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Published on: May 26, 2023
Pitavastatin activates mitophagy to protect EPC proliferation through a calcium-dependent CAMK1-PINK1 pathway in
Jie Yang1,2, Mengjia Sun1,2, Ran Cheng1,2
1Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
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.
Insights
Statins like pitavastatin enhance endothelial progenitor cell proliferation by activating mitophagy, a cellular cleaning process. This mechanism involves mitochondrial calcium release and the PINK1-PARK2 pathway, offering new therapeutic avenues for atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Cellular Mechanisms
- Mitochondrial Dynamics
Background:
- Statins are crucial for managing cholesterol and preventing coronary artery disease.
- Emerging evidence suggests statins upregulate mitophagy, but the underlying mechanisms and effects on endothelial progenitor cells (EPCs) remain unclear.
Purpose of the Study:
- To investigate the role and molecular mechanisms of statin-activated mitophagy in EPC proliferation.
- To elucidate how pitavastatin (PTV) influences mitophagy and EPC function in atherosclerosis.
Main Methods:
- Utilized ApoE knockout mice fed a high-fat diet to model atherosclerosis.
- Assessed EPC proliferation, mitochondrial function, and mitophagy markers (PINK1-PARK2 pathway).
- Investigated the effects of Pink1 knockout and Atg7 silencing on PTV-induced EPC proliferation.
Main Results:
- Atherosclerosis impaired EPC proliferation and mitophagy via the PINK1-PARK2 pathway.
- Pitavastatin treatment reversed these impairments, increasing EPC proliferation.
- Mitophagy activation was essential for PTV's beneficial effects on EPC proliferation.
- PTV induced mitochondrial calcium release, activating CAMK1, which promoted PINK1 phosphorylation and mitophagy.
Conclusions:
- A novel molecular pathway for mitophagy activation by statins in EPCs was identified, involving mitochondrial calcium release, CAMK1, and PINK1-PARK2.
- This mechanism explains statins' pleiotropic cardiovascular effects and highlights mitophagy as a therapeutic target for atherosclerosis.
