Cardiomyocyte-Restricted Low Density Lipoprotein Receptor-Related Protein 6 (LRP6) Deletion Leads to Lethal Dilated Cardiomyopathy Partly Through Drp1 Signaling
Authors: Yichun Zhu
Hui Gong
Mingqiang Fu
Ying Chen
Yang Li
Leilei Ma
Chunjie Yang
Zheyong Huang
Yanpeng An
Huiru Tang
Hong Ma
Junbo Ge
Xiang Wang
Jianguo Jia
Yunzeng Zou
Juying Qian
Le Kang
Wei Gao
Zhidan Chen
Ming Liu
Guoping Zhang
Guoliang Jiang
Ying Wang
Journal: Theranostics (2018)
Discipline: CLINICAL MEDICINE
Keywords: Autophagy; Heart failure; LRP6; TFEB; mTOR.
Affiliations: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China., State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Sciences, Fudan University. International Centre for Molecular Phenomics, Collaborative Innovation Center for Genetics and Development, Shanghai 200438, China., Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Abstract:  Low density lipoprotein receptor-related protein 6 (LRP6), a wnt co-receptor, regulates multiple functions in various organs. However, the roles of LRP6 in the adult heart are not well understood. Methods: We observed LRP6 expression in heart with end-stage dilated cardiomyopathy (DCM) by western blot. Tamoxifen-inducible cardiac-specific LRP6 knockout mouse was constructed. Hemodynamic and echocardiographic analyses were performed to these mice. Results: Cardiac LRP6 expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to control group. Tamoxifen-inducible cardiac-specific LRP6 knockout mice developed acute heart failure and mitochondrial dysfunction with reduced survival. Proteomic analysis suggests the fatty acid metabolism disorder involving peroxisome proliferator-activated receptors (PPARs) signaling in the LRP6 deficient heart. Accumulation of mitochondrial targeting to autophagosomes and lipid droplet were observed in LRP6 deletion hearts. Further analysis revealed cardiac LRP6 deletion suppressed autophagic degradation and fatty acid utilization, coinciding with activation of dynamin-related protein 1 (Drp1) and downregulation of nuclear TFEB (Transcription factor EB). Injection of Mdivi-1, a Drp1 inhibitor, not only promoted nuclear translocation of TFEB, but also partially rescued autophagic degradation, improved PPARs signaling, and attenuated cardiac dysfunction induced by cardiac specific LRP6 deletion. Conclusions: Cardiac LRP6 deficiency greatly suppressed autophagic degradation and fatty acid utilization, and subsequently leads to lethal dilated cardiomyopathy and cardiac dysfunction through activation of Drp1 signaling. It suggests that heart failure progression may be attenuated by therapeutic modulation of LRP6 expression. 

Retracted: No

PubPeer comments:
 A control band seems to appear twice in Figure 4A for two different treatment groups. Could the authors please provide the original uncropped scans? *** ![file] , 
 Thank you for spotting this mistake. The mistake was made during the figure arrangement. We have checked the original bands of GAPDH in Figure 4A, and corrected them. We sincerely apologize for the misuse. We have written to the editor to correct the image. The authors declare the amendments donu2019t change the results and conclusions of the paper, for the statistica![file] l analysis were from the raw bands ,