AXL receptor tyrosine kinase is increased in patients with heart failure

Batlle, Montserrat; Recarte-Pelz, Pedro; Roig, Eulàlia; Castel, M.A.; Cardona, Montserrat; Farrero, Marta; Ortiz, José T.; Campos, Begoña; Pulgarín, M.J.; Ramírez, José; Pérez‐Villa, Félix; Frutos, Pablo García de

doi:10.1016/j.ijcard.2014.03.016

Cited by 48 publications

(58 citation statements)

References 56 publications

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“…Serum levels of Gas6 and/or sAxl have been related to cancer prognosis and to other pathologies, such as heart failure or sepsis [27,28]. Since our results point to Gas6/Axl axis as a relevant signaling pathway in liver fibrogenesis, we decided to evaluate this pathway in patients with different degrees of alcoholic liver disease (ALD) in which progression from asymptomatic fibrosis to decompensated cirrhosis is a well-studied process [29].…”

Section: Resultsmentioning

confidence: 99%

“…Although it has been reported an increase in Gas6/Axl proteins in patients with hepatocellular carcinoma from different etiologies [41], and sAxl levels are increased in end-stage heart failure patients undergoing heart transplantation [27], which frequently suffer cardiac fibrosis, Gas6/Axl as serological markers of liver function have not been previously proposed. We have confirmed in serum samples from ALD and HCV patients an enhancement in Gas6 and sAxl serum levels.…”

Section: Discussionmentioning

confidence: 99%

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Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Bárcena

Stefanović

Tutusaus

et al. 2015

Journal of Hepatology

135

152

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Background & Aims Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase, and its ligand Gas6 are involved in cell differentiation, immune response and carcinogenesis. Methods HSCs were obtained from wild type and Axl−/− mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated wild type and Axl−/− mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. Results In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl KO mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. Conclusions: The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Bárcena

Stefanović

Tutusaus

et al. 2015

Journal of Hepatology

135

152

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“…Intriguingly, the protein level of Axl was significantly higher in both myocardial biopsies and serum in patients with end-stage heart failure than in control heart donors. 29 Meanwhile, the biological function of Axl is mainly exerted by binding with GAS6. 11 These phenomena suggest that the expression of GAS6 is likely to increase during heart failure.…”

Section: Discussionmentioning

confidence: 99%

Growth Arrest–Specific 6 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy

Zhao

Zhu

et al. 2016

Hypertension

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Growth arrest–specific 6 (GAS6) is a member of the vitamin K–dependent protein family that is involved in the regulation of the cardiovascular system, including vascular remodeling, homeostasis, and atherosclerosis. However, there is still no study that systemically elucidates the role of GAS6 in cardiac hypertrophy. Here, we found that GAS6 was upregulated in human dilated cardiomyopathic hearts, hypertrophic murine hearts, and angiotensin II–treated cardiomyocytes. Next, we examined the influence of GAS6 expression in response to a cardiac stress by inducing chronic pressure overload with aortic banding in wild-type and GAS6-knockout mice or cardiac-specific GAS6 overexpressing mice. Under basal conditions, the GAS6-knockout mice had normal left ventricular structure and function but after aortic banding, the mice demonstrated less hypertrophy, fibrosis, and contractile dysfunction when compared with wild-type mice. Conversely, cardiac-specific overexpression of GAS6 exacerbated aortic banding–induced cardiac hypertrophy, fibrosis, and dysfunction. Furthermore, we demonstrated that GAS6 activated the mitogen-activated protein kinase kinase 1/2–extracellular signal-regulated kinase 1/2 pathway during pressure overload–induced cardiac hypertrophy, and the pharmacological mitogen-activated protein kinase kinase 1/2 inhibitor U0126 almost completely reversed GAS6 overexpression–induced cardiac hypertrophy and fibrosis, resulting in improved cardiac function. Collectively, our data support the notion that GAS6 impairs ventricular adaptation to chronic pressure overload by activating mitogen-activated protein kinase kinase 1/2–extracellular signal-regulated kinase 1/2 signaling. Our findings suggest that strategies to reduce GAS6 activity in cardiac tissue may be a novel approach to attenuate the development of congestive heart failure.

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“…A detailed description of subject enrollment and collection of clinical data has been reported previously [1].…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

“…Statistical significance was indicated by P value <0.05. A detailed description data analysis can be found elsewhere [1], [2].…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Data on clinical characteristics of a heart failure patients’ cohort with reduced ejection fraction and analysis of the circulating values of five different heart failure biomarkers; high sensitivity troponin T, galectin-3, C-terminal propeptide of type I procollagen, soluble AXL and BNP

et al. 2016

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In this article, the full description of a heart failure with reduced ejection fraction (HF_REF) cohort of 192 patients is provided. Tables with the baseline demographic, prior history, ECG parameters, echocardiographic parameters, laboratory values and pharmacological treatment of these patients are included. Also, the quartile values of the analyzed circulating biomarkers: high sensitivity Troponin T (hs-TnT), galectin-3 (Gal-3), C-terminal propeptide of type I procollagen (CICP), soluble AXL (sAXL) and Brain Natriuretic Peptide (BNP) are given. The main demographic and clinical features of the patients’ subgroups that have hs-TnT, Gal-3, CICP or BNP above the third quartile are described. Tables with Pearson correlation analysis of the HF_REF patients’ biomarker levels are included. And Pearson correlation analysis of the HF_REF patients’ hs-TnT, Gal-3, CICP levels with patients’ biochemical parameters, blood count and inflammation parameters are also described. These data are related to the research articles (AXL receptor tyrosine kinase is increased in patients with heart failure (M. Batlle, P. Recarte-Pelz, E. Roig, M.A. Castel, M. Cardona, M. Farrero, et al., 2014) [1] and Use of serum levels of high sensitivity troponin T, galectin-3 and C-terminal propeptide of type I procollagen at long term follow-up in Heart Failure patients with reduced ejection fraction: comparison with soluble AXL and BNP (M. Batlle, B. Campos, M. Farrero, M. Cardona, B. González, M.A. Castel, et al., 2016) [2].

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AXL receptor tyrosine kinase is increased in patients with heart failure

Cited by 48 publications

References 56 publications

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Growth Arrest–Specific 6 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy

Data on clinical characteristics of a heart failure patients’ cohort with reduced ejection fraction and analysis of the circulating values of five different heart failure biomarkers; high sensitivity troponin T, galectin-3, C-terminal propeptide of type I procollagen, soluble AXL and BNP

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