Detalle Publicación

Role of LCN2 in a murine model of hindlimb ischemia and in peripheral artery disease patients, and its potential regulation by miR-138-5P

Autores: Sáenz de Pipaon Echarren, Goren; Jover, E.; van der Bent, M. L.; Orbe Lopategui, Josune; Rodríguez García, José Antonio; Fernández-Celis, A.; Quax, P. H. A.; Páramo Fernández, José Antonio; López Andrés, Natalia; Marín-Ventura, J. L.; Nossent, A. Y.; Roncal Mancho, Carmen (Autor de correspondencia)
Título de la revista: ATHEROSCLEROSIS
ISSN: 1879-1484
Volumen: 385
Páginas: 117343
Fecha de publicación: 2023
BACKGROUND AND AIMS: Peripheral arterial disease (PAD) is a leading cause of morbimortality worldwide. Lipocalin-2 (LCN2) has been associated with higher risk of amputation or mortality in PAD and might be involved in muscle regeneration. Our aim is to unravel the role of LCN2 in skeletal muscle repair and PAD. METHODS AND RESULTS: WT and Lcn2-/- mice underwent hindlimb ischemia. Blood and crural muscles were analyzed at the inflammatory and regenerative phases. At day 2, Lcn2-/- male mice, but not females, showed increased blood and soleus muscle neutrophils, and elevated circulating pro-inflammatory monocytes (p<0.05), while locally, total infiltrating macrophages were reduced (p<0.05). Moreover, Lcn2-/- soleus displayed an elevation of Cxcl1 (p<0.001), and Cxcr2 (p<0.01 in males), and a decrease in Ccl5 (p<0.05). At day 15, Lcn2 deficiency delayed muscle recovery, with higher density of regenerating myocytes (p<0.04) and arterioles (alphaSMA+, p<0.025). Reverse target prediction analysis identified miR-138-5p as a potential regulator of LCN2, showing an inverse correlation with Lcn2 mRNA in skeletal muscles (rho=-0.58, p<0.01). In vitro, miR-138-5p mimic reduced Lcn2 expression and luciferase activity in murine macrophages (p<0.05). Finally, in human serum miR-138-5p was inversely correlated with LCN2 (p¿0.001 adjusted, n=318), and associated with PAD (Odds ratio 0.634, p=0.02, adjusted, PAD n=264, control n=54). CONCLUSIONS: This study suggests a possible dual role of LCN2 in acute and chronic conditions, with a probable role in restraining inflammation early after skeletal muscle ischemia, while being associated with vascular damage in PAD, and identifies miR-138-5p as one potential post-transcriptional regulator of LCN2.