Theranostics 2018; 8(3):627-643. doi:10.7150/thno.22177
Cardiomyocyte-Restricted Low Density Lipoprotein Receptor-Related Protein 6 (LRP6) Deletion Leads to Lethal Dilated Cardiomyopathy Partly Through Drp1 Signaling
1. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
2. 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.
3. Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
# These authors contributed equally to this work.
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.
Keywords: LRP6, Autophagy, Heart failure, mTOR, TFEB
Chen Z, Li Y, Wang Y, Qian J, Ma H, Wang X, Jiang G, Liu M, An Y, Ma L, Kang L, Jia J, Yang C, Zhang G, Chen Y, Gao W, Fu M, Huang Z, Tang H, Zhu Y, Ge J, Gong H, Zou Y. Cardiomyocyte-Restricted Low Density Lipoprotein Receptor-Related Protein 6 (LRP6) Deletion Leads to Lethal Dilated Cardiomyopathy Partly Through Drp1 Signaling. Theranostics 2018; 8(3):627-643. doi:10.7150/thno.22177. Available from http://www.thno.org/v08p0627.htm