Specific receptor subtype mediation of LPA-induced dual effects in cardiac fibroblasts

Lysophosphatidic acid (LPA) is a phospholipid messenger with diverse effects mediated via receptors LPA1, LPA2 and LPA3. Our previous study revealed that serum LPA level is elevated after myocardial infarction (MI). However, very little is known about the effects of LPA on cardiac fibroblasts (CFs) that play a crucial role in left ventricular remodeling after MI. Here we demonstrated that LPA dose-dependently induced proliferation and collagen synthesis with the maximum stimulation at 10 microM that was preferentially mediated by LPA3. LPA also dose-dependently induced apoptotic cell death, as estimated by MTT assay, hoechst staining, TUNEL and flow cytometric analysis, with an IC(50) of 50 microM. Moreover, apoptotic cell death may involve mitochondrial dysfunction and activation of caspase-3. Apoptosis induced by LPA might be mediated by LPA1. These data suggest that LPA exerts dual proliferative and proapoptotic actions mediated by specific LPA receptor subtypes.     

Possible mechanism of GATA4 inhibiting myocardin activity during cardiac hypertrophy

Myocardin is an important factor that regulates cardiac hypertrophy, and its activity can be regulated by GATA4. However, the molecular mechanism of the above process remains unclear. This paper presents three kinds of possible molecular mechanisms of GATA4 inhibiting myocardin activity in the process of cardiac hypertrophy. First, a competitive combination of GATA4 and SRF with myocardin could reduce the formation of the myocardin-SRF-CarG box complex when GATA4 was overexpressed. Second, overexpression of GATA4 could inhibit the combination of myocardin and p300 and downregulate acetylated myocardin levels. Finally, GATA4 could upregulate the phosphorylation of myocardin protein upon activation of the ERK pathway. These findings may provide insight into the function of GATA4 and myocardin in the occurrence and development of cardiac hypertrophy.     

溶血磷脂酸受体及下游信号通路在心脏细胞生长中的调节作用

溶血磷脂酸（1ysophosphatidic acid,LPA）是一种十分活跃的磷脂信号分子,具有广泛的生物学效应,包括诱导神经轴突回缩、应力纤维形成、促进血小板凝集、诱导平滑肌收缩、刺激血管平滑肌细胞增殖等。LPA通过其受体及耦联的G蛋白调节细胞内信号途径,介导各种生物学效应。心脏组织中存在多种LPA受体亚型,尤其受体LPAl亚型在心脏组织中的含量仅次于脑,位居第二,暗示LPA在心脏中有重要的生物学功能。本文着重对LPA的5种受体亚型的组织分布、与G蛋白的耦联和对第二信使的活性调节,以及LPA及其受体亚型对心脏细胞的生长调节作一综述。     

Silibinin attenuates cardiac hypertrophy and fibrosis through blocking EGFR‐dependent signaling

Cardiac hypertrophy is a major determinant of heart failure. The epidermal growth factor receptor (EGFR) plays an important role in cardiac hypertrophy. Since silibinin suppresses EGFR in vitro and in vivo, we hypothesized that silibinin would attenuate cardiac hypertrophy through disrupting EGFR signaling. In this study, we examined this hypothesis using neonatal cardiac myocytes and fibroblasts induced by angiotensin II (Ang II) and animal model by aortic banding (AB) mice. Our data revealed that silibinin obviously blocked cardiac hypertrophic responses induced by pressure overload. Meanwhile, silibinin markedly reduced the increased generation of EGFR. Moreover, these beneficial effects were associated with attenuation of the EGFR‐dependent ERK1/2, PI3K/Akt signaling cascade. We further demonstrated silibinin decreased inflammation and fibrosis by blocking the activation of NF‐κB and TGF‐β1/Smad signaling pathways in vitro and in vivo. Our results indicate that silibinin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through blocking EGFR activity and EGFR‐dependent different intracellular signaling pathways. J. Cell. Biochem. 110: 1111–1122, 2010. Published 2010 Wiley‐Liss, Inc.     

