LEAP2 modulates β-adrenergic triggered cardiac responses and provokes antihypertensive effects
Year: 2026
Type: article
Abstract: Receptors for orexigenic hormones are broadly expressed in different tissues. Growth hormone secretagogue receptor (GHSR) is the receptor for the gastric peptide hormone ghrelin, although it further displays an intrinsic ligand-independent activity. The liver-expressed antimicrobial peptide 2 (LEAP2) has been recently identified as GHSR endogenous antagonist and inverse agonist. To understand LEAP2 effects on cardiac performance, we assessed (in-vivo) Wistar (WT) and spontaneously hypertensive rats (SHR), isolated hearts (ex-vivo) and cardiomyocytes (in-vitro). Intravenous LEAP2 injection reduced arterial pressure, with a greater effect in SHR. LEAP2 also reduced cardiac inotropism in both WT and SHR, whereas a negative chronotropy was observed only in SHR. LEAP2 perfusion reduced intraventricular pressure in isolated SHR hearts and attenuated the responses to isoproterenol on coronary flow, whereas responses to acetylcholine were almost unaffected by LEAP2. Fluorescent LEAP2 or ghrelin labeled cardiomyocytes. LEAP2 or the synthetic inverse agonist PF04628935 produced an equipotent reduction in maximum contraction speed, reduced cardiomyocyte shortening area, and attenuated the responses to isoproterenol, but not to acetylcholine. Plasma levels of ghrelin and LEAP2 were not different between strains, but higher GHSR levels were found in SHR hearts. In conclusion, LEAP2 exerted marked cardiovascular effects, reducing arterial pressure and left ventricular systolic performance in both WT and SHR, with a greater impact in hypertensive animals. However, GHSR involvement in SHR cardiac abnormalities is unrelated to the circulating levels of its endogenous ligands and instead seems to depend on altered cardiac GHSR expression and function. The cardiac LEAP2 interaction with β-adrenergic receptors reveals an important cardioprotective potential.
Source: Life Sciences
Authors: Sixta Isabel Atencio Berrio, Jhulle Horrane Carvalho, João Batista Dutra, Marcos Eliezeck, Sergio Scalzo, Juliana Vila Verde Ribeiro, Michelle Mendanha Mendonça, Rodrigo Mello Gomes, Gustavo Rodrigues Pedrino, Eduardo Colombari, Daniel Castrogiovanni, Sisti Maria Milagros, Maria Florencia Racioppi, Martin Vila Petroff, Sonia Cantel, Jean-Alain Fehrentz, Silvia Guatimosim, Mario Perelló, Carlos Henrique de Castro, Carlos Henrique Xavier
Institutions: Universidade Federal de Goiás, Universidade Federal de Minas Gerais, Universidade Estadual Paulista (Unesp), Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto Multidisciplinario de Biología Celular, Universidad Nacional de La Plata, Biochemistry Research Institute of La Plata, Centro de Investigaciones Cardiovasculares, École Nationale Supérieure de Chimie de Montpellier, Centre National de la Recherche Scientifique, Université de Montpellier, Institut des Biomolécules Max Mousseron
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,810
Awards: G206113272, G486855214
OpenAlex ID: W7126044644