H2 and H3 relaxin inhibit high glucose-induced apoptosis in neonatal rat ventricular myocytes

Zhang, Xiaohui; Ma, Xiao; Zhao, Meng; Zhang, Bo; Chi, Jinyu; Liu, Wenxiu; Chen, Wen-Jia; Fu, Yu; Liu, Yue; Yin, Xinhua

doi:10.1016/j.biochi.2014.11.004

Cited by 25 publications

(21 citation statements)

References 39 publications

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“…rhRLX may also indirectly inhibit cardiac fibrosis through its anti‐inflammatory (Nistri et al , ; Perna et al , ; ), antioxidant (Perna et al , ), anti‐hypertrophic (Dschietzig et al , ; Moore et al , ; Parikh et al , ) and anti‐apoptotic (Moore et al , ; Bonacchi et al , ; Samuel et al , ; Zhang et al , ) actions, while being able to promote tissue repair via its angiogenic (Formigli et al , ; Samuel et al , ; Segal et al , ), vasodilatory (Conrad and Shroff, ; McGuane et al , ) and wound healing (Mu et al , ) properties. However, the effects of rhRLX have largely been shown to be independent of blood pressure regulation (Du et al , ; Samuel et al , ).…”

Section: Anti‐fibrotic Effects Of Relaxin In the Cardiovascular Systemmentioning

confidence: 99%

Anti‐fibrotic actions of relaxin

Samuel

Royce

Hewitson

et al. 2016

British J Pharmacology

119

115

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Fibrosis refers to the hardening or scarring of tissues that usually results from aberrant wound healing in response to organ injury, and its manifestations in various organs have collectively been estimated to contribute to around 45-50% of deaths in the Western world. Despite this, there is currently no effective cure for the tissue structural and functional damage induced by fibrosisrelated disorders. Relaxin meets several criteria of an effective anti-fibrotic based on its specific ability to inhibit pro-fibrotic cytokine and/or growth factor-mediated, but not normal/unstimulated, fibroblast proliferation, differentiation and matrix production. Furthermore, relaxin augments matrix degradation through its ability to up-regulate the release and activation of various matrix-degrading matrix metalloproteinases and/or being able to down-regulate tissue inhibitor of metalloproteinase activity. Relaxin can also indirectly suppress fibrosis through its other well-known (anti-inflammatory, antioxidant, antihypertrophic, anti-apoptotic, angiogenic, wound healing and vasodilator) properties. This review will outline the organ-specific and general anti-fibrotic significance of exogenously administered relaxin and its mechanisms of action that have been documented in various non-reproductive organs such as the cardiovascular system, kidney, lung, liver, skin and tendons. In addition, it will outline the influence of sex on relaxin's anti-fibrotic actions, highlighting its potential as an emerging anti-fibrotic therapeutic. LINKED ARTICLESThis article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc Abbreviations α-SMA, α-smooth muscle actin; AT 2 receptor, angiotensin type 2 receptor; CCl 4 , carbon tetrachloride; ECM, extracellular matrix; HSC, hepatic stellate cell; INSL, insulin-like; KO, knockout; MSC, mesenchymal stem cell; PMA, phorbol 12-myristate 13-acetate; RLN, relaxin gene; rhRLX, synthetically or recombinantly produced drug form of relaxin; RXFP1, relaxin family peptide receptor 1; TIMP, tissue inhibitor of metalloproteinase IntroductionThe tissue response to stress depends on a number of intrinsic and extrinsic factors including the length and extent of injury. When injury or disease is mild or transient, then the tissue response leads to remodelling or regeneration of the organ parenchyma. However, if the injury is either severe or prolonged, the process is characterized by ongoing inflammation and extracellular matrix (ECM) production. Fibrosis is therefore a failure of the wound healing process, where ECM synthesis is ongoing (Wynn, 2008;Hewitson, 2009). This maladaptive response is particularly dependent on paracrine and autocrine production of TGF-β1 and the consequent recruitment of activated fibroblasts (myofibroblasts). Over-abundant ECM production and failure to resolve lead to significant organ damage and dysfunction, wh...

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Section: Anti‐fibrotic Effects Of Relaxin In the Cardiovascular Systemmentioning

confidence: 99%

Anti‐fibrotic actions of relaxin

Samuel

Royce

Hewitson

et al. 2016

British J Pharmacology

119

115

View full text Add to dashboard Cite

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“…Interestingly, the onset of ventricular arrhythmias during acute IR was reduced in relaxin‐treated rat or porcine hearts, likely to be due to reduced myocardial injury (Bani et al , ; Nistri et al , ). In vitro studies show that relaxin protects against cardiomyocyte apoptotic death induced by oxidative stress (Moore et al , ), hypoxia–reoxygenation (Boccalini et al , ) or high glucose exposure (Zhang et al , ) and involved activation of Akt together with increased Bcl‐2/Bax ratio, Notch‐1 activation or suppressed endoplasmic reticulum (ER) stress.…”

Section: Relaxin In Animal Models Of Cardiovascular Diseasementioning

confidence: 99%

The actions of relaxin on the human cardiovascular system

Sarwar¹,

Dschietzig

et al. 2016

British J Pharmacology

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The insulin-like peptide relaxin, originally identified as a hormone of pregnancy, is now known to exert a range of pleiotropic effects including vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory effects in both males and females. Relaxin produces these effects by binding to a cognate receptor RXFP1 and activating a variety of signalling pathways including cAMP, cGMP and MAPKs as well as by altering gene expression of TGF-β, MMPs, angiogenic growth factors and endothelin receptors. The peptide has been shown to be effective in halting or reversing many of the adverse effects including fibrosis in animal models of cardiovascular disease including ischaemia/reperfusion injury, myocardial infarction, hypertensive heart disease and cardiomyopathy. Relaxin given to humans is safe and produces favourable haemodynamic changes. Serelaxin, the recombinant form of relaxin, is now in extended phase III clinical trials for the treatment of acute heart failure. Previous clinical studies indicated that a 48 h infusion of relaxin improved 180 day mortality, yet the mechanism underlying this effect is not clear. This article provides an overview of the cellular mechanism of effects of relaxin and summarizes its beneficial actions in animal models and in the clinic. We also hypothesize potential mechanisms for the clinical efficacy of relaxin, identify current knowledge gaps and suggest new ways in which relaxin could be useful therapeutically. LINKED ARTICLESThis article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc Abbreviations ADHF, acute decompensated heart failure; AHF, acute heart failure; Ang II, angiotensin II; AC, arterial compliance; b-FGF, basic FGF; BMDECs, bone marrow-derived endothelial cells; CI, cardiac index; CO, cardiac output; ET-1, endothelin-1; ECM, extracellular matrix; i Ca 2+ , intracellular calcium; IR, ischaemia-reperfusion; mRen2, murine renin gene; MI, myocardial infarction; PGF, placental growth factor; PVR, pulmonary vascular resistance; SHR, spontaneously hypertensive rat; SVR, systemic vascular resistance; TIMP, tissue inhibitors of metalloproteinase; TGF-β1, transforming growth factor β1; VSMC, vascular smooth muscle cells; VAS, visual analogue scale IntroductionRelaxin is a heterodimeric peptide hormone closely related structurally to insulin. The major circulating form of relaxin is that produced by the RLN2 gene and is the cognate ligand for the RXFP1 receptor, a classical GPCR containing seven transmembrane spanning regions as well as a large extracellular domain with 10 leucine-rich repeats and a unique N-terminal LDL receptor type A module (Hsu et al., 2002). Relaxin is closely related to insulin-like peptide 3, relaxin-3 and insulin-like peptide 5, which are the cognate ligands for the relaxin family peptide receptors RXFP2, RXFP3 and RXFP4 respectively (Alexander et al., 2015b). ...

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“…In addition, as previously described, cell apoptosis induced by ER stress is reported to be independent of death receptor and mitochondrial pathways (22). In animals with hyperglycemia, which is associated with the pathogenesis of diabetes, the level of ER stress was upregulated and associated with myocardial cell apoptosis (3)(4)(5). Therefore, the suppression of ER stress may serve as an effective strategy to alleviate myocardial cell apoptosis to protect the myocardial function.…”

Section: Introductionmentioning

confidence: 71%

“…Diabetic cardiomyopathy, a severe diabetic complication, refers to ventricular dysfunction independent of alterations in blood pressure and coronary artery disease (2,3). In the past decades, numerous studies have investigated the mechanisms involved in diabetic cardiomyopathy (4)(5)(6)(7). At present, of the various etiologies that have been reported to be associated the pathogenesis of diabetic cardiomyopathy, the apoptosis of cardiomyocytes is considered to be one of the primary causes of diabetic cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

Melatonin ameliorates myocardial apoptosis by suppressing endoplasmic reticulum stress in rats with long‑term diabetic cardiomyopathy

Xiong

Tang

et al. 2017

Mol Med Report

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The effects of melatonin (MLT), which exerts cardioprotective effects against myocardial apoptosis, in long‑term diabetic cardiomyopathy are not currently well defined. The present study aimed to investigate how MLT protects the heart through modulating myocardial apoptosis in rats with type 2 diabetes mellitus (DM). In total, 36 rats were randomly divided into three groups, including control (n=12), DM (n=12) and DM + MLT (n=12) groups. The results demonstrated that, in DM rats, a significant increase was observed in the serum fasting blood glucose and lipid levels, in addition to insulin resistance and cardiac dysfunction, which were attenuated in DM rats treated with MLT. Additionally, cellular apoptosis in rats with DM was increased, and the expression of Bcl‑2 was downregulated, while levels of Bcl‑2‑associated X and caspase‑3 were upregulated, and these observations were reversed by MLT, as determined by TUNEL and western blot analysis, respectively. As increased endoplasmic reticulum (ER) stress induced by hyperglycemia is reported to be a factor for apoptosis, the present study also determined the expression of proteins associated with ER stress in cardiac tissues following MLT treatment by western blotting. The results further indicated that MLT decreased the expression of ER stress hallmarks, including CCAAT/enhancer‑binding protein homologous protein, glucose‑regulated protein 78, protein kinase RNA‑like endoplasmic reticulum kinase (PERK) and activating transcription factor 6α in cardiac tissues. In conclusion, the results of the present study indicate that MLT may protect heart by ameliorating cardiac ER stress‑induced apoptosis in diabetic cardiomyopathy.

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H2 and H3 relaxin inhibit high glucose-induced apoptosis in neonatal rat ventricular myocytes

Cited by 25 publications

References 39 publications

Anti‐fibrotic actions of relaxin

Anti‐fibrotic actions of relaxin

The actions of relaxin on the human cardiovascular system

Melatonin ameliorates myocardial apoptosis by suppressing endoplasmic reticulum stress in rats with long‑term diabetic cardiomyopathy

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