Untargeted Metabolomics Identifies Succinate as a Biomarker and Therapeutic Target in Aortic Aneurysm and Dissection

Hongtu Cui; Yanghui Chen; Ke Li; Rui Zhan; Mingming Zhao; Yangkai Xu; Zhiyong Lin; Yi Fu; Qihua He; Paul C. Tang; Ienglam Lei; Jifeng Zhang; Chenze Li; Yang Sun; Xinhua Zhang; Tiffany Horng; Hong S. Lu; Y. Eugene Chen; Alan Daugherty; Daowen Wang; Lemin Zheng

Disclosures

Eur Heart J. 2021;42(42):4373-4385. 

In This Article

Abstract and Introduction

Abstract

Aims:Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance.

Methods and Results: We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKO Apoe –/– mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD.

Conclusion: Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α–CREB–OGDH axis in macrophages.

Graphical Abstract

Introduction

Aortic aneurysm and dissection (AAD) have a prevalence of 1.3–8% and are associated with high mortality due to acute aortic complications.[1–3] Sporadic AAD are associated with smoking, hypertension, old age, and male gender. The pathogenesis of AAD is associated with inflammation, apoptosis, smooth muscle cell phenotype switch, and degradation of the extracellular matrix.[4,5] There are no effective drugs to prevent the occurrence and development of AAD.[6] Therefore, it is essential to explore potential therapeutic targets for AAD.

Succinate plays critical roles in a variety of physiological and pathophysiological conditions. It accumulates in the myocardium during myocardial ischaemia and is rapidly oxidized to generate reactive oxygen species (ROS) with the occurrence of reperfusion, which led to the death of myocardial cells and aggravated ischaemia–reperfusion injury.[7] Dimethyl malonate, by inhibiting succinate dehydrogenase, improved ischaemia–reperfusion injury during myocardial infarction in mice and pigs.[7,8] Succinate also plays an important role in maintaining glucose homeostasis. For example, succinate contributes to intestinal gluconeogenesis and accelerates adipose tissue thermogenesis.[9,10] Succinate released from muscles during exercise contributes to the formation of extracellular matrix and muscle regeneration.[11] Furthermore, succinate plays an important role in the pathophysiological process of diseases such as diabetes, chronic neuroinflammation, osteoclastogenesis, rheumatoid arthritis, systemic lupus erythematosus, and intestinal type 2 immunity.[12–18] However, the contribution of succinate to AAD and its clinical relevance remain unclear.

Macrophages are known to display a diverse array of metabolic characteristics that depend upon their functional states.[19] In M1 inflammatory macrophages, glycolysis is enhanced, whereas the tricarboxylic acid (TCA) cycle is interrupted at several key points, thereby leading to the accumulation of TCA intermediate products. Succinate is an important intermediate product of the TCA cycle that accumulates in M1 pro-inflammatory macrophages.[20] Succinate transported from mitochondria to the cytoplasm inhibits proline hydroxylase activity, increases the levels of hypoxia-inducible factor 1-alpha, and induces the expression of interleukin (IL)-1β. In addition, succinate in mitochondria generates a large amount of ROS through oxidation by succinate dehydrogenase, promoting M1 polarization.[21]

In our current study, we found that plasma succinate concentrations were positively correlated with human aortic diseases and succinate plays an important role in the pathogenesis of AAD as demonstrated in three well-established murine AAD models.

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