Aliskiren‐attenuated myocardium apoptosis via regulation of autophagy and connexin‐43 in aged spontaneously hypertensive rats

There are controversies about the mechanism of myocardium apoptosis in hypertensive heart disease. The aim of this study was to investigate the relationship among autophagy, Cx43 and apoptosis in aged spontaneously hypertensive rats (SHRs) and establish whether Aliskiren is effective or not for the treatment of myocardium apoptosis. Twenty‐one SHRs aged 52 weeks were randomly divided into three groups, the first two receiving Aliskiren at a dose of 10 and 25 mg/kg/day respectively; the third, placebo for comparison with seven Wistar‐Kyoto (WKY) as controls. After a 2‐month treatment, systolic blood pressure (SBP), heart to bw ratios (HW/BW%) and angiotensin II (AngII) concentration were significantly enhanced in SHRs respectively. Apoptotic cardiomyocytes detected with TUNEL and immunofluorescent labelling for active caspase‐3 increased nearly fourfolds in SHRs, with a decline in the expression of survivin and AKT activation, and an increase in caspase‐3 activation and the ratio of Bax/Bcl‐2. Myocardium autophagy, detected with immunofluorescent labelling for LC3‐II, increased nearly threefolds in SHRs, with the up‐regulation of Atg5, Atg16L1, Beclin‐1 and LC3‐II. The expression of Cx43 plaque was found to be down‐regulated in SHRs. Aliskiren significantly reduced SBP, HW/BW%, AngII concentration and the expression of AT₁R. Thus, Aliskiren protects myocardium against apoptosis by decreasing autophagy, up‐regulating Cx43. These effects showed a dose‐dependent tendency, but no significance. In conclusion, the myocardium apoptosis developed during the hypertensive end‐stage of SHRs could be ameliorated by Aliskiren via the regulation of myocardium autophagy and maladaptive remodelling of Cx43.     

Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

Cardiac fibrosis is a hallmark of heart disease and plays a vital role in cardiac remodeling during heart diseases, including hypertensive heart disease. Hexarelin is one of a series of synthetic growth hormone secretagogues (GHSs) possessing a variety of cardiovascular effects via action on GHS receptors (GHS-Rs). However, the role of hexarelin in cardiac fibrosis in vivo has not yet been investigated. In the present study, spontaneously hypertensive rats (SHRs) were treated with hexarelin alone or in combination with a GHS-R antagonist for 5 wk from an age of 16 wk. Hexarelin treatment significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts. Hexarelin treatment also increased matrix metalloproteinase (MMP)-2 and MMP-9 activities and decreased myocardial mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 in SHRs. In addition, hexarelin treatment significantly attenuated left ventricular (LV) hypertrophy, LV diastolic dysfunction, and high blood pressure in SHRs. The effect of hexarelin on cardiac fibrosis, blood pressure, and cardiac function was mediated by its receptor, GHS-R, since a selective GHS-R antagonist abolished these effects and expression of GHS-Rs was upregulated by hexarelin treatment. In summary, our data demonstrate that hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation via regulation of MMPs/TIMP. Hexarelin-reduced systolic blood pressure may also contribute to this reduced cardiac fibrosis in SHRs. The present findings provided novel insights and underscore the therapeutic potential of hexarelin as an antifibrotic agent for the treatment of cardiac fibrosis.     

Overexpression of FNTB and the activation of Ras induce hypertrophy and promote apoptosis and autophagic cell death in cardiomyocytes

