Abstract
BackgroundAXL 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.MethodsThoracic 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.ResultsSuccessful 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.ConclusionsAxl 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.
Highlights
AXL is a receptor tyrosine kinase that belongs to the TAM family (Tyro3, Axl, MerTK receptors)
Successful transverse aortic constriction (TAC) rats were classified into left ventricle (LV) hypertrophy (LVH) or heart failure (HF), modeling the progressive cardiac changes after pressure overload
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 Soluble AXL (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
Summary
AXL is a receptor tyrosine kinase that belongs to the TAM family (Tyro, Axl, MerTK receptors). Gas 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]. The Gas6/AXL axis regulates collagen deposition in different organs. Angiotensin II (AngII), a main pro-fibrotic factor, triggers Axl expression in VSMCs in vitro [3]. Gas6/Axl promotes collagen deposition through modulation of the myofibroblast phenotype of hepatic stellate cells [4,5]. Soluble AXL (sAXL) increases in patients with liver cirrhosis [6,7], evolving as a potential biomarker for hepatopathies. Tissue-wise, AXL expression is increased in keloid fibroblasts [8] and in lung fibroblasts in idiophatic pulmonary fibrosis [9]. AXL is a receptor tyrosine kinase that has been related to kidney and vascular disorders. No information about Axl expression with HF progression is available
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