The long noncoding RNA NR_045363 involves cardiomyocyte apoptosis and cardiac repair via p53 signal pathway

Long noncoding RNAs (lncRNAs) can participate in various biological behaviors, including regulating cell differentiation, proliferation, and apoptosis. The investigators have previously confirmed that highly conserved lncRNA NR_045363 controls cardiomyocyte (CM) proliferation and cardiac repair. The present study investigates the effects of NR_045363 on CM apoptosis. Seven‐day‐old mice were subjected to permanent left anterior descending coronary artery ligation (LAD), and the NR_045363 expression was analyzed by quantitative real‐time polymerase chain reaction (qRT‐PCR). The expression of NR_045363 in the MI group significantly exceeded the Sham group during the first week after the operation. The NR_045363 expression was knocked down in primary cultured CMs using an NR_045363‐targeting lncRNA Smart silencer, and the apoptosis of CMs was analyzed by terminal‐deoxynucleoitidyl transferase mediated nick end labeling and Annexin‐V/PI double staining. These present results indicate that the NR_045363 knockdown significantly promoted the apoptosis of CMs. In order to investigate the underlying mechanism, RNA‐sequencing (RNA‐seq) was performed, and ingenuity pathway analysis (IPA) was used to analyze the RNA‐seq results. The RNA‐seq data revealed that a total of 2,291 genes were upregulated or downregulated in NR_045363 knockdown CMs, and the IPA analysis indicated that tumor protein 53 (p53) was the upstream regulator. In vivo, the NR_045363 overexpression through the AAV9 system improved the heart function after MI in 7‐day‐old mice and inhibited the CM apoptosis. These data suggest that NR_045363 is involved in CM apoptosis and that NR_045363 overexpression exerts positive effects on cardiac repair by alleviating CM apoptosis through the inhibition of the p53 pathway.     

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.     

血小板源生长因子受体介导的信号转导在自发性高血压大鼠心肌肥大中的作用

为了探索血小板源生长因子 (platelet derivedgrowthfactor,PDGF)受体介导的信号转导在自发性高血压大鼠(spontaneouslyhypertensiverats,SHR)心肌肥大中的作用 ,实验采用Westernblot法检测SHR及其对照WKY大鼠心肌PDGF受体β和细胞外信号调节激酶 (extracellularsignal regulatedkinase1/ 2 ,ERK 1/ 2 )的蛋白表达和ERK 1/ 2磷酸化水平的变化。结果显示 :4周龄SHR的收缩压、舒张压、±dp/dtmax和心肌肥大指数与同龄WKY大鼠相比均无明显差异 ,而 12周龄SHR上述指标与同龄WKY大鼠相比均明显升高 ,表明 12周SHR已发生高血压 ,心脏收缩功能代偿性增强 ,并出现心肌肥大。 4周龄SHR心肌PDGF受体 β和ERK1/ 2的磷酸化水平以及ERK 1/ 2的蛋白表达水平与同龄对照相比均无明显变化 ,12周时SHR心肌PDGF受体 β的蛋白表达较同龄WKY增加 32 77% (P <　　　　　　　　　 0 0 5 ) ,PDGF受体介导的信号转导通路的下游信号分子ERK 1/ 2的磷酸化水平较同龄WKY升高 19 6 % (P =0 0 1) ,表明ERK 1/ 2的活化增加 ,但ERK 1/ 2的蛋白表达水平尚无变化。为进一步明确PDGF受体 β在心肌细胞生长中的作用及其与ERK 1/ 2活性的关系 ,采用PDGF BB刺激培养的乳鼠心肌细胞 ,发现 [3 H]亮氨酸掺入量明显增加 ,ERK 1/ 2的磷酸化水平明     

雌激素受体信号通路在乳腺癌发生和治疗中的作用

雌激素受体信号通路在调控乳腺细胞增殖和凋亡等生理机能中发挥重要功能,该通路出现调控异常时可导致乳腺癌发生。雌激素受体在乳腺癌发生中的作用机制包括核受体介导的基因组信号通路和膜受体介导的非基因组信号通路以及二者的相互作用。基于雌激素受体信号通路及其关键信号分子的靶向治疗是开展乳腺癌治疗的重要策略与有效途径。对雌激素受体结构以及雌激素受体信号通路在乳腺癌发生和治疗中的作用作一综述。     

Lysophosphatidic receptor, LPA3, is positively and negatively regulated by progesterone and estrogen in the mouse uterus

