Store-operated calcium entry-activated autophagy protects EPC proliferation via the CAMKK2-MTOR pathway in ox-LDL exposure

• Published in: Autophagy Vol. 13; no. 1; pp. 82 - 98
• Main Authors: Yang, Jie, Yu, Jie, Li, Dongdong, Yu, Sanjiu, Ke, Jingbin, Wang, Lianyou, Wang, Yanwei, Qiu, Youzhu, Gao, Xubin, Zhang, Jihang, Huang, Lan
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.01.2017
• Subjects: Animals; autophagy; Autophagy - drug effects; Basic Research Paper; Calcium - metabolism; Calcium Channels - metabolism; Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism; CAMKK2; Cell Proliferation; cell-based therapy; Chelating Agents - pharmacology; Endothelial Cells - cytology; endothelial progenitor cells; Gene Silencing; Green Fluorescent Proteins - metabolism; Humans; Hypercholesterolemia - metabolism; Lipoproteins, LDL - metabolism; Male; MTOR; oxidized low-density lipoprotein; Phosphorylation; proliferation; Rats; Rats, Sprague-Dawley; Signal Transduction; Stem Cells - cytology; store-operated calcium entry; TOR Serine-Threonine Kinases - metabolism; autophagy; proliferation; cell-based therapy; endothelial progenitor cells; store-operated calcium entry; oxidized low-density lipoprotein; MTOR; CAMKK2
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2016.1245261

Improving biological functions of endothelial progenitor cells (EPCs) is beneficial to maintaining endothelium homeostasis and promoting vascular re-endothelialization. Because macroautophagy/autophagy has been documented as a double-edged sword in cell functions, its effects on EPCs remain to be elucidated. This study was designed to explore the role and molecular mechanisms of store-operated calcium entry (SOCE)-activated autophagy in proliferation of EPCs under hypercholesterolemia. We employed oxidized low-density lipoprotein (ox-LDL) to mimic hypercholesterolemia in bone marrow-derived EPCs from rat. Ox-LDL dose-dependently activated autophagy flux, while inhibiting EPC proliferation. Importantly, inhibition of autophagy either by silencing Atg7 or by 3-methyladenine treatment, further aggravated proliferative inhibition by ox-LDL, suggesting the protective effects of autophagy against ox-LDL. Interestingly, ox-LDL increased STIM1 expression and intracellular Ca 2+ concentration. Either Ca 2+ chelators or deficiency in STIM1 attenuated ox-LDL-induced autophagy activation, confirming the involvement of SOCE in the process. Furthermore, CAMKK2 (calcium/calmodulin-dependent protein kinase kinase 2, β) activation and MTOR (mechanistic target of rapamycin [serine/threonine kinase]) deactivation were associated with autophagy modulation. Together, our results reveal a novel signaling pathway of SOCE-CAMKK2 in the regulation of autophagy and offer new insights into the important roles of autophagy in maintaining proliferation and promoting the survival capability of EPCs. This may be beneficial to improving EPC transplantation efficacy and enhancing vascular re-endothelialization in patients with hypercholesterolemia.