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.