Reciprocal interactions between blastocysts and receptive uteri are essential for successful implantation. This process is regulated by the timely interplay of two ovarian hormones, progesterone and estrogen. However, the molecular targets of these hormones are largely unknown. We showed recently that a small bioactive lysophospholipid, lysophosphatidic acid, plays a pivotal role in the establishment of implantation via its cellular receptor, LPA(3). Here we demonstrate that LPA(3) expression is positively and negatively regulated by steroid hormones in mouse uteri. The LPA(3) mRNA level in the uteri increased during early pseudopregnancy, peaking around 3.5 days post coitus (3.5 d.p.c.), then, decreased to the basal level on 4.5 d.p.c. LPA(3) expression remained at a low level in ovariectomized mice, and administration of progesterone to ovariectomized mice up-regulated LPA(3) mRNA expression. In addition, simultaneous administration of estrogen counteracted the effect of progesterone. These results show that progesterone and estrogen cooperatively regulate LPA(3) expression, thereby contributing to the receptivity of uteri during early pregnancy.     

Differential expression and localization of annexin V in cardiac myocytes during growth and hypertrophy

Recently it was shown that annexin V is the most prominent member of the annexin family in the adult heart [1]. Amongst others, annexin V has been suggested to play a role in developmental processes. The aim of the present study was to explore whether in the heart annexin V content and localization change during maturational and hypertrophic growth, in order to obtain indications that annexin V is involved in cardiac growth processes. First, in the intact rat heart annexin V content and localization were studied during perinatal development. It was clearly demonstrated that annexin V content in total heart transiently increased in the first week after birth, from 0.79 ± 0.06 µg/mg protein at l day before birth to a peak value of 1.24 ± 0.08 µg/mg protein 6 days after birth, whereafter annexin V protein levels declined to a value of 0.70 ± 0.06 µg/mg protein at 84 days after birth (p < 0.05). Differences in annexin V content were also observed between myocytes isolated from neonatal and adult hearts [0.81 ± 0.09 and 0.17 ± 0.08 µg/mg protein, respectively (p < 0.05)]. Moreover, during cardiac maturational growth the subcellular localization of annexin V might change from a cytoplasmic to a more prominent sarcolemmal localization. Second, in vivo hypertrophy induced by aortic coarctation resulted in a marked degree of hypertrophy (22% increase in ventricular weight), but was not associated with a change in annexin V localization or content. The quantitative results obtained with intact hypertrophic rat hearts are supported by findings in neonatal ventricular myocytes, in which hypertrophy was induced by phenylephrine (10^-5 M). In the latter model no changes in annexin V content could be observed either. In conclusion, the marked alterations in annexin V content during the maturational growth in the heart suggest a possible involvement of this protein in this process. In contrast, the absence of changes in annexin V content and localization in hypertrophied hearts compared to age matched control hearts suggests that annexin V does not play a crucial role in the maintenance of the hypertrophic phenotype of the cardiac muscle cell. This notion is supported by observations in phenylephrine-induced hypertrophied neonatal cardiomyocytes.     

Isoproterenol-induced hypertrophy of neonatal cardiac myocytes and H9c2 cell is dependent on TRPC3-regulated CaV1.2 expression

