AMPK deficiency inhibits fatty acid oxidation in endothelial progenitor cells to aggravate impaired angiogenesis after ischemic stroke in hyperlipidemic mice

ABSTRACT

Background

Hyperlipidemia is a risk factor for stroke, and worsens neurological outcome after stroke. Endothelial progenitor cells (EPCs), which become dysfunctional in cerebral ischemia, hold capacity to promote revascularization.

Objective

We investigated the role of dyslipidemia in impairment of EPC-mediated angiogenesis in cerebral ischemic mice.

Methods and Results

The high fat diet (HFD)-fed mice following by ischemic stroke exhibited increased infarct volumes and neurological severity scores, and poorer angiogenesis. Bone marrow-EPCs treated with palmitic acid (PA) showed impaired functions and inhibited activity of AMP-activated protein kinase (AMPK). Notably, AMPK deficiency aggravated EPC dysfunction, further decreased mitochondrial membrane potential, and increased reactive oxygen species level in EPCs with PA treatment. Furthermore, the expression of fatty acid oxidation (FAO)-related genes was remarkably reduced, and carnitine palmitoyltransferase 1A (CPT1A) protein expression was downregulated in AMPK-deficient EPCs. AMPK deficiency aggravated neurological severity scores and angiogenesis in ischemic brain of HFD-fed mice, accompanied by suppressed protein level of CPT1A. EPC transplantation corrected impaired neurological severity scores and angiogenesis in AMPK-deficient mice.

Conclusion

Our findings suggest that AMPK deficiency aggravates poor angiogenesis in ischemic brain by mediating FAO and oxidative stress thereby inducing EPC dysfunction in hyperlipidemic mice.

KEYWORDS:

• Hyperlipidemia
• ischemic stroke
• endothelial progenitor cells
• AMPK
• fatty acid β-oxidation
• angiogenesis

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data presented in this study are available from the correspondence authors upon request.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/02699052.2024.2349776.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China [31900381], the Basic Scientific Research Project of Hangzhou Medical College [KYZD202102 and KYYB202114], and the Science and Technology Project of Huzhou City [2020GY46].