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Review
. 2019 Jan:111:33-41.
doi: 10.1016/j.peptides.2018.05.009. Epub 2018 May 25.

Effect of the peptides Relaxin, Neuregulin, Ghrelin and Glucagon-like peptide-1, on cardiomyocyte factors involved in the molecular mechanisms leading to diastolic dysfunction and/or heart failure with preserved ejection fraction

Ian Warbrick  1 , Simon W Rabkin  2
Affiliations
Review

Effect of the peptides Relaxin, Neuregulin, Ghrelin and Glucagon-like peptide-1, on cardiomyocyte factors involved in the molecular mechanisms leading to diastolic dysfunction and/or heart failure with preserved ejection fraction

Ian Warbrick et al. Peptides. 2019 Jan.

Abstract

Heart failure with preserved ejection fraction (HFpEF) represents an important cardiac condition because of its increasing prevalence, resistance to treatment and high associated morbidity and mortality. Two of the major mechanisms responsible for HFpEF are impaired cardiomyocyte sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a), which is responsible for calcium reuptake into the SR, and cardiac fibroblasts/myofibroblasts that produce collagen or myocardial fibrosis. Phospholamban (PLB), in the SR and endoplasmic reticulum, is the primary regulator of SERCA2a in the heart and acts as a reversible inhibitor of SERCA2a. Glucagon-like peptide-1, a 30 amino acid peptide, improves diastolic function through increasing SERCA2a expression and activity as well as by decreasing phosphorylation of Ryanodine receptors. It also enhances collagen production through enhanced procollagen IalphaI/IIIalphaI, connective tissue growth factor, fibronectin, TGF-β3 as well as Interleukin -10, -1beta, and -6 gene expression. Relaxin-2, a two chain, 53 amino acid peptide, increases Ser16- and Thr17-phosphorylation levels of PLB, thereby relieving SERCA2a of its inhibition. H3 Relaxin inhibits TGF-β1-stimulated collagen deposition through H3 relaxin-induced increases in pSmad2. Neuregulin-1, an epidermal growth factor, induces nitric oxide and PI-3 kinase activation that enhance SERCA2 activity. Neuregulin-1 was associated with less myocardial macrophage infiltration and cytokine expression reducing collagen deposition. Ghrelin, a 28 amino acid peptide, improves SERCA2a function by inducing PLB phosphorylation. Ghrelin also reduces cardiac fibrosis. In summary, Glucagon-like peptide-1, Relaxin-2, Neuregulin-1, and Ghrelin each modify calcium dynamics, collagen expression, and myocardial fibrosis through attenuation of deleterious signaling cascades, and induction of adaptive pathways, representing potential therapeutic targets for HFpEF.

Keywords: Ghrelin; Glucagon-like peptide-1; Heart failure with preserved ejection fraction (HFpEF); Myocardial fibrosis; Neuregulin-1; Relaxin-2; SR Ca(2+) ATPase.

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