Ca_V1.2 and transient receptor potential canonical channel 3 (TRPC3) are two proteins known to have important roles in pathological cardiac hypertrophy; however, such roles still remain unclear. A better understanding of these roles is important for furthering the clinical understanding of heart failure. We previously reported that Trpc3-knockout (KO) mice are resistant to pathologic hypertrophy and that their Ca_V1.2 protein expression is reduced. In this study, we aimed to examine the relationship between these two proteins and characterize their role in neonatal cardiomyocytes. We measured Ca_V1.2 expression in the hearts of wild-type (WT) and Trpc3^−/− mice, and examined the effects of Trpc3 knockdown and overexpression in the rat cell line H9c2. We also compared the hypertrophic responses of neonatal cardiomyocytes cultured from Trpc3^−/− mice to a representative hypertrophy-causing drug, isoproterenol (ISO), and measured the activity of nuclear factor of activated T cells 3 (NFAT3) in neonatal cardiomyocytes (NCMCs). We inhibited the L-type current with nifedipine, and measured the intracellular calcium concentration using Fura-2 with 1-oleoyl-2-acetyl-sn-glycerol (OAG)-induced Ba²⁺ influx. When using the Trpc3-mediated Ca²⁺ influx, both intracellular calcium concentration and calcium influx were reduced in Trpc3-KO myocytes. Not only was the expression of Ca_V1.2 greatly reduced in Trpc3-KO cardiac lysate, but the size of the Ca_V1.2 currents in NCMCs was also greatly reduced. When NCMCs were treated with Trpc3 siRNA, it was confirmed that the expression of Ca_V1.2 and the intracellular nuclear transfer activity of NFAT decreased. In H9c2 cells, the ISO activated- and verapamil inhibited- Ca²⁺ influxes were dramatically attenuated by Trpc3 siRNA treatment. In addition, it was confirmed that both the expression of Ca_V1.2 and the size of H9c2 cells were regulated according to the expression and activation level of TRPC3. We found that after stimulation with ISO, cell hypertrophy occurred in WT myocytes, while the increase in size of Trpc3-KO myocytes was greatly reduced. These results suggest that not only the cell hypertrophy process in neonatal cardiac myocytes and H9c2 cells were regulated according to the expression level of Ca_V1.2, but also that the expression level of Ca_V1.2 was regulated by TRPC3 through the activation of NFAT.     

Attenuation of cardiac hypertrophy by inhibiting both mTOR and NFkappaB activation in vivo

A role for the PI3K/Akt/mTOR pathway in cardiac hypertrophy has been well documented. We reported that NFκB activation is needed for cardiac hypertrophy in vivo. To investigate whether both NFκB activation and PI3K/Akt/mTOR signaling participate in the development of cardiac hypertrophy, two models of cardiac hypertrophy, namely, induction in caAkt-transgenic mice and by aortic banding in mice, were employed. Rapamycin (2 mg/kg/daily), an inhibitor of the mammalian target of rapamycin, and the antioxidant pyrrolidine dithiocarbamate (PDTC; 120 mg/kg/daily), which can inhibit NFκB activation, were administered to caAkt mice at 8 weeks of age for 2 weeks. Both rapamycin and PDTC were also administered to the mice immediately after aortic banding for 2 weeks. Administration of either rapamycin or PDTC separately or together to caAkt mice reduced the ratio of heart weight/body weight by 21.54, 32.68, and 42.07% compared with untreated caAkt mice. PDTC administration significantly reduced cardiac NFκB activation by 46.67% and rapamycin significantly decreased the levels of p70S6K by 34.20% compared with untreated caAkt mice. Similar results were observed in aortic-banding-induced cardiac hypertrophy in mice. Our results suggest that both NFκB activation and the PI3K/Akt signaling pathway participate in the development of cardiac hypertrophy in vivo.     

Molecular modeling and mutagenesis of the ligand-binding pocket of the mGlu3 subtype of metabotropic glutamate receptor

A homology model of the extracellular domain of the mGlu3 subtype of metabotropic glutamate (mGlu) receptor was generated and tested using site-directed mutagenesis, a radioligand-binding assay using the Group II selective agonist (2S,2'R,3'R)-2-(2',3'-[3H]dicarboxycyclopropyl) glycine ([3H]DCG-IV), and in a fluorescence-based functional assay in live transiently transfected human embryonic kidney cells. Ten of the 12 mGlu3 mutants (R64A, R68A, Y150A, S151A, T174A, D194A, Y222A, R277A, D301A and K389) showed either no binding or a 90% or greater loss of specific [3H]DCG-IV binding. Several analogous mutations in mGlu2 supported the results obtained with mGlu3. These results demonstrate that the binding of [3H]DCG-IV to mGlu3 is exceptionally sensitive to mutagenesis-induced perturbations. In silico docking of DCG-IV into the agonist binding pocket of mGlu3 facilitated the interpretation the mutagenesis results. Tyrosines 150 and 222, and arginine 277 show close contacts with the third carboxylic acid group in DCG-IV, which is not present in glutamate or (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I). Mutation of these three amino acids to alanine resulted in a near complete loss of receptor activation by DCG-IV and retention of near wild-type affinity for L-CCG-I. It is proposed that hydrogen bonding between this carboxylate and tyrosines 150 and 222 and arginine 277 provide a partial explanation for the high affinity and Group II selectivity of DCG-IV. These findings define the essential features of the ligand-binding pocket of mGlu3 and, together with other recent studies on mGlu receptors, provide new opportunities for structure-based drug design.     

