Abstract
Statins play a major role in reducing circulating cholesterol levels and are widely used to prevent coronary artery disease. Although they are recently confirmed to up-regulate mitophagy, little is known about the molecular mechanisms and its effect on endothelial progenitor cell (EPC). Here, we explore the role and mechanism underlying statin (pitavastatin, PTV)-activated mitophagy in EPC proliferation. ApoE−/− mice are fed a high-fat diet for 8 weeks to induce atherosclerosis. In these mice, EPC proliferation decreases and is accompanied by mitochondrial dysfunction and mitophagy impairment via the PINK1-PARK2 pathway. PTV reverses mitophagy and reduction in proliferation. Pink1 knockout or silencing Atg7 blocks PTV-induced proliferation improvement, suggesting that mitophagy contributes to the EPC proliferation increase. PTV elicits mitochondrial calcium release into the cytoplasm and further phosphorylates CAMK1. Phosphorylated CAMK1 contributes to PINK1 phosphorylation as well as mitophagy and mitochondrial function recover in EPCs. Together, our findings describe a molecular mechanism of mitophagy activation, where mitochondrial calcium release promotes CAMK1 phosphorylation of threonine177 before phosphorylation of PINK1 at serine228, which recruits PARK2 and phosphorylates its serine65 to activate mitophagy. Our results further account for the pleiotropic effects of statins on the cardiovascular system and provide a promising and potential therapeutic target for atherosclerosis.
Highlights
Vascular endothelial injury contributes to the development of major cardiovascular diseases (CVDs), and promoting re-endothelialization after arterial injury is critical for their prevention
We revealed both proliferation inhibition and mitophagy impairment in atherosclerotic endothelial progenitor cell (EPC)
We showed that PTV elicits calcium release from mitochondria to activate CAMK1, which increases the level of phosphorylated PINK1 and PINK1 further recruits PARK2; PARK2 localizes to the mitochondrial membrane and was phosphorylated to activate mitophagy (Fig. 9c)
Summary
Vascular endothelial injury contributes to the development of major cardiovascular diseases (CVDs), and promoting re-endothelialization after arterial injury is critical for their prevention. Our recent study revealed that store-operated calcium entry (SOCE)-induced autophagy protects EPC proliferation during ox-LDL exposure[15], providing potential evidence that statin-activated autophagy or mitophagy is related to EPC regulation. In the early stage of atherosclerosis, increased production of reactive oxygen species (ROS) in mitochondria, accumulation of mitochondrial DNA (mtDNA) damage, and progressive respiratory chain dysfunction, resulted in endothelial cells (ECs) dysfunction and vascular smooth muscle cells (VSMCs) phenotypic conversion[17]. Multiple mitophagy programs that operate independently or undergo crosstalk have been revealed, which function through modulated autophagy receptor activities at the mitochondrial outer membrane (OMM). Statins might activate mitophagy through OMM protein ubiquitylation, phosphorylation, and/or binding with autophagosomes, accounting for their pleiotropic effects. We proposed that statins might elicit mitochondrial calcium release in EPCs and be associated with mitophagy induction. We investigated EPC mitophagy and proliferation in atherosclerotic mice, as well as the role of pitavastatin (PTV) in mitophagy induction and EPC proliferation
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