APJ Receptor Activity Can Be Independent by Its Ligand Apelin

Introduction: The APJ/Apelin system has been the center of a growing interest in cardiovascular medicine because of the inotropic effect of apelin and its possible use as a treatment for heart failure. Hypothesis: Given the inotropic effect of apelin, we tested the hypothesis that the lack of the APJ receptor could be detrimental for cardiac function in the setting of overload pressure model (trans-aortic constriction, TAC). Results: 32 wild type (WT) and 23 APJ knock out (KO) mice 9-12 weeks were subjected to aortic banding constriction, and cardiac function was analyzed after 7 and 30 days by echocardiographic assessment. Cardiac function parameters as fractional shortening (%FS) was dramatically impaired in the WT animals, but not in APJ -/- animals (%FS = WT 27,68 ± 2,61% vs KO 39,58 ± 3,1% p = 0,006; at 7 days after TAC and FS% = WT 19,14 ± 2.42% vs KO 33,79 ± 4,19%, p = 0,02 at 30 days after TAC). Histological evaluation of the hearts was performed, confirming the preponderantly higher quantity of fibrosis in the WT hearts compared to the APJ -/- . Biochemical assay showed activation of distinct pathways in APJ-/- mice under stress situation. In a second set of in vivo experiments, administration of apelin has demonstrated that it can partially restore cardiac function in WT animals after 7 days of TAC compared to WT animals (FS% = WT animals 24,81 ± 1,96% vs 7 days apelin treated WT 31,48 ± 1,93%, p = 0,05). Our in vivo data support the hypothesis that APJ receptor activity can also be independent by apelin stimulation. To confirm this hypothesis, in vitro assays using a stretch system model have been performed on HEK 293 overexpressing APJ and on neonatal rat cardiomyocytes. The molecular mechanism by which APJ receptor is activated independently by the presence of apelin has been elucidated. Conclusions: We are demonstrating for the first time that the presence of the APJ receptor under a condition of chronic stimulation such as aortic banding is detrimental for cardiac function. We have determined the molecular mechanisms underlying this effect. Moreover, in our in vivo model (TAC) infusion of apelin is beneficial for cardiac function under the aortic banding condition. We have been able to elucidate the molecular mechanism by which both scenarios, lacking the receptor and stimulating it through its ligand, are able to protect cardiac function in the setting of pathological hypertrophy.