Griepke S, Grentzmann A, Tripodi G L, Hansen J, Fonseca M P, Nilsson M D, Tallouzi Y, Grupe E, Jensen P S, Beck H C, Temprano-Sagrera G, Sabater-Lleal M, Burton M, Dembic M, Thomassen M, Forteza M J, Terp M G, Lindholt J S, Rasmussen L M, Steffensen L B, Stubbe J, Ketelhuth D F J
Cardiovascular and Renal Research Unit, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Cancer and Inflammation Research Unit, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Cardiovasc Res. 2025 Mar 4. doi: 10.1093/cvr/cvaf032.
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.
Analysis of three separate transcriptome datasets 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 to 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 approximately 58% compared to controls. Further analysis showed that DCA treatment upregulated contractile 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 traps (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.
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.
腹主动脉瘤（AAA）是一种危及生命的疾病，炎症在其中起关键作用。目前，AAA的治疗完全依赖于手术干预，尚无预防动脉瘤生长或破裂的指导性药物治疗方法。通过调节丙酮酸脱氢酶激酶/丙酮酸脱氢酶（PDK/PDH）轴对免疫细胞代谢进行药理学重编程，已被确定为对抗炎症的一种有吸引力的策略。在此，我们首次旨在研究PDK/PDH轴在AAA中的作用及其作为治疗靶点的潜力。
对三个独立的转录组数据集进行分析，结果显示PDK同工酶的表达在人类AAA中存在偏差。因此，与对照组相比，人类AAA匀浆中磷酸化PDH-Ser293和乳酸水平升高，证实了代谢偏差。在接受猪胰弹性蛋白酶（PPE）诱导的AAA的小鼠中，用二氯乙酸（DCA）（一种PDK同工酶的泛抑制剂）进行治疗，可预防主动脉扩张，与对照组相比，主动脉内径增加减少了约58%。进一步分析表明，DCA治疗上调了小鼠中与收缩性血管平滑肌细胞（VSMC）相关的基因，并下调了与中性粒细胞相关的基因。与之前的研究一致，抑制PDK可防止弹性蛋白分解，保留主动脉α-平滑肌肌动蛋白和胶原蛋白表达，并减少中性粒细胞浸润和中性粒细胞胞外陷阱（NET）释放。因此，用DCA或PDK1小干扰RNA（siRNA）处理VSMC表明，PDK/PDH轴调节其去分化，影响收缩性基因表达和增殖。此外，我们发现DCA诱导的PDK抑制在体内和体外均抑制中性粒细胞NET释放。
我们表明，PDK/PDH轴在人类AAA中存在偏差。通过在体外和体内抑制PDK，我们证明PDK/PDH轴是与AAA形成相关的血管和中性粒细胞相关病理反应的关键调节因子。我们的研究指出，使用PDK抑制剂进行免疫代谢重编程是对抗AAA疾病的一种有吸引力的策略。