Farnesyltransferase (FTase) is an important enzyme that catalyses the modification of protein isoprene downstream of the mevalonate pathway. Previous studies have shown that the tissue of the heart in the suprarenal abdominal aortic coarctation (AAC) group showed overexpression of FTaseβ (FNTB) and the activation of the downstream protein Ras was enhanced. FTase inhibitor (FTI) can alleviate myocardial fibrosis and partly improve cardiac remodelling in spontaneously hypertensive rats. However, the exact role and mechanism of FTase in myocardial hypertrophy and remodelling are not fully understood. Here, we used recombinant adenovirus to transfect neonatal rat ventricular cardiomyocytes to study the effect of FNTB overexpression on myocardial remodelling and explore potential mechanisms. The results showed that overexpression of FNTB induces neonatal rat ventricular myocyte hypertrophy and reduces the survival rate of cardiomyocytes. FNTB overexpression induced a decrease in mitochondrial membrane potential and increased apoptosis in cardiomyocytes. FNTB overexpression also promotes autophagosome formation and the accumulation of autophagy substrate protein, LC3II. Transmission electron microscopy (TEM) and mCherry‐GFP tandem fluorescent‐tagged LC3 (tfLC3) showed that FNTB overexpression can activate autophagy flux by enhancing autophagosome conversion to autophagolysosome. Overactivated autophagy flux can be blocked by bafilomycin A1. In addition, salirasib (a Ras farnesylcysteine mimetic) can alleviate the hypertrophic phenotype of cardiomyocytes and inhibit the up‐regulation of apoptosis and autophagy flux induced by FNTB overexpression. These results suggest that FTase may have a potential role in future treatment strategies to limit the adverse consequences of cardiac hypertrophy, cardiac dysfunction and heart failure.     

Hesperetin protects against cardiac remodelling induced by pressure overload in mice

Cardiac remodelling is a major determinant of heart failure (HF) and is characterised by cardiac hypertrophy, fibrosis, oxidative stress and myocytes apoptosis. Hesperetin, which belongs to the flavonoid subgroup of citrus flavonoids, is the main flavonoid in oranges and possesses multiple pharmacological properties. However, its role in cardiac remodelling remains unknown. We determined the effect of hesperetin on cardiac hypertrophy, fibrosis and heart function using an aortic banding (AB) mouse. Male, 8–10-week-old, wild-type C57 mice with or without oral hesperetin administration were subjected to AB or a sham operation. Our data demonstrated that hesperetin protected against cardiac hypertrophy, fibrosis and dysfunction induced by AB, as 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. Also, hesperetin attenuated oxidative stress and myocytes apoptosis induced by AB. The inhibitory effect of hesperetin on cardiac remodelling was mediated by blocking PKCα/βII-AKT, JNK and TGFβ1-Smad signalling pathways. In conclusion, we found that the orange flavonoid hesperetin protected against cardiac remodelling induced by pressure overload via inhibiting cardiac hypertrophy, fibrosis, oxidative stress and myocytes apoptosis. These findings suggest a potential therapeutic drug for cardiac remodelling and HF.     

ICS II protects against cardiac hypertrophy by regulating metabolic remodelling,not by inhibiting autophagy

Cardiac hypertrophy is characterized by a shift in metabolic substrate utilization. Therefore, the regulation of ketone body uptake and metabolism may have beneficial effects on heart injuries that induce cardiac remodelling. In this study, we investigated whether icariside II (ICS II) protects against cardiac hypertrophy in mice and cardiomyocytes. To create cardiac hypertrophy animal and cell models, mice were subjected to transverse aortic constriction (TAC), and embryonic rat cardiomyocytes (H9C2) were stimulated with angiotensin II, a neurohumoral stressor. Both the in vivo and in vitro results suggest that ICS II treatment ameliorated pressure overload–induced cardiac hypertrophy and preserved heart function. In addition, apoptosis and oxidative stress were reduced in the presence of ICS II. Moreover, ICS II inhibited excess autophagy in TAC-induced hearts and angiotensin II–stimulated cardiomyocytes. Mechanistically, we found that ICS II administration regulated SIRT3 expression in cardiac remodelling. SIRT3 activation increased ketone body transportation and utilization. Collectively, our data show that ICS II attenuated cardiac hypertrophy by modulating ketone body and fatty acid metabolism, and that this was likely due to the activation of the SIRT3-AMPK pathway. ICS II treatment may provide a new therapeutic strategy for improving myocardial metabolism in cardiac hypertrophy and heart failure.     

MBNL1 regulates isoproterenol-induced myocardial remodelling in vitro and in vivo

Myocardial remodelling is a common phenomenon in cardiovascular diseases, which threaten human health and the quality of life. Due to the lack of effective early diagnosis and treatment methods, the molecular mechanism of myocardial remodelling should be explored in depth. In this study, we observed the high expression of MBNL1 in cardiac tissue and peripheral blood of an isoproterenol (ISO)-induced cardiac hypertrophy mouse model. MBNL1 promoted ISO-induced cardiac hypertrophy and fibrosis by stabilizing Myocardin mRNA in vivo and in vitro. Meanwhile, an increase in MBNL1 may induce the apoptosis of cardiomyocytes treated with ISO via TNF-α signalling. Interestingly, MBNL1 can be activated by p300 in cardiomyocytes treated with ISO. At last, Myocardin can reverse activate the expression of MBNL1. These results suggest that MBNL1 may be a potential target for the early diagnosis and clinical treatment of myocardial remodelling.     

