title: Store-operated calcium entry-activated autophagy protects EPC proliferation via the CAMKK2-MTOR pathway in ox-LDL exposure.
abstract: 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 Ca2+concentration. Either Ca2+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.
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Jie
authors: J
authors: Yang
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Jie
authors: J
authors: Yu
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Dongdong
authors: D
authors: Li
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Sanjiu
authors: S
authors: Yu
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Jingbin
authors: J
authors: Ke
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Lianyou
authors: L
authors: Wang
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Yanwei
authors: Y
authors: Wang
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Youzhu
authors: Y
authors: Qiu
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Xubin
authors: X
authors: Gao
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Jihang
authors: J
authors: Zhang
authors: a Institute of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University , Chongqing , China.
authors: Lan
authors: L
authors: Huang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D049109:Cell Proliferation; D002614:Chelating Agents / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology*; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D002614:Chelating Agents; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D049452:Green Fluorescent Proteins; D058570:TOR Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517702:Camkk2 protein, rat; D002118:Calcium
keywords: CAMKK2; MTOR; autophagy; cell-based therapy; endothelial progenitor cells; oxidized low-density lipoprotein; proliferation; store-operated calcium entry