The potential signaling pathway between peroxisome proliferator-activated receptor gamma and retinoic acid receptor alpha in renal interstitial fibrosis disease

Abstract

Peroxisome proliferator-activated receptorγ (PPARγ) can regulate the process of cell apoptosis and is related to the progression of renal disorders. Retinoic acid receptor alpha (RARα) is one of the nuclear receptors involved in a variety of kidney diseases. Renal interstitial fibrosis (RIF) is a common denominator of chronic kidney disease (CKD). This study investigated whether a potential signaling pathway existed between PPARγ and RARα in RIF rats with unilateral ureteral obstruction (UUO). The rats were randomly divided into four groups: a model group subjected to UUO (GU), and three other groups treated with rosiglitazone sodium (GRS), GW9662 and dimethyl sulfoxide (DMSO), n?=?40, respectively. Renal tissues were collected two and four weeks after post-surgery. The relevant indicators were detected. In comparison with the GU group, the expressions of PPARγ and RARα (protein and mRNA) were increased in the GRS group, and decreased in the GW9662 group (all p?<?0.01). The RIF index, mRNA and protein expression of transforming growth factor-β1 (TGF-β1), and the protein expressions of collagen-IV (Col-IV) and fibronectin (FN) in the GRS group were more markedly reduced than those in the GU group; their levels in the GW9662 group were elevated (all p?<?0.01). PPARγ or RARα was negatively correlated to the RIF index, TGF-β1, Col-IV and FN. PPARγ was positively correlated with RARα (all p?<?0.01). In conclusion, PPARγ agonist can elevate the expression of PPARγ or RARα in RIF rats. There might be a potential signaling pathway between PPARγ and RARα in RIF disease.     

溶血磷脂酸在皮肤损伤疾病中的作用及其分子机制

皮肤作为人体最大器官覆盖于全身,能阻挡有害物质的侵入,保护人体内环境稳态,参与人体代谢过程。皮肤损伤、炎症和纤维化等,都会导致皮肤屏障功能的减退,影响正常的生命活动。溶血磷脂酸(lysophosphatidic acid,LPA)是十分活跃的磷脂信号分子,参与多种生理和病理生理过程。LPA是维持体内平衡所必需的生物活性脂质介质,在皮肤中通过不同的信号通路发挥多功能磷脂信使作用。本文综述了皮肤中溶血磷脂酸受体(lysophosphatidic acid receptor,LPA1-6)及其细胞信号通路的作用及机制,综述了LPA在皮肤创面愈合、皮肤瘢痕、皮肤黑色素瘤、硬皮病、皮肤瘙痒、过敏性皮炎、皮肤屏障、皮肤疼痛,皮肤毛发生长中的作用及分子机制,有助于了解LPA在皮肤中的生理和病理生理作用。深入研究LPA的作用机制将有助于挖掘其在皮肤治疗中的作用,开发以LPA为靶点的药物。     

Anatomical location of LPA1 activation and LPA phospholipid precursors in rodent and human brain

Lysophosphatidic acid (LPA) is a signaling molecule that binds to six known G protein‐coupled receptors: LPA₁–LPA₆. LPA evokes several responses in the CNS, including cortical development and folding, growth of the axonal cone and its retraction process. Those cell processes involve survival, migration, adhesion proliferation, differentiation, and myelination. The anatomical localization of LPA₁ is incompletely understood, particularly with regard to LPA binding. Therefore, we have used functional [³⁵S]GTPγS autoradiography to verify the anatomical distribution of LPA₁ binding sites in adult rodent and human brain. The greatest activity was observed in myelinated areas of the white matter such as corpus callosum, internal capsule and cerebellum. MaLPA₁‐null mice (a variant of LPA₁‐null) lack [³⁵S]GTPγS basal binding in white matter areas, where the LPA₁ receptor is expressed at high levels, suggesting a relevant role of the activity of this receptor in the most myelinated brain areas. In addition, phospholipid precursors of LPA were localized by MALDI‐IMS in both rodent and human brain slices identifying numerous species of phosphatides and phosphatidylcholines. Both phosphatides and phosphatidylcholines species represent potential LPA precursors. The anatomical distribution of these precursors in rodent and human brain may indicate a metabolic relationship between LPA and LPA₁ receptors.

