부산대학교 도서관

Thoracic aortic aneurysms are life-threatening and often diagnosed too late, underscoring the need to identify the underlying molecular sequence of events. We therefore examined the molecular mechanisms involved in aneurysm formation. In Fibulin-4 mice, the extracellular matrix protein Fibulin-4 is reduced, resulting in progressive ascending aneurysm formation and early death around 3 months of age. We performed proteomics and genomics studies on the aortas of these mice. Intriguingly, we observed alterations in mitochondrial protein composition in Fibulin-4 aortas compared to controls. Consistently, functional studies in Fibulin-4 vascular smooth muscle cells (VSMCs) revealed lower oxygen consumption rates, but increased acidification rates. Mitochondria in Fibulin-4 VSMCs showed a normal distribution and localization, but were reduced in size. Remarkably, we also found reduced mitochondrial respiration in Tgfbr-1 VSMCs, a model for Loeys-Dietz syndrome. Importantly, decreased oxygen consumption was also observed in human fibroblasts from aneurysmal patients (TGFBR2 c1573delA; SMAD3 c.859C>T, p.R287W; FBN1 c.4817-1G>A) Fibulin-4 heart and muscle tissue similarly showed decreased oxygen consumption, whereas mitochondrial complex activities were normal. Furthermore, aortas of aneurysmal Fibulin-4 mice displayed increased ROS levels. In line, gene expression analyses revealed dysregulation of metabolic pathways. Also, Fibulin-4 blood ketone levels were reduced and liver fatty acids were decreased, while liver glycogen was increased, indicating dysregulated metabolism at the organismal level. Moreover, activity of PGC1α, a key regulator switch between mitochondrial function and organismal metabolism, was downregulated in Fibulin-4 VSMCs. Interestingly, stimulation of PGC1α activity increased the mitochondrial oxygen consumption in these cellsTaken together, our data indicate altered mitochondrial function and metabolic dysregulation, leading to increased ROS levels and altered energy production, as a novel mechanism which may contribute to thoracic aortic aneurysm formation. These findings open up novel (nutritional) intervention strategies for aneurysmal disease.