MicroRNA and receptor mediated signaling pathways as potential therapeutic targets in heart failure

Introduction: Cardiac remodelling is a complex pathogenetic pathway involving genome expression, molecular, cellular, and interstitial changes that cause changes in size, shape and function of the heart after cardiac injury.

Areas covered: We will review recent advances in understanding the role of several receptor-mediated signaling pathways and micro-RNAs, in addition to their potential as candidate target pathways in the pathogenesis of heart failure. The myocyte is the main target cell involved in the remodelling process via ischemia, cell necrosis and apoptosis (by means of various receptor pathways), and other mechanisms mediated by micro-RNAs. We will analyze the role of some receptor mediated signaling pathways such as natriuretic peptides, mediators of glycogen synthase kinase 3 and ERK1/2 pathways, beta-adrenergic receptor subtypes and relaxin receptor signaling mechanisms, TNF/TNF receptor family and TWEAK/Fn14 axis, and some micro-RNAs as candidate target pathways in pathogenesis of heart failure. These mediators of receptor-mediated pathways and micro-RNA are the most addressed targets of emerging therapies in modern heart failure treatment strategies.

Expert opinion: Future treatment strategies should address mediators involved in multiple steps within heart failure pathogenetic pathways.     

Novel CTRP8‐RXFP1‐JAK3‐STAT3 axis promotes Cdc42‐dependent actin remodeling for enhanced filopodia formation and motility in human glioblastoma cells

C1q tumor necrosis factor‐related peptide 8 (CTRP8) is the least studied member of the C1Q‐TNF‐related peptide family. We identified CTRP8 as a ligand of the G protein‐coupled receptor relaxin family peptide receptor 1 (RXFP1) in glioblastoma multiforme (GBM). The CTRP8‐RXFP1 ligand–receptor system protects human GBM cells against the DNA‐alkylating damage‐inducing temozolomide (TMZ), the drug of choice for the treatment of patients with GBM. The DNA protective role of CTRP8 was dependent on a functional RXFP1‐STAT3 signaling cascade and targeted the monofunctional glycosylase N‐methylpurine DNA glycosylase (MPG) for more efficient base excision repair of TMZ‐induced DNA‐damaged sites. CTRP8 also improved the survival of GBM cells by upregulating anti‐apoptotic BCl‐2 and BCL‐XL. Here, we have identified Janus‐activated kinase 3 (JAK3) as a novel member of a novel CTRP8‐RXFP1‐JAK3‐STAT3 signaling cascade that caused an increase in cellular protein content and activity of the small Rho GTPase Cdc42. This is associated with significant F‐actin remodeling and increased GBM motility. Cdc42 was critically important for the upregulation of the actin nucleation complex N‐Wiskott–Aldrich syndrome protein/Arp3/4 and actin elongation factor profilin‐1. The activation of the RXFP1‐JAK3‐STAT3‐Cdc42 axis by both RXFP1 agonists, CTRP8 and relaxin‐2, caused extensive filopodia formation. This coincided with enhanced activity of ezrin, a key factor in tethering F‐actin to the plasma membrane, and inhibition of the actin filament severing activity of cofilin. The F‐actin remodeling and pro‐migratory activities promoted by the novel RXFP1‐JAK3‐STAT3‐Cdc42 axis were blocked by JAK3 inhibitor tofacitinib and STAT3 inhibitor STAT3 inhibitor VI. This provides a new rationale for the design of JAK3 and STAT3 inhibitors with better brain permeability for clinical treatment of the pervasive brain invasiveness of GBM.     

松弛素对高糖诱导的肾小管上皮细胞转分化及分泌细胞外基质的影响

目的:观察人松弛素(Relaxin)对高糖培养人肾小管上皮细胞(HK-2)转分化、分泌细胞外基质的影响。方法:实验分组:正常糖组:含5.5 mmol/L葡萄糖;高糖组:含30 mmol/L葡萄糖;高渗组(甘露醇组);高糖+松弛素干预组;ELISA法检测细胞上清中TGF-β1、细胞胶原(ColⅠ)、纤连蛋白(FN)的表达。免疫印迹技术(Western blot)检测α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)表达,确定肾小管上皮细胞表型转化情况。结果:与正常糖组相比,高糖组肾小管上皮细胞分泌ColⅠ、FN、TGF-β1显著增加,在高糖培养基中加入人松弛素干预后可显著抑制由高糖诱导的ColⅠ、FN、TGF-β1的高表达,降低α-SMA表达,抑制肾小管上皮细胞转分化。结论:松弛素能抑制高糖诱导HK-2细胞分泌细胞外基质,抑制HK-2细胞转分化,具有抗纤维化作用。     

Seminal immunoreactive relaxin in domestic animals and its relationship to sperm motility as a possible index for predicting the fertilizing ability of sires