     

心梗大鼠通过有氧运动激活PI3K-Akt-PKG-1/p-PLN-SERCA2a通路抑制心肌细胞凋亡改善心功能

为探讨有氧运动对心梗大鼠心功能的影响,将3月龄SD雄性大鼠适应性喂养1周后随机分为正常组(C组)、假手术组(S组)、心梗安静组(MI组)、正常+运动组(CE组)、心梗+运动组(ME组),每组8只. MI组结扎左冠状动脉前降支制备心梗模型;S组只穿线不结扎;CE组与ME组术后1周开始有氧训练,运动方式为依次以10 m/min×10 min,13 m/min×10 min,16 m/min×40 min进行跑台训练,60 min/d,每周5 d,连续4周.训练结束后次日,采用血流动力学检测左室收缩压(left ventricular systolic pressure,LVSP)、左室舒张末压(left ventricular end-diastolic pressure,LVEDP)和收缩/舒张速率(±dp/dtmax)等心功能相关指标,单细胞可视化动缘探测系统(IonOptix)测定[Ca²⁺]i变化百分数([Ca²⁺]iamplitude)、[Ca²⁺]i荧光比率(ratio)、达峰速率(departure veloc...     

心梗后心肌重构过程中AT_(1A)、AT_2受体表达的变化

为探讨AT1、AT2 受体在心肌重构演变过程中的作用 ,本实验应用免疫组化、电镜技术和图像分析方法 ,观察了大鼠心梗后心肌重构过程中非梗塞区AT1、AT2 受体表达的动态变化。结果显示 ,心梗术后 3d ,电镜显示非梗塞区心肌细胞肌原纤维横纹消失 ,线粒体肿胀 ,成纤维细胞增多 ,免疫组化显示AT1A受体在非梗塞区心肌组织表达明显升高 (P <0 0 0 1) ,AT2 受体表达无明显变化 (P >0 0 5 ) ;心梗术后 14d ,可见心肌细胞肌原纤维横纹 ,心肌细胞间胶原纤维明显增多 ,同时AT1A受体在心肌的表达比心梗术后 3d时减弱 ,但仍高于对照组 (P <0 0 5 ) ,AT2 受体表达明显增加 (P <0 0 0 1)。结果提示 :心梗后非梗塞区心肌AT1A、AT2 受体表达先后上调 ,可能参与介导心肌重构过程     

Regulation of the (pro)renin-renin receptor in cardiac remodelling

The (pro)renin-renin receptor [(P)RR] was discovered as an important novel component of the renin-angiotensin system (RAS). The functional significance of (P)RR is widely studied in renal and vascular pathologies and has sparked interest for a potential role in cardiovascular disease. To investigate the role of (P)RR in cardiac pathophysiology, we aimed to assess (P)RR regulation in adverse cardiac remodelling of the failing heart. In particular, we evaluated the expression of (P)RR in different models of heart failure and across different species. Significantly increased levels of (P)RR mRNA were found in post-myocardial infarcted (MI) hearts of rats (1.6-fold, P < 0.05) and mice (5-fold, P < 0.01), as well as in transgenic rats with overexpression of the mouse renin gene (Ren2) (2.2-fold, P < 0.01). Moreover, we observed a strong increase of (P)RR expression in hearts of dilated cardiomyopathy (DCM) patients (5.3-fold, P < 0.001). Because none of the tested commercially available antibodies appeared to detect endogenous (P)RR, a (P)RR-specific polyclonal antibody was generated to study (P)RR protein levels. (P)RR protein levels were significantly increased in the post-MI rat heart (1.4-fold, P < 0.05) as compared to controls. Most interestingly in DCM patients, a significant 8.7-fold (P < 0.05) increase was observed. Thus, protein expression paralleled gene expression. These results demonstrate that (P)RR expression is strongly up-regulated both in rodent models of heart failure and in the failing human heart, hinting to a potential role for (P)RR in cardiac pathophysiology.