Neurotensin prevents harmful cardiac remodelling

NTSR2 agonists open up new avenues for the treatment of heart failure
 

To the Point

• A previously unknown function of lymphatic vessels: These vessels play an important role in maintaining heart health by mitigating pathological remodeling processes in the damaged heart.
• Mitigating harmful remodeling processes: This is due to neurotensin, a molecule produced in lymphatic vessels that was previously known mainly for its role in the nervous system.
• Potential new therapeutic strategy: Neurotensin is thus a new endogenous inhibitor of pathological tissue remodeling in the damaged heart.

Alongside arteries and veins, the body possesses a third type of blood vessel: the lymphatic vessels. These form the body's natural drainage and filtration system, removing excess fluid and waste products from tissues while supporting immune defence. Lymphatic vessels are found in most organs, including the heart. Like blood vessels, they are lined by a specialised layer of endothelial cells.

At the beginning of the study, the research group led by Nina Wettschureck from the Department of Pharmacology at the Max Planck Institute for Heart and Lung Research in Bad Nauheim discovered that lymphatic endothelial cells undergo profound changes following cardiac injury.

Mice without neurotensin

This observation had not previously been reported, and the role of neurotensin in the diseased heart was unknown. To investigate further, first author Niharika Shiva initially examined the effects of neurotensin on isolated cardiac muscle cells and connective tissue cells known as fibroblasts. "In cell culture, we reproduced pathological changes such as enlargement of cardiomyocytes and activation of fibroblasts, and found that neurotensin reduced these damaging responses," says Shiva. To determine whether these findings were also relevant in living organisms, the researchers used a genetically modified mouse model in which neurotensin production could be selectively switched off in the heart's lymphatic vessels.

"When we induced cardiac disease in these animals, either through pressure overload or myocardial infarction, the heart tissue responded with fibrosis and thickening of the heart wall," Shiva explains. "While this response is beneficial in the short term, over time it can impair the heart's pumping function. We hypothesised that neurotensin suppresses this harmful process, and that its absence would therefore make it worse."

That is precisely what the researchers observed. Mice lacking neurotensin developed markedly greater cardiac wall thickening and fibrosis, and their heart function was significantly poorer than that of control animals. The team then sought to determine whether this protective mechanism could be exploited therapeutically. They investigated how neurotensin exerts its beneficial effects and identified the NTSR2 receptor as the key mediator. "Among the three known neurotensin receptors, NTSR2 proved to be the receptor responsible for mediating the cardioprotective effect," says Wettschureck. Accordingly, the protective effects of neurotensin disappeared completely in cells lacking the NTSR2 receptor.

Reversed damage to the heart

These findings shifted the researchers' focus towards the therapeutic potential of NTSR2. Working together with Peter Gmeiner's group at Friedrich-Alexander University Erlangen-Nürnberg, the team investigated whether a specific NTSR2 agonist could reduce pathological cardiac wall thickening and fibrosis after heart injury. The results were encouraging. Administration of the NTSR2 agonist partially reversed structural damage to the heart following both myocardial infarction and pressure overload, while also improving cardiac pumping function. The researchers identified activation of cGMP-mediated signalling pathways as the underlying mechanism.

The research group is now conducting further studies to evaluate the clinical relevance of these findings.