Although immunoassayable relaxin has been detected in human and boar seminal plasma, there is no evidence suggesting the existence of immunoreactive relaxin in the seminal plasma of other domestic animals. The first objective of this study was to determine whether immunoreactive relaxin was present in the seminal plasma of bulls, rams and he-goats. In addition, the correlation of immunoreactive relaxin with sperm motility as an index for predicting the fertilizing ability of bull sires was investigated. Semen with normal sperm motility was collected from bulls, rams and he-goats, and the relaxin immunoreactivity of the semen samples was measured using a time-resolved fluoroimmunoassay (TR-FIA) for porcine relaxin that we developed. The presence of relaxin immunoreactivity was demonstrated in seminal plasma from bulls, rams and he-goats. The level of immunoreactive relaxin in seminal plasma was the highest in bulls followed by humans, rams, boars and he-goats in that order, when relaxin levels in boar and human semen having normal sperm motility were also assayed under the same conditions. When the correlation between the seminal plasma level of immunoreactive relaxin and sperm motility was examined in bull semen samples as an index for predicting fertilizing ability, it was found that the relaxin level was significantly correlated with the percentage of spermatozoa showing the most intensive motility (r = 0.64, p < 0.05). These results indicate that immunoreactive relaxin is widely found in the seminal plasma of domestic animals and that measuring the relaxin concentration of seminal plasma may be useful to identify subfertile sires or predict the fertility potential of individual sires.     

松弛素在慢性心血管及肾脏疾病中的作用及应用前景

纤维化是多种慢性心血管和肾脏疾病的共同特征,包括心肌和血管硬化、肾脏间质纤维化、肾小球硬化等,导致了器官功能异常和结构改变。松弛素是目前新发现的具有抗纤维化效应的激素,它可通过抑制胶原合成、增加胶原降解延缓器官纤维化进程,此外还有增加器官血供、促进血管新生及创伤愈合的作用。     

Mechanism of the Haemotensive Action of Porcine Relaxin in Anaesthetized Rats

Experiments were done to examine the pressor effect of iv porcine relaxin in anaesthetized rats. Acute injections of relaxin caused consistent and sustained rises in systemic blood pressure that were dose-dependent within the physiological range. Pretreatment of rats with a specific vasopressin (V1) receptor antagonist, but not an α-adrenoreceptor antagonist, substantially reduced the pressor effect of relaxin. After the vasopressin receptor antagonist, small rises in blood pressure occurred after a longer latent period, compared with the responses in intact animals. The data clearly indicate that acute injections of relaxin cause a pressor response that is predominantly affected via the release of vasopressin. The possible sources of the persistent hypertensive component are discussed and it is suggested that relaxin might act through the central angiotensinergic systems to release vasopressin and cause a pressor response.     

Administration study of recombinant human relaxin‐2 in horse for doping control purpose

The insulin‐like peptide relaxin (RLX), an endogenous peptide hormone produced in human for pregnancy and reproduction, is also known to exert a range of physiological and pathological effects. Its use is banned in human sports, horseracing, and equestrian competitions due to its potential performance enhancing effect through vasodilation resulting in the increase of blood and oxygen supplies to muscles. Little is known about the biotransformation and elimination of RLX in horses. This paper describes an administration study of rhRLX‐2 and its elimination in horses, and the development of sensitive methods for the detection and confirmation of rhRLX‐2 in both horse plasma and urine by nano‐liquid chromatography/high resolution mass spectrometry (nano‐LC/HRMS) after immunoaffinity extraction with the objective of controlling the abuse of rhRLX‐2 in horses. The limits of detection in plasma and urine are 2 pg/mL and 5 pg/mL, respectively. Two thoroughbred geldings were each administered one dose of 10 mg rhRLX‐2 subcutaneously daily for 3 consecutive days. The rhRLX‐2 could be detected and confirmed in the plasma and urine samples collected 105 h and 80 h, respectively, after the last dose of administration. For doping control purposes, rhRLX‐2 ELISA could be used as a screening test to identify potential positive samples for further investigation using the nano‐LC/HRMS methods.     

松弛素在放射性肺损伤模型中的表达和作用

目的动态观察放射性肺损伤大鼠模型及松弛素的表达和作用,寻求防治放射性肺损伤的新途径。方法 72只大鼠随机分为对照组和照射组,照射组可分为单纯照射组和松弛素组。照射组第0天25Gy全肺照射,松弛素组第42天起应用松弛素治疗,第1、7、14、28、35、42、49、56天终止实验,肺组织行病理学观察、羟脯氨酸含量及松弛素基因水平表达的测定。结果与对照组相比,照射组松弛素mRNA表达升高,呈现先上升后下降的趋势,照射组第42天出现明显的肺纤维化,应用松弛素治疗后,胶原沉积减少,松弛素组的松弛素mRNA表达较单纯照射组显著升高,差异有统计学意义(P0.05)。结论松弛素与放射性肺损伤的发生、发展有很大的关系,并能改善已形成的肺纤维化。     

Relaxin concentrations in exoembryonic fluids during the first trimester

In 15 women undergoing therapeutic termination of pregnancy(8–13 weeks), the median concentration of relaxin was1000 ng/l in maternal serum, 122 ng/l in coelomic fluid and9 ng/l in amniotic fluid. Its presence in coelomic fluid suggeststhat relaxin may be present in the fetal circulation and thusbe able to influence embryonic development during the periodof organogenesis.