Targeting the pyruvate dehydrogenase kinase/pyruvate dehydrogenase axis modulates neutrophil and smooth muscle cell pathological responses and prevents abdominal aortic aneurysm formation

Abstract

Aims: Abdominal aortic aneurysm (AAA) is a life-threatening condition where inflammation plays a key role. Currently, AAA treatment relies exclusively on surgical interventions, and no guideline drug therapy to prevent aneurysm growth or rupture is available. Pharmacological reprogramming of immune cell metabolism, through the modulation of the pyruvate dehydrogenase kinase/pyruvate dehydrogenase (PDK/PDH) axis, has been identified as an attractive strategy to combat inflammation. Here, we aimed, for the first time, to investigate the role of the PDK/PDH axis in AAA and its potential as a therapeutic target.

Methods and results: Analysis of three separate transcriptome data sets revealed that the expression of PDK isoenzymes is skewed in human AAA. Thus, human AAA homogenates showed increased levels of phosphorylated PDH-Ser293 and lactate compared with controls, confirming a metabolic deviation. In mice subjected to porcine pancreatic elastase (PPE)-induced AAA, treatment with dichloroacetate (DCA), a pan inhibitor of PDK isoenzymes, prevented aortic dilation, reducing the increase in inner aortic diameter by ∼58% compared with controls. Further analysis showed that DCA treatment upregulated contractile vascular smooth muscle cell (VSMC)-related genes and downregulated neutrophil-related genes in the mice. In line with the previous, PDK inhibition prevented elastin breakdown, preserved aortic alpha-smooth muscle actin and collagen expression, and decreased neutrophil infiltration and neutrophil extracellular trap (NET) release. Thus, treating VSMC with DCA or PDK1-siRNA revealed that the PDK/PDH axis regulates their dedifferentiation, influencing contractile gene expression and proliferation. Moreover, we found that DCA-induced PDK inhibition inhibited neutrophil NET release in vivo and in vitro.

Conclusion: We show that the PDK/PDH axis is skewed in human AAA. Through the inhibition of PDK, in vitro and in vivo, we demonstrated that the PDK/PDH axis is a key regulator of vascular- and neutrophil-associated pathological responses with AAA formation. Our study pinpoints immunometabolic reprogramming using PDK inhibitors as an attractive strategy to fight AAA disease.

Keywords: Aneurysm; Immunometabolism; Inflammation; PDK; Therapy.