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Molitor, Michael; Rudi, Wolf-Stephan; Garlapati, Venkata; Finger, Stefanie; Schüler, Rebecca; Kossmann, Sabine; Lagrange, Jeremy; Nguyen, Thanh Son; Wild, Johannes; Knopp, Tanja; Karbach, Susanne H; Knorr, Maike; Ruf, Wolfram; Münzel, Thomas; Wenzel, Philip

Nox2+ myeloid cells drive vascular inflammation and endothelial dysfunction in heart failure after myocardial infarction via angiotensin II receptor type 1

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  • Medientyp: E-Artikel
  • Titel: Nox2+ myeloid cells drive vascular inflammation and endothelial dysfunction in heart failure after myocardial infarction via angiotensin II receptor type 1
  • Beteiligte: Molitor, Michael; Rudi, Wolf-Stephan; Garlapati, Venkata; Finger, Stefanie; Schüler, Rebecca; Kossmann, Sabine; Lagrange, Jeremy; Nguyen, Thanh Son; Wild, Johannes; Knopp, Tanja; Karbach, Susanne H; Knorr, Maike; Ruf, Wolfram; Münzel, Thomas; Wenzel, Philip
  • Erschienen: Oxford University Press (OUP), 2021
  • Erschienen in: Cardiovascular Research
  • Sprache: Englisch
  • DOI: 10.1093/cvr/cvaa042
  • ISSN: 0008-6363; 1755-3245
  • Schlagwörter: Physiology (medical) ; Cardiology and Cardiovascular Medicine ; Physiology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <jats:p>Heart failure (HF) ensuing myocardial infarction (MI) is characterized by the initiation of a systemic inflammatory response. We aimed to elucidate the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function in a mouse model of HF after MI.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and results</jats:title> <jats:p>HF was induced in male C57BL/6J mice by permanent ligation of the left anterior descending coronary artery. Compared to sham, HF mice had significantly impaired endothelial function accompanied by enhanced mobilization of Sca-1+c-Kit+ haematopoietic stem cells and Sca-1−c-Kit+ common myeloid and granulocyte-macrophage progenitors in the bone marrow as well as increased vascular infiltration of CD11b+Ly6G−Ly6Chigh monocytes and accumulation of CD11b+ F4/80+ macrophages, assessed by flow cytometry. Using mice with Cre-inducible expression of diphtheria toxin receptor in myeloid cells, we selectively depleted lysozyme M+ myelomonocytic cells for 10 days starting 28 days after MI. While the cardiac phenotype remained unaltered until 38 days post-MI, myeloid cell depletion attenuated vascular accumulation of Nox2+CD45+ cells, endothelial dysfunction, oxidative stress, and vascular expression of adhesion molecules and angiotensin II receptor type 1 (AT1R). Pharmacological blockade of this receptor for 4 weeks did not significantly alter cardiac function, but mimicked the effects of myeloid cell depletion: telmisartan (20 mg/kg/day, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid reactive oxygen species production, attenuated endothelial leucocyte rolling and vascular accumulation of CD11b+Ly6G−Ly6Chigh monocytes and macrophages, resulting in improved vascular function with less abundance of Nox2+CD45+ cells.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Endothelial dysfunction in HF ensuing MI is mediated by inflammatory Nox2+ myeloid cells infiltrating the vessel wall that can be targeted by AT1R blockade.</jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang