Abstract 2015: Pyruvate Carboxylase-mediated Vascular Smooth Muscle Cell Mitochondrial Dysfunction Activates Cgas-sting Signaling In Aortic Dissection.

Abstract

Background: Aortic Dissection (AD), characterized by the loss of vascular smooth muscle cells (VSMC) and degradation of the extracellular matrix, carries an exceptionally high mortality rate, and as of now, there are no effective drugs to impede its occurrence and progression. Deciphering the mechanisms governing the onset and progression of aortic dissection is paramount for the development of innovative therapeutic modalities. Recent evidence suggests a pivotal role of mitochondrial metabolism in vascular inflammation, with pyruvate carboxylase (PC) emerging as a crucial component of the tricarboxylic acid cycle. In this study, we investigated the influence of PC on the occurrence and development of AD, elucidating the underlying mechanisms. Methods: Investigating alterations in PC expression levels in aortic tissues of both humans and C57BL/6 mice, and assessing the impact of PC on the occurrence and AD in PC SMKO mice. The study further explores the role of PC through both in vivo and in vitro investigations to delineate the associated pathways. Results: We observed a significant upregulation in the expression of PC in AD tissues. In the AD model of mice, the occurrence rate of AD and the mortality resulting from aortic dissection rupture were significantly reduced in PC SMKO mice. Transcriptomic results revealed that overexpression of PC in VSMCs could activate the STING pathway. Inhibition of the STING pathway significantly reduced both the occurrence and mortality rates of AD in mice. Mechanistically, overexpression of PC induced mitochondrial metabolic dysregulation, leading to nuclear and mitochondrial DNA damage. The released DNA into the cytoplasm activated the transduction of the STING signaling pathway, consequently causing necrosis of VSMC. Conclusions: Our results indicated that PC could facilitate the occurrence and progression of AD by activating the STING pathway. Targeting PC has the potential to prevent the onset of AD.