Neurotensin receptor 2 agonism attenuates adverse cardiac remodeling in preclinical models

Cardiac lymphatic vessels drain excess fluid, immune cells, and waste products from the myocardium, thereby preserving tissue homeostasis and limiting edema and inflammation. Researchers led by Nina Wettschureck at the Max Planck Institute for Heart and Lung Research in Bad Nauheim found that endothelial cells of lymphatic vessels undergo substantial changes following cardiac injury, including increased production of neuropeptides such as neurotensin, which had previously been associated primarily with the brain and gastrointestinal tract.

To investigate the function of neurotensin in the injured heart, first author Niharika Shiva examined its effects on isolated cardiomyocytes and cardiac fibroblasts. Neurotensin reduced pathological cardiomyocyte enlargement and fibroblast activation in cell culture. The researchers then used genetically modified mice in which neurotensin production in cardiac lymphatic vessels could be selectively disrupted. Following myocardial infarction or pressure overload, these mice developed more pronounced cardiac wall thickening and fibrosis and showed impaired cardiac function compared with control animals, demonstrating a protective role for lymphatic neurotensin in vivo.

The researchers identified the neurotensin receptor NTSR2 as the mediator of this cardioprotective effect. Both in vitro and in vivo, the protective NTS response was abrogated when cardiomyocytes or fibroblasts were lacking NTSR2, highlighting the receptor as a potential therapeutic target.

In collaboration with Peter Gmeiner’s group at Friedrich-Alexander-Universität Erlangen-Nürnberg, the researchers subsequently tested a specific NTSR2 agonist, NT150. Treatment with NT150 reduced pathological cardiac remodeling and fibrosis and improved cardiac function in mouse models of both myocardial infarction and pressure overload. The underlying mechanism involved activation of cGMP-dependent signaling pathways.

Importantly, the NTSR2 agonist also produced beneficial effects in cardiac biopsy samples from patients with severe heart disease, supporting the potential clinical relevance of this pathway. Further studies will investigate its therapeutic potential and relevance to human heart failure.

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