Chronic lower-dose relaxin administration protects from arrhythmia in experimental myocardial infarction due to anti-inflammatory and anti-fibrotic properties

Beiert, Thomas; Knappe, Vincent; Tiyerili, Vedat; Stöckigt, Florian; Effelsberg, Verena; Linhart, Markus; Steinmetz, Martin; Klein, Sabine; Schierwagen, Robert; Trebicka, Jonel; Roell, Wilhelm; Nickenig, Georg; Schrickel, Jan W.; Andrié, René

doi:10.1016/j.ijcard.2017.09.017

Cited by 24 publications

(21 citation statements)

References 42 publications

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“…In aged rats, this hypothesis was strengthened by RNA-sequencing data [8] showing reduced SCN5A in aging and increased SCN5A expression by RLX in male and female LV [8] (GSE106377). Many of these findings have been confirmed in two studies in a murine myocardial infarction (MI) model [76,77] showing a significant reduction in AF by RLX (75 μg/kg/day) after MI compared to control mice, significantly reduced fibrosis in the RLX group and reduced inflammatory markers In a rat model of MI, Wang et al [78] showed that RLX (500 μg/kg/day) significantly blunted the reduction of Cx43 in the infarcted myocardium and suppressed ventricular tachyarrhythmia.…”

Section: Relaxin As An Anti-arrhythmicmentioning

confidence: 83%

Cardioprotective actions of relaxin

Martin

Romero

Salama

2019

Molecular and Cellular Endocrinology

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Relaxin, a hormone of pregnancy, has shown broad cardioprotective effects including anti-fibrotic (reversed excess TGFβ signaling), anti-arrhythmic (Nav1.5 and INa upregulation and Cx43 phosphorylation and trafficking to intercalated disks) and anti-inflammatory properties (reduced IL-1β and IL-6). While relaxin's anti-fibrotic effects are thought to occur through the SMAD2/3/TGFβ pathway, there is a general lack of understanding of relaxin's mode of action to increase sodium current and alter connexin43 localization to suppress arrhythmias. Based on a rat model of aging, we tested the hypothesis that relaxin acts through activation of Wnt/βcatenin signaling to mediate its effects on Nav1.5 and Cx43 and to regulate collagen expression. We show for the first time that relaxin activates canonical Wnt signaling (increased nuclear βcatenin) to increase Nav1.5 in isolated cardiomyocytes. Block of canonical Wnt signaling (via Dikkopf-1) abrogated relaxin's effect on both Nav1.5 in cardiomyocytes and suppression of excess collagen from fibroblasts. Further, we show that relaxin significantly suppressed expression of Dikkopf-1 in isolated cardiomyocytes and whole LV tissue. In addition, show that relaxin suppressed the age-associated genetic upregulation in inflammatory markers in a sexdependent manner. Finally, we tested the hypothesis that relaxin would be an effective therapy in a rat model of pulmonary arterial hypertension and show that it reduced occlusion of small pulmonary arteries, myocardial and lung fibrosis and reversed the cardiac phenotype of ventricular arrhythmia or arrest. These results suggest that relaxin signals through multiple

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Section: Relaxin As An Anti-arrhythmicmentioning

confidence: 83%

Cardioprotective actions of relaxin

Martin

Romero

Salama

2019

Molecular and Cellular Endocrinology

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“…Relaxin blunts the NLRP3 inflammasome (which induces the synthesis of IL-1β and IL-18 in leukocytes and cardiomyocyte pyroptosis and apoptosis as well as increases the risk of MI) via the attenuation of caspase-1 activity through an eNOS-dependent mechanism in conditions of I/R injury [ 261 , 262 ]. Additionally, relaxin reduced the expression of the pro-inflammatory cytokines IL-6, IL-1β, TNFα, and MCP-1 and decreased macrophage infiltration in mice hearts with MI [ 263 , 264 , 265 ]. This deregulation of cytokine production, in combination with a decline in leukocyte density and an attenuation of endothelial leakage mediated by relaxin, helps to blunt the microvascular damage after events of cardiac IR [ 266 ].…”

Section: Role Of Some Adipokines In Inflammatory Processes Associamentioning

confidence: 99%

Adipokines and Inflammation: Focus on Cardiovascular Diseases

Feijóo‐Bandín

Aragón-Herrera

Moraña-Fernández

et al. 2020

IJMS

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It is well established that adipose tissue, apart from its energy storage function, acts as an endocrine organ that produces and secretes a number of bioactive substances, including hormones commonly known as adipokines. Obesity is a major risk factor for the development of cardiovascular diseases, mainly due to a low grade of inflammation and the excessive fat accumulation produced in this state. The adipose tissue dysfunction in obesity leads to an aberrant release of adipokines, some of them with direct cardiovascular and inflammatory regulatory functions. Inflammation is a common link between obesity and cardiovascular diseases, so this review will summarise the role of the main adipokines implicated in the regulation of the inflammatory processes occurring under the scenario of cardiovascular diseases.

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“…Unresolved inflammation, followed by dysregulated wound healing, can lead to fibrosis-induced organ failure. Serelaxin and/or porcine relaxin has been shown to reduce the infiltration of inflammatory cells within several tissues including neutrophils, basophils, mast cells, endothelial cells and macrophages (Bani et al, 1997;Bani et al, 2002;Beiert et al, 2018;Garber et al, 2001;Nistri et al, 2003;Nistri et al, 2008), the latter being a source of TGF-β1 production. Furthermore, relaxin decreases granule exocytosis and mast cell degranulation to reduce proinflammatory and allergic cytokines such as histamine, leukotrienes and serotonin .…”

Section: Relaxin Effects On Inflammation and Fibrogenesismentioning

confidence: 99%

Relaxin and extracellular matrix remodeling: Mechanisms and signaling pathways

Shen

Samuel

et al. 2019

Molecular and Cellular Endocrinology

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Fibrosis is associated with accumulation of excess fibrillar collagen, leading to tissue dysfunction. Numerous processes, including inflammation, myofibroblast activation, and endothelial-tomesenchymal transition, play a role in the establishment and progression of fibrosis. Relaxin is a peptide hormone with well-known antifibrotic properties that result from its action on numerous cellular targets to reduce fibrosis. Relaxin activates multiple signal transduction pathways as a mechanism to suppress inflammation and myofibroblast activation in fibrosis. In this review, the general mechanisms underlying fibrotic diseases are described, along with the current state of knowledge regarding cellular targets of relaxin. Finally, an overview is presented summarizing the signaling pathways activated by relaxin and other relaxin family peptide receptor agonists to suppress fibrosis.

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Chronic lower-dose relaxin administration protects from arrhythmia in experimental myocardial infarction due to anti-inflammatory and anti-fibrotic properties

Cited by 24 publications

References 42 publications

Cardioprotective actions of relaxin

Cardioprotective actions of relaxin

Adipokines and Inflammation: Focus on Cardiovascular Diseases

Relaxin and extracellular matrix remodeling: Mechanisms and signaling pathways

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