Knockdown of farnesylpyrophosphate synthase prevents angiotensin II-mediated cardiac hypertrophy

The Rho guanosine triphosphatases (Rho GTPases) family, including RhoA, plays an important role in angiotensin II (Ang II)-mediated cardiac hypertrophy. Farnesylpyrophosphate synthase (FPPS)-catalyzed isoprenoid intermediates are vital for activation of RhoA. The present study was designed to investigate the role of FPPS in myocardial hypertrophy mediated with Ang II. First, we demonstrated that FPPS expression was elevated both in cultured neonatal cardiomyocytes (NCMs) following Ang II treatment and in the hypertrophic myocardium of 18-week-old spontaneously hypertensive rats (SHRs). Then, the importance of FPPS was assessed by RNA interference (RNAi) against FPPS in NCMs. Successful FPPS silencing in NCMs completely inhibited the hypertrophy marker genes of β-myosin heavy chain (β-MHC) and brain natriuretic peptide (BNP), as well as cell surface area. Furthermore, FPPS knockdown prevented elevated RhoA activity compared with non-silenced controls. Similarly, increased-phosphorylation of p-38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPK) by Ang II was attenuated. In vivo gene transfer also attenuated hypertrophic responses as indexed by left ventricular weight/body weight (LVW/BW), heart weight/body weight (HW/BW), and echocardiography, as well as expression of β-MHC and BNP mRNA in SHRs. In conclusion, FPPS with RhoA associated p-38 and JNK MAPK signaling might play an important role in Ang II-induced cardiac hypertrophy.     

Echinacoside reverses myocardial remodeling and improves heart function via regulating SIRT1/FOXO3a/MnSOD axis in HF rats induced by isoproterenol

Myocardial remodelling is important pathological basis of HF, mitochondrial oxidative stress is a promoter to myocardial hypertrophy, fibrosis and apoptosis. ECH is the major active component of a traditional Chinese medicine Cistanches Herba, plenty of studies indicate it possesses a strong antioxidant capacity in nerve cells and tumour, it inhibits mitochondrial oxidative stress, protects mitochondrial function, but the specific mechanism is unclear. SIRT1/FOXO3a/MnSOD is an important antioxidant axis, study finds that ECH binds covalently to SIRT1 as a ligand and up-regulates the expression of SIRT1 in brain cells. We hypothesizes that ECH may reverse myocardial remodelling and improve heart function of HF via regulating SIRT1/FOXO3a/MnSOD signalling axis and inhibit mitochondrial oxidative stress in cardiomyocytes. Here, we firstly induce cellular model of oxidative stress by ISO with AC-16 cells and pre-treat with ECH, the level of mitochondrial ROS, mtDNA oxidative injury, MMP, carbonylated protein, lipid peroxidation, intracellular ROS and apoptosis are detected, confirm the effect of ECH in mitochondrial oxidative stress and function in vitro. Then, we establish a HF rat model induced by ISO and pre-treat with ECH. Indexes of heart function, myocardial remodelling, mitochondrial oxidative stress and function, expression of SIRT1/FOXO3a/MnSOD signalling axis are measured, the data indicate that ECH improves heart function, inhibits myocardial hypertrophy, fibrosis and apoptosis, increases the expression of SIRT1/FOXO3a/MnSOD signalling axis, reduces the mitochondrial oxidative damages, protects mitochondrial function. We conclude that ECH reverses myocardial remodelling and improves cardiac function via up-regulating SIRT1/FOXO3a/MnSOD axis and inhibiting mitochondrial oxidative stress in HF rats.     

Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo

In this study, we evaluated whether blocking myeloid differentiation factor-88 (MyD88) could decrease cardiac myocyte apoptosis following pressure overload. Adenovirus expressing dominant negative MyD88 (Ad5-dnMyD88) or Ad5-green fluorescent protein (GFP) (Ad5-GFP) was transfected into rat hearts (n = 8/group) immediately followed by aortic banding for 3 wk. One group of rats (n = 8) was subjected to aortic banding for 3 wk without transfection. Sham surgical operation (n = 8) served as control. The ratios of heart weight to body weight (HW/BW) and heart weight to tibia length (HW/TL) were calculated. Cardiomyocyte size was examined by FITC-labeled wheat germ agglutinin staining of membranes. Cardiac myocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and myocardial interstitial fibrosis was examined by Masson's Trichrome staining. Aortic banding significantly increased the HW/BW by 41.0% (0.44 +/- 0.013 vs. 0.31 +/- 0.008), HW/TL by 47.2% (42.7 +/- 1.30 vs. 29.0 +/- 0.69), cardiac myocyte size by 49.6%, and cardiac myocyte apoptosis by 11.5%, and myocardial fibrosis and decreased cardiac function compared with sham controls. Transfection of Ad5-dnMyD88 significantly reduced the HW/BW by 18.2% (0.36 +/- 0.006 vs. 0.44 +/- 0.013) and HW/TL by 22.3% (33.2 +/- 0.95 vs. 42.7 +/- 1.30) and decreased cardiomyocyte size by 56.8%, cardiac myocyte apoptosis by 76.2%, as well as fibrosis, and improved cardiac function compared with aortic-banded group. Our results suggest that MyD88 is an important component in the Toll-like receptor-4-mediated nuclear factor-kappaB activation pathway that contributes to the development of cardiac hypertrophy. Blockade of MyD88 significantly reduced cardiac hypertrophy, cardiac myocyte apoptosis, and improved cardiac function in vivo.     

Chronic inhibition of chemokine receptor CXCR2 attenuates cardiac remodeling and dysfunction in spontaneously hypertensive rats

System hypertension is a major risk factor for cardiac hypertrophy and heart failure. Our recent findings reveal that the ablation or inhibition of C-X-C chemokine receptor (CXCR) 2 blocks this process in mice; however, it is not clear whether the pharmacological inhibition of CXCR2 attenuates hypertension and subsequent cardiac remodeling in spontaneously hypertensive rats (SHRs). In the present study, we showed that chemokines (CXCL1 and CXCL2) and CXCR2 were significantly upregulated in SHR hearts compared with Wistar–Kyoto rat (WKY) hearts. Moreover, the administration of CXCR2-specific inhibitor N-(2-hydroxy-4-nitrophenyl)-N′-(2-bromophenyl)-urea (SB225002) in SHRs (at 2 months of age) for an additional 4 months significantly suppressed the elevation of blood pressure, cardiac myocyte hypertrophy, fibrosis, inflammation, and superoxide production and improved heart dysfunction in SHRs compared with vehicle-treated SHRs. SB225002 treatment also reduced established hypertension, cardiac remodeling and contractile dysfunction. Moreover, CXCR2-mediated increases in the recruitment of Mac-2-positive macrophages, proinflammatory cytokines, vascular permeability and ROS production in SHR hearts were markedly attenuated by SB225002. Accordingly, the inhibition of CXCR2 by SB225002 deactivates multiple signaling pathways (AKT/mTOR, ERK1/2, STAT3, calcineurin A, TGF-β/Smad2/3, NF-κB-p65, and NOX). Our results provide new evidence that the chronic blocking of CXCR2 activation attenuates progression of cardiac hypertrophic remodeling and dysfunction in SHRs. These findings may be of value in understanding the benefits of CXCR2 inhibition for hypertensive cardiac hypertrophy and provide further support for the clinical application of CXCR2 inhibitors for the prevention and treatment of heart failure.     

