Neurotensin receptor 2 agonism attenuates adverse cardiac remodeling in preclinical models

Shiva N, Kawase H, Einsiedel J, Kwon J, Kumar S, Shao J, Du Z, Kubin N, Shimari M, Günther S, Li T, Dierickx P, Sossalla S, Offermanns S, Gmeiner P, Wettschureck N (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Science Translational Medicine American Association for the Advancement of Science

Book Volume: 18

Article Number: eaea9877

Journal Issue: 856

DOI: 10.1126/scitranslmed.aea9877

Abstract

The neuropeptide neurotensin (NTS) is up-regulated in cardiac lymphatic endothelial cells (LECs) in response to ischemic or mechanical damage, but its role in cardiac remodeling is unknown. Here, we aimed to define the role of LEC-derived NTS in cardiac injury responses and to assess the therapeutic potential of targeting cardiac NTS signaling. In cultured murine and human cells, NTS reduced cardiomyocyte hypertrophy and fibroblast activation, and these effects were mediated by NTS receptor 2 (NTSR2)-dependent guanosine 3′,5′-monophosphate (cGMP) production. Consistent with an antihypertrophic and antifibrotic role of NTS, mice with LEC-specific Nts deletion exhibited aggravated hypertrophy and fibrosis after transverse aortic constriction (TAC) and myocardial infarction (MI). Similarly, cardiomyocyte-specific or activated fibroblast-specific inactivation of Ntsr2 led to enhanced cardiac remodeling after TAC. NTSR2 agonist NT150 reproduced the beneficial effects of NTS in cultured human and murine cells and ameliorated cardiac remodeling and dysfunction in both TAC and MI. Additionally, in freshly isolated cardiac tissues from patients with heart failure, NT150 induced cGMP production and suppressed prohypertrophic signaling. These findings identify NTS as an endogenous inhibitor of adverse cardiac remodeling and suggest NTSR2 agonism as a therapeutic strategy in heart failure.

Authors with CRIS profile

Jürgen Einsiedel Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

Max Planck Institute for Heart and Lung Research / Max-Planck-Institut für Herz- und Lungenforschung DE Germany (DE) Justus-Liebig-Universität Gießen DE Germany (DE) University of Oklahoma US United States (USA) (US) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) DE Germany (DE)

How to cite

APA:

Shiva, N., Kawase, H., Einsiedel, J., Kwon, J., Kumar, S., Shao, J.,... Wettschureck, N. (2026). Neurotensin receptor 2 agonism attenuates adverse cardiac remodeling in preclinical models. Science Translational Medicine, 18(856). https://doi.org/10.1126/scitranslmed.aea9877

MLA:

Shiva, Niharika, et al. "Neurotensin receptor 2 agonism attenuates adverse cardiac remodeling in preclinical models." Science Translational Medicine 18.856 (2026).

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