1 receptor induces cardiac hypertrophy through calcineurin pathway

Mechanical stress can induce cardiac hypertrophy through angiotensin II (AngII) type 1 (AT₁) receptor independently of AngII, however, the intracellular mechanisms remain largely indeterminate. Since calcineurin, a Ca²⁺-dependent phosphatase, plays a critical role in pressure overload-induced cardiac hypertrophy, we therefore, asked whether calcineurin is involved in the AT₁ receptor-mediated but AngII-independent cardiac hypertrophy. Mechanical stretch failed to elicit hypertrophic responses in COS7 cells co-transfected with plasmid of AT₁ receptor and siRNA of calcineurin. Mechanical stresses for 2 weeks in vivo and for 24 h in vitro significantly induced upregulation of calcineurin expression and hypertrophic responses, such as the increases in cardiomyocytes size and specific gene expressions, in cardiomyocytes of angiotensinogen gene knockout (ATG^−/−) mice, both of which were significantly suppressed by a specific calcineurin inhibitor FK506, suggesting a critical role of calcineurin in mechanical stress-induced cardiac hypertrophy in the ATG^−/− mice. Furthermore, an AT₁ receptor blocker Losartan not only attenuated cardiac hypertrophy but also abrogated upregulation of cardiac calcineurin expression induced by mechanical stresses in the AngII-lacking mice, indicating that calcineurin expression is regulated by AT₁ receptor without the involvement of AngII after mechanical stress. These findings collectively suggest that mechanical stress-evoked but AngII-independent activation of AT₁ receptor induces cardiac hypertrophy through calcineurin pathway.     

Development of pressure overload induced cardiac hypertrophy is unaffected by long-term treatment with losartan

Left ventricular hypertrophy with adequate wall thickness, preserved adult phenotype and extracellular matrix may be useful in the prevention of heart failure. Because activation of subtype 1 of angiotensin II (AT₁) receptors is thought to be involved in the hypertrophic response of cardiomyocytes, we tested the potential of systemic AT₁ blockade to modify the development of left ventricular hypertrophy due to pressure overload.Sham-operated rats and rats with ascending aorta constriction were treated with losartan (30 mg/kg/day) for 8 weeks. Left ventricular geometry, dynamics of isovolumic contractions, hydroxyproline concentration as well as myosin isozymes (marker of fetal phenotype) were assessed. Rats with aortic constriction exhibited a marked increase in left ventricular weight and the diastolic pressure-volume relationship was shifted to smaller volumes. An enlarged ventricular pressure-volume area and increased (p < 0.05) peak values of +dP/dtmax and -dP/dtmax demonstrated an enhanced overall ventricular performance. Signs of congestive heart failure were not apparent. In contrast, parameters of myocardial fimction (normalized length-stress area, +d/dtmax and -d/dtmax) were depressed (p < 0.05), indicating an impaired myocardial contractility. The hydroxyproline concentration remained unaltered. However, the proportion of -myosin heavy chains (NMC) was increased (p < 0.05). Administration of losartan decreased (p < 0.05) blood pressure and body weight in sham operated and pressure overloaded rats. By contrast, neither the concentric left ventricular hypertrophy or depressed myocardial function nor the increased -MHC expression were significantly altered. Thus, activation of AT₁ receptors appears not to be involved in the initial expression of the fetal phenotype of pressure overloaded heart which may be responsible for the progressive functional deterioration of the hypertrophied ventricle.     

Long‐term administration of pyridostigmine attenuates pressure overload‐induced cardiac hypertrophy by inhibiting calcineurin signalling

Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload‐induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and β‐myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4 pathway and suppression of the interaction of Orai1/STIM1.     

Endothelial S1pr1 regulates pressure overload‐induced cardiac remodelling through AKT‐eNOS pathway

Cardiac vascular microenvironment is crucial for cardiac remodelling during the process of heart failure. Sphingosine 1‐phosphate (S1P) tightly regulates vascular homeostasis via its receptor, S1pr1. We therefore hypothesize that endothelial S1pr1 might be involved in pathological cardiac remodelling. In this study, heart failure was induced by transverse aortic constriction (TAC) operation. S1pr1 expression is significantly increased in microvascular endothelial cells (ECs) of post‐TAC hearts. Endothelial‐specific deletion of S1pr1 significantly aggravated cardiac dysfunction and deteriorated cardiac hypertrophy and fibrosis in myocardium. In vitro experiments demonstrated that S1P/S1pr1 praxis activated AKT/eNOS signalling pathway, leading to more production of nitric oxide (NO), which is an essential cardiac protective factor. Inhibition of AKT/eNOS pathway reversed the inhibitory effect of EC‐S1pr1‐overexpression on angiotensin II (AngII)‐induced cardiomyocyte (CM) hypertrophy, as well as on TGF‐β‐mediated cardiac fibroblast proliferation and transformation towards myofibroblasts. Finally, pharmacological activation of S1pr1 ameliorated TAC‐induced cardiac hypertrophy and fibrosis, leading to an improvement in cardiac function. Together, our results suggest that EC‐S1pr1 might prevent the development of pressure overload‐induced heart failure via AKT/eNOS pathway, and thus pharmacological activation of S1pr1 or EC‐targeting S1pr1‐AKT‐eNOS pathway could provide a future novel therapy to improve cardiac function during heart failure development.     