PKM2 promotes angiotensin-II-induced cardiac remodelling by activating TGF-β/Smad2/3 and Jak2/Stat3 pathways through oxidative stress

Hypertensive cardiac remodelling is a common cause of heart failure. However, the molecular mechanisms regulating cardiac remodelling remain unclear. Pyruvate kinase isozyme type M2 (PKM2) is a key regulator of the processes of glycolysis and oxidative phosphorylation, but the roles in cardiac remodelling remain unknown. In the present study, we found that PKM2 was enhanced in angiotensin II (Ang II)-treated cardiac fibroblasts and hypertensive mouse hearts. Suppression of PKM2 by shikonin alleviated cardiomyocyte hypertrophy and fibrosis in Ang-II-induced cardiac remodelling in vivo. Furthermore, inhibition of PKM2 markedly attenuated the function of cardiac fibroblasts including proliferation, migration and collagen synthesis in vitro. Mechanistically, suppression of PKM2 inhibited cardiac remodelling by suppressing TGF-β/Smad2/3, Jak2/Stat3 signalling pathways and oxidative stress. Together, this study suggests that PKM2 is an aggravator in Ang-II-mediated cardiac remodelling. The negative modulation of PKM2 may provide a promising therapeutic approach for hypertensive cardiac remodelling.     

Gallic acid attenuates calcium calmodulin‐dependent kinase II‐induced apoptosis in spontaneously hypertensive rats

Hypertension causes cardiac hypertrophy and leads to heart failure. Apoptotic cells are common in hypertensive hearts. Ca²⁺/calmodulin‐dependent protein kinase II (CaMKII) is associated with apoptosis. We recently demonstrated that gallic acid reduces nitric oxide synthase inhibition‐induced hypertension. Gallic acid is a trihydroxybenzoic acid and has been shown to have beneficial effects, such as anti‐cancer, anti‐calcification and anti‐oxidant activity. The purpose of this study was to determine whether gallic acid regulates cardiac hypertrophy and apoptosis in essential hypertension. Gallic acid significantly lowered systolic and diastolic blood pressure in spontaneously hypertensive rats (SHRs). Wheat germ agglutinin (WGA) and H&E staining revealed that gallic acid reduced cardiac enlargement in SHRs. Gallic acid treatment decreased cardiac hypertrophy marker genes, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), in SHRs. The four isoforms, α, β, δ and γ, of CaMKII were increased in SHRs and were significantly reduced by gallic acid administration. Gallic acid reduced cleaved caspase‐3 protein as well as bax, p53 and p300 mRNA levels in SHRs. CaMKII δ overexpression induced bax and p53 expression, which was attenuated by gallic acid treatment in H9c2 cells. Gallic acid treatment reduced DNA fragmentation and the TUNEL positive cells induced by angiotensin II. Taken together, gallic acid could be a novel therapeutic for the treatment of hypertension through suppression of CaMKII δ‐induced apoptosis.     

Calcium-sensing receptors induce apoptosis in cultured neonatal rat ventricular cardiomyocytes during simulated ischemia/reperfusion

Calcium-sensing receptors (CaSRs) are G-protein coupled receptors which regulate systemic calcium homeostasis and also participate in cell proliferation, differentiation and apoptosis. We have previously shown that CaSR can induce apoptosis in isolated rat adult hearts and in normal rat neonatal cardiomyocytes. However, no knowledge exists concerning the role of CaSR in apoptosis induced by ischemia and reperfusion in neonatal cardiac myocytes. Therefore, in the present study, we incubated primary neonatal rat ventricular cardiomyocytes in ischemia-mimetic solution for 2h, then re-incubated them in a normal culture medium for 24h to establish a model of simulated ischemia/reperfusion (I/R). We assayed the apoptotic ratio of the cardiomyocytes by flow cytometry; observed morphological alterations by transmission electron microscope; analyzed the expression of caspase-3, Bcl-2, CaSR, extracellular signal-regulated protein kinase (ERK), and Fas/Fas ligand (FasL) by Western blotting; and measured the concentration of intracellular calcium by Laser Confocal Scanning Microscopy. The results showed that simulated I/R increased the expression of CaSR and cardiomyocyte apoptosis. GdCl3, a specific activator of CaSR, further enhanced CaSR expression, along with increases in intracellular calcium and apoptosis in cardiomyocytes during I/R. Activation of CaSR down-regulated Bcl-2 expression, up-regulated caspase-3 and Fas/FasL expression and stimulated ERK1/2 phosphorylation. In summary, CaSR is involved in I/R injury and apoptosis of neonatal rat ventricular cardiomyocytes by inhibiting Bcl-2, inducing calcium overload and activating the Fas/FasL death receptor pathway.     

