Neuraminidase-1 promotes heart failure after ischemia/reperfusion injury by affecting cardiomyocytes and invading monocy
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ORIGINAL CONTRIBUTION
Neuraminidase‑1 promotes heart failure after ischemia/reperfusion injury by affecting cardiomyocytes and invading monocytes/ macrophages Maren Heimerl1 · Irina Sieve1 · Melanie Ricke‑Hoch1 · Sergej Erschow1 · Karin Battmer2 · Michaela Scherr2 · Denise Hilfiker‑Kleiner1 Received: 10 July 2020 / Accepted: 1 September 2020 © The Author(s) 2020
Abstract Neuraminidase (NEU)1 forms a multienzyme complex with beta-galactosidase (β-GAL) and protective-protein/cathepsin (PPC) A, which cleaves sialic-acids from cell surface glycoconjugates. We investigated the role of NEU1 in the myocardium after ischemia/reperfusion (I/R). Three days after inducing I/R, left ventricles (LV) of male mice (3 months-old) displayed upregulated neuraminidase activity and increased NEU1, β-GAL and PPCA expression. Mice hypomorphic for neu1 (hNEU1) had less neuraminidase activity, fewer pro-inflammatory ( Lin−CD11b+F4/80+Ly-6Chigh), and more anti-inflammatory macrophages (Lin−CD11b+F4/80+Ly-6Clow) 3 days after I/R, and less LV dysfunction 14 days after I/R. WT mice transplanted with hNEU1-bone marrow (BM) and hNEU1 mice with WT-BM showed significantly better LV function 14 days after I/R compared with WT mice with WT-BM. Mice with a cardiomyocyte-specific NEU1 overexpression displayed no difference in inflammation 3 days after I/R, but showed increased cardiomyocyte hypertrophy, reduced expression and mislocalization of Connexin-43 in gap junctions, and LV dysfunction despite a similar infarct scar size to WT mice 14 days after I/R. The upregulation of NEU1 after I/R contributes to heart failure by promoting inflammation in invading monocytes/macrophages, enhancing cardiomyocyte hypertrophy, and impairing gap junction function, suggesting that systemic NEU1 inhibition may reduce heart failure after I/R. Keywords Neuraminidase 1 · Sialidase 1 · Ischemia/reperfusion · Inflammation · Monocytes
Introduction Despite the successful implementation of reperfusion strategies to rescue the ischemic myocardium and thereby to reduce acute death, the long-term morbidity and mortality Maren Heimerl and Irina Sieve equally contributing first authors Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00395-020-00821-z) contains supplementary material, which is available to authorized users. * Denise Hilfiker‑Kleiner hilfiker.denise@mh‑hannover.de 1
Molecular Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Carl‑Neuberg Str. 1, 30625 Hannover, Germany
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl‑Neuberg‑Str.1, 30625 Hannover, Germany
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of patients with heart failure, due to adverse remodelling, have increased. Inflammation triggers not only the ischemic insult but also the reperfusion injury is considered to modulate post-MI outcome [17].Cell-to-cell communication plays an important role in cardiac performance after an ischemic insult. In this regard, the glycocalyx, composed of glycoconjug
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