Rohan Bhandari and Scott J. Cameron
This editorial refers to ‘Untargetedmetabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysmand dissection’, byH. Cui et al., http://dx.doi.org/10.1093/eurheartj/ehab605.
In this issue of the European Heart Journal, Cui et al. utilize untargeted metabolomics to identify plasma succinate concentration as a biomarker for discriminating aortic diseases (AAA and aortic dissection) from healthy individuals and patients with PE or acute MI. Furthermore, the authors characterized mechanisms of succinate-induced mitochondrial dysfunction, succinate production via enhanced oxoglutarate dehydrogenase (OGDH) activity, and regulation of OGDH transcription by CREB and phosphorylation by the MAPK family member p38a using three murine models of AAA.
In parallel with data from humans with AAA, the authors use murine models of AAA including the angiotensin II and the BAPN/elastase models in wild-type, ApoE-/-, and myeloid knockdown p38a mice– to establish succinate and mitochondrial dysfunction as contributory to aortic aneurysmal growth at the cellular level. The authors show macrophage-derived succinate generation promotes metabolic dysfunction and oxidative stress in the aortic wall, resulting in AAA progression and aortic aneurysm dissection (AAD). The authors propose that plasma succinate may be used as an adjunctive biomarker for the diagnosis of AAD and that targeted inhibition of the monocyte p38a-CREB-OGDH module may represent a potential therapeutic intervention to abrogate AAA development and AAD.