NTSR2 Agonist NT150 Attenuates Adverse Cardiac Remodeling and Dysfunction in Preclinical Models

Heart failure (HF) remains a leading cause of morbidity and mortality, often driven by adverse cardiac remodeling, characterized by hypertrophy and fibrosis. Current therapies often target neurohormonal pathways but don't fully address the complex cellular changes. The neuropeptide neurotensin (NTS) is known to be upregulated in cardiac lymphatic endothelial cells (LECs) following ischemic or mechanical damage, yet its specific role in cardiac remodeling and its therapeutic potential have remained largely undefined. Understanding this pathway could unlock novel strategies to prevent or reverse detrimental cardiac changes.

Researchers investigated the role of NTS in cardiac injury using cultured murine and human cells, as well as mouse models of transverse aortic constriction (TAC) and myocardial infarction (MI). They generated mice with LEC-specific Nts deletion and cardiomyocyte- or fibroblast-specific Ntsr2 inactivation. The synthetic NTSR2 agonist NT150 was administered to both cell cultures and mouse models to assess its therapeutic effects on cardiac remodeling and dysfunction. Additionally, freshly isolated cardiac tissues from human patients with heart failure were treated with NT150 to evaluate cGMP production and prohypertrophic signaling.

Endogenous NTS was identified as an inhibitor of adverse cardiac remodeling. In cultured murine and human cells, NTS reduced cardiomyocyte hypertrophy and fibroblast activation, effects mediated by NTSR2-dependent cGMP production. Similarly, specific inactivation of Ntsr2 in cardiomyocytes or activated fibroblasts led to enhanced cardiac remodeling following TAC. The NTSR2 agonist NT150 consistently reproduced the beneficial effects of NTS in cultured human and murine cells. Furthermore, NT150 ameliorated cardiac remodeling and dysfunction in both TAC and MI mouse models. In human heart failure tissues, NT150 induced cGMP production and suppressed prohypertrophic signaling, confirming its potential translational relevance. > Mice with LEC-specific Nts deletion exhibited aggravated hypertrophy and fibrosis after both TAC and MI, underscoring NTS's protective role.