Date Published: June 10, 2019
Publisher: Public Library of Science
Author(s): Montserrat Batlle, Nadia Castillo, Anna Alcarraz, Sebastian Sarvari, Gemma Sangüesa, Helena Cristóbal, Pablo García de Frutos, Marta Sitges, Lluis Mont, Eduard Guasch, Vincenzo Lionetti.
AXL is a receptor tyrosine kinase that has been related to kidney and vascular disorders. Heart failure patients with reduced ejection fraction have higher AXL in serum than controls. No information about Axl expression with HF progression is available.
Thoracic transverse aortic constriction (TAC) was successfully performed on male Wistar rats (n = 25) with different constriction levels. Controls underwent sham surgery (n = 12). Echocardiography measurements were performed 4–8 weeks after surgery. Collagen deposition was measured with picrosirius red staining. Axl mRNA levels in left ventricle (LV), left kidney (LK) and ascending aorta (aAo) and the LV expression of cardiac remodeling and fibrogenic factors were quantified with real-time PCR. AXL LV protein levels were quantified with western blot and localization was analyzed by immunohistochemistry. Soluble AXL levels in plasma were assayed with ELISA.
Successful TAC rats were classified into LV hypertrophy (LVH) or heart failure (HF), modeling the progressive cardiac changes after pressure overload. Collagen deposition was increased only in the HF group. LV Axl mRNA levels were higher in LVH and HF than in Sham rats, and correlated with LVHi, and hypertrophic and fibrogenic mediators. However, no association was found with LV systolic function. AXL was expressed in LV myocytes and other cell types. Concentration of circulating sAXL in plasma was increased in the LVH group compared to Sham and HF rats. Axl mRNA levels were similar in all groups in the LK and aAo.
Axl expression pattern suggests a role in the early progression of LV remodeling in HF but not in the later systolic dysfunction. The higher levels of circulating AXL found in HF patients most probably shed from the heart.
AXL is a receptor tyrosine kinase that belongs to the TAM family (Tyro3, Axl, MerTK receptors). Gas6 is the only recognized Axl receptor ligand, and its binding triggers Axl oligomerization and activation of downstream signal cascades that are involved in cancer, chronic immune disorders and other diseases [1,2].
This work describes for the first time changes in the LV expression of the tyrosine kinase receptor Axl in a pressure-overload murine model. Our main findings are that (a) Axl mRNA levels are increased in the LV of rats subjected to pressure-overload, (b) Axl expression correlates with the degree of LV hypertrophy but not with systolic function impairment, (c) circulating sAXL levels estimate LV expression and are higher in plasma from LVH rats compared to Sham and HF rats, and (d) renal and vascular Axl expression are not altered in this model.
Axl expression is increased in the LV of compensated and decompensated forms of pressure-overload insults, while its expression in the kidney and ascending aorta remains unaltered. The higher sAXL plasma levels in LVH rats and the relationship between Axl mRNA and LVHi suggest a role of Axl in early cardiac remodeling stages. Nevertheless, further research will be needed to gain more insight about the Axl role in the cardiac remodeling process that leads to HF.