Renal dopamine receptors are involved in the development of cardiac hypertrophy

The present study examined the effect of fenoldopam, a known dopamine-1 receptor (DA1) agonist in order to understand its involvement in the cardiac hypertrophic process. Male Sprague-Dawley rats underwent abdominal aortic constriction (AB) with placement of a suprarenal ligature while sham operated animals served as controls. The AB groupsshowed an increase in their heart wt, left ventricular (LV) wt, heart wt/body wt and LV wt/body wt ratio. Furthermore, the length of these hearts, as measured from the auriculoventricular border to the apex, LV wall and interventricular (IV) septal thickness were increased from control levels. Treatment with SCH 23390, a DA1 antagonist, on the other hand, was able to partially regress the cardiac hypertrophic changes. All these parameters were also increased in control animals treated with fenoldopam (F). Such changes were more striking in the F+AB group which showed a significant acceleration of the cardiac hypertrophic process on super-imposing the two treatments. Plasma dopamine and renin activity were increased in all the groups as compared to control. These results indicate that dopamine receptors are implicated in the development of cardiac hypertrophy.     

高血压大鼠心肌肥大及逆转过程中相关因素的探讨

目的：探讨在心肌肥大及逆转过程中收缩压(SBP)、舒张压(DBP)、平均动脉压(MAP)、神经肽Y(NPY)等与左心室肥大的关系。方法：血压和心率用生物信号分析系统记录;NPY用放射免疫法测定,用SPSS软件求出了相关系数和回归方程。结果：SBP、DBP、MAP、心肌匀浆中NPY与心系数(LVW／BW)呈正相关,血液中NPY和心率(HR)与心系数不相关。结论：血压升高是导致左室肥大的因素之一,收缩压的影响大于舒张压;SBP、DBP、MAP、心肌匀浆中NPY与心系数(LVW/BW)有相关的趋势。     

The role of post‐translational modifications in cardiac hypertrophy

Pathological cardiac hypertrophy involves excessive protein synthesis, increased cardiac myocyte size and ultimately the development of heart failure. Thus, pathological cardiac hypertrophy is a major risk factor for many cardiovascular diseases and death in humans. Extensive research in the last decade has revealed that post‐translational modifications (PTMs), including phosphorylation, ubiquitination, SUMOylation, O‐GlcNAcylation, methylation and acetylation, play important roles in pathological cardiac hypertrophy pathways. These PTMs potently mediate myocardial hypertrophy responses via the interaction, stability, degradation, cellular translocation and activation of receptors, adaptors and signal transduction events. These changes occur in response to pathological hypertrophy stimuli. In this review, we summarize the roles of PTMs in regulating the development of pathological cardiac hypertrophy. Furthermore, PTMs are discussed as potential targets for treating or preventing cardiac hypertrophy.     

血红素氧合酶-1/一氧化碳通路参与辛伐他汀抗高血压诱发的大鼠心肌肥厚

为了探讨他汀类药物抑制心肌肥厚的作用机制,本研究应用一氧化氮合酶抑制剂左旋硝基精氨酸[N-nitro-L-arginine, L-NNA,15 mg／(kg·d)]制备大鼠高血压心肌肥厚模型,并分别给予不同剂量辛伐他汀[5或30 mg／(kg·d)进行干预。6周后测大鼠左心室功能、左心室重量指数(left ventricular mass index,LVMI)、心肌脑钠素(brain natriuretic peptide,BNP)含量、心肌羟脯氨酸含量和心肌血红素氧合酶(heme oxygenase,HO)活性。在体外培养的新生大鼠心肌细胞中,观察辛伐他汀对血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)引起的心肌细胞肥大的抑制作用与细胞血红素氧合酶-1(HO-1)表达、HO活性及CO生成间的关系。结果表明,辛伐他汀干预明显减轻L-NNA处理大鼠的心肌肥厚(LVMI值、心肌BNP和羟脯氨酸含量均显著低于单纯L-NNA处理组),改善左心室舒张功能,而且心肌HO活性显著升高。在离体培养的原代乳鼠心肌细胞,辛伐他汀浓度依赖性地抑制Ang Ⅱ引起的细胞肥大(3H-亮氨酸掺入),并相应增加HO-1 mRNA表达、HO活性和CO生成量。应用HO抑制剂锌卟啉能有效抑制辛伐他汀抗Ang Ⅱ诱导的心肌肥大作用。结果提示:辛伐他汀上调HO-1／CO通路是其抗高血压诱发的心肌肥厚的机制之一。