Alterations in apoptosis regulatory factors during hypertrophy and heart failure

Cardiac hypertrophy from pathological stimuli often proceeds to heart failure, whereas cardiac hypertrophy from physiological stimuli does not. In this study, physiological hypertrophy was created by a daily exercise regimen and pathological hypertrophy was created from a high-salt diet in Dahl salt-sensitive rats. The rats continued on a high-salt diet progressed to heart failure associated with an increased rate of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. We analyzed primary cultures of these hearts and found that only cardiomyocytes made hypertrophic by a pathological stimulus show increased sensitivity to apoptosis. Examination of the molecular changes associated with these distinct types of hypertrophy revealed changes in Bcl-2 family members and caspases favoring survival during physiological hypertrophy. However, in pathological hypertrophy, there were more diffuse proapoptotic changes, including changes in Fas, the Bcl-2 protein family, and caspases. Therefore, we speculate that this increased sensitivity to apoptotic stimulation along with proapoptotic changes in the apoptosis program may contribute to the development of heart failure seen in pathological cardiac hypertrophy.     

金丝桃苷对主动脉弓缩窄所致的小鼠心肌肥厚的保护作用

目的:研究金丝桃苷(hyperoside, HYP)对主动脉弓缩窄所致小鼠病理性心肌肥厚的保护作用及其机制。方法:将32只C57BL/6J小鼠随机分为4组:假手术(Sham)组、单纯给药(HYP)组、主动脉弓缩窄(TAC)组及主动脉弓缩窄给药(TAC+HYP)组,每组8只。采用经典的主动脉弓缩窄术建立小鼠压力负荷型心肌肥厚模型。TAC术后4周,超声心动图仪检测心脏功能;左心室导管监测血流动力学指标;分离心脏、肺脏和胫骨计算心/体比、肺/体比和心/胫比,HE染色计算心肌细胞平均横截面积,Masson染色观察心肌纤维化程度,试剂盒检测心肌组织中SOD的活性和MDA的含量;DHE荧光探针检测心肌组织ROS生成量;Western blotting检测SIRT3、NOX 4、Collagen-1和Collagen-3蛋白表达,实时定量PCR检测SIRT3、ANP、α-MHC、β-MHC的m RNA表达情况。结果:与Sham组相比,TAC组小鼠的LVPWD值增加,LVSP和LVEDP值上升,LVEF、LVFS、E/A和±dp/dtmax值均降低;HM/BW、LW/BW和HW/TL值升高,心肌细胞横截面积增加;心肌组织胶原沉积加重;肥厚基因ANP的m RNA表达水平显著上升,α-MHC/β-MHC的比例倒置;心肌组织SOD活性降低,MDA和ROS生成量增加;SIRT3信号表达明显降低(均P<0.05)。给予HYP药物处理后,TAC+HYP组小鼠的心脏功能、血流动力学改变、心肌细胞肥厚程度、心肌组织纤维化和氧化应激水平均明显改善,并且心肌细胞SIRT3信号表达也显著增强(均P<0.05)。结论:HYP能够通过减轻心肌组织氧化应激损伤,抑制心肌纤维化进展,改善压力负荷引起的病理性心肌肥厚,且其作用机制可能与激活SIRT3信号有关。     

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.     

Rutaecarpine prevents hypertensive cardiac hypertrophy involving the inhibition of Nox4‐ROS‐ADAM17 pathway

Rutaecarpine attenuates hypertensive cardiac hypertrophy in the rats with abdominal artery constriction (AAC); however, its mechanism of action remains largely unknown. Our previous study indicated that NADPH oxidase 4 (Nox4) promotes angiotensin II (Ang II)‐induced cardiac hypertrophy through the pathway between reactive oxygen species (ROS) and a disintegrin and metalloproteinase‐17 (ADAM17) in primary cardiomyocytes. This research aimed to determine whether the Nox4‐ROS‐ADAM17 pathway is involved in the protective action of rutaecarpine against hypertensive cardiac hypertrophy. AAC‐induced hypertensive rats were adopted to evaluate the role of rutaecarpine in hypertensive cardiac hypertrophy. Western blotting and real‐time PCR were used to detect gene expression. Rutaecarpine inhibited hypertensive cardiac hypertrophy in AAC‐induced hypertensive rats. These findings were confirmed by the results of in vitro experiments that rutaecarpine significantly inhibited Ang II‐induced cardiac hypertrophy in primary cardiomyocytes. Likewise, rutaecarpine significantly suppressed the Nox4‐ROS‐ADAM17 pathway and over‐activation of extracellular signal‐regulated kinase (ERK) 1/2 pathway in the left ventricle of AAC‐induced hypertensive rats and primary cardiomyocytes stimulated with Ang II. The inhibition of Nox4‐ROS‐ADAM17 pathway and over‐activation of ERK1/2 might be associated with the beneficial role of rutaecarpine in hypertensive cardiac hypertrophy, thus providing additional evidence for preventing hypertensive cardiac hypertrophy with rutaecarpine.     

