Characterization of Genetic and Metabolic Somatic Events in Aortic Atherosclerotic Plaques

Objectives: The pathogenicity, origin, and development of atherosclerosis in the ascending aorta are not well understood. However, during lifetime the aortic tissue has to cope with metabolic, toxic and mechanic stress, which can lead to intracellular DNA damage. The aim of the project is to elucidate the amount of accumulating somatic mutations and inadequate metabolic consequences within the aortic tissue and its implication for the atherosclerotic pathogenesis.

Methods: Aneurysmal aortic tissue of the ascending aorta of seven patients was excised during surgical ascending replacement. Hard and soft arteriosclerotic plaques were identified macroscopically. Identified plaques were analyzed by next-generation sequencing, qPCR and mass-spectrometry–based lipidomic analysis. Plaques and surrounding tissue of two patients were used for sequencing of 96 genes encoding for proteins involved in proliferation, microsatellite instability and DNA repair processes. Identified variants were classified according to their likelihood for pathogenicity (benign, unknown significance, pathogenic). Moreover, expression of genes associated with lipid metabolism and inflammation was analyzed.

Result: This pilot analysis revealed that atherosclerotic lesions per se accumulate somatic mutations. In two patients, 13 out of 96 analyzed genes were affected. Three of these mutations were classified as benign, ten variants were of unknown significance, and one variant was classified as pathogenic. On gene expression level, soft plaques showed an increased gene expression of DNA-damage inducible transcripts. Moreover, especially soft atherosclerotic plaques showed signs of increased lipid synthesis. The expression of lipid synthesis-associated genes correlated positively with the levels of its product palmitic acid. Moreover, plaques with high activity of lipid synthesis also showed an increased inflammation status.

Conclusion: This pilot study generated the hypothesis that soft atherosclerotic plaques of the ascending aorta might show a triad of metabolic errors: DNA damage, inflammation, and aberrant lipid synthesis. Although it was previously assumed that cells of arteriosclerotic plaques mainly take up lipids from blood circulation, it seems that cells within the plaque also synthesize them by themselves.

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Artikel online veröffentlicht:
19. Februar 2021