Ubiquitin‐specific protease 19 blunts pathological cardiac hypertrophy via inhibition of the TAK1‐dependent pathway

Ubiquitin‐specific protease 19 (USP19) belongs to USP family and is involved in promoting skeletal muscle atrophy. Although USP19 is expressed in the heart, the role of USP19 in the heart disease remains unknown. The present study provides in vivo and in vitro data to reveal the role of USP19 in preventing pathological cardiac hypertrophy. We generated USP19‐knockout mice and isolated neonatal rat cardiomyocytes (NRCMs) that overexpressed or were deficient in USP19 to investigate the effect of USP19 on transverse aortic constriction (TAC) or phenylephrine (PE)‐mediated cardiac hypertrophy. Echocardiography, pathological and molecular analysis were used to determine the extent of cardiac hypertrophy, fibrosis, dysfunction and inflammation. USP19 expression was markedly increased in rodent hypertrophic heart or cardiomyocytes underwent TAC or PE culturing, the increase was mediated by the reduction of Seven In Absentia Homolog‐2. The extent of TAC‐induced cardiac hypertrophy, fibrosis, dysfunction and inflammation in USP19‐knockout mice was exacerbated. Consistently, gain‐of‐function and loss‐of‐function approaches that involved USP19 in cardiomyocytes suggested that the down‐regulation of USP19 promoted the hypertrophic phenotype, while the up‐regulation of USP19 improved the worsened phenotype. Mechanistically, the USP19‐elicited cardiac hypertrophy improvement was attributed to the abrogation of the transforming growth factor beta‐activated kinase 1 (TAK1)‐p38/JNK1/2 transduction. Furthermore, the inhibition of TAK1 abolished the aggravated hypertrophy induced by the loss of USP19. In conclusion, the present study revealed that USP19 and the downstream of TAK1‐p38/JNK1/2 signalling pathway might be a potential target to attenuate pathological cardiac hypertrophy.     

Changes in short‐chain acyl‐coA dehydrogenase during rat cardiac development and stress

This study was designed to investigate the expression of short‐chain acyl‐CoA dehydrogenase (SCAD), a key enzyme of fatty acid β‐oxidation, during rat heart development and the difference of SCAD between pathological and physiological cardiac hypertrophy. The expression of SCAD was lowest in the foetal and neonatal heart, which had time‐dependent increase during normal heart development. In contrast, a significant decrease in SCAD expression was observed in different ages of spontaneously hypertensive rats (SHR). On the other hand, swim‐trained rats developed physiological cardiac hypertrophy, whereas SHR developed pathological cardiac hypertrophy. The two kinds of cardiac hypertrophy exhibited divergent SCAD changes in myocardial fatty acids utilization. In addition, the expression of SCAD was significantly decreased in pathological cardiomyocyte hypertrophy, however, increased in physiological cardiomyocyte hypertrophy. SCAD siRNA treatment triggered the pathological cardiomyocyte hypertrophy, which showed that the down‐regulation of SCAD expression may play an important role in pathological cardiac hypertrophy. The changes in peroxisome proliferator‐activated receptor α (PPARα) was accordant with that of SCAD. Moreover, the specific PPARα ligand fenofibrate treatment increased the expression of SCAD and inhibited pathological cardiac hypertrophy. Therefore, we speculate that the down‐regulated expression of SCAD in pathological cardiac hypertrophy may be responsible for ‘the recapitulation of foetal energy metabolism’. The deactivation of PPARα may result in the decrease in SCAD expression in pathological cardiac hypertrophy. Changes in SCAD are different in pathological and physiological cardiac hypertrophy, which may be used as the molecular markers of pathological and physiological cardiac hypertrophy.