PRDM16 Deficiency in Vascular Smooth Muscle Cells Aggravates Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is usually asymptomatic until severe complications with high risk of lethality occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. PR domain-containing protein 16 (PRDM16) is a transcriptional regulator that governs gene expression by cooperating with other transcription factors. It is highly expressed in the aorta, but its functions in the aortic tissue and AAA pathology are largely unknown. In this study, we investigated the roles of PRDM16 in vascular smooth muscle cells (VSMCs). By RNA-seq analysis, we found that VSMCs-specific Prdm16 knockout mice ( Prdm16 SMKO) already showed extensive changes in the expression of genes associated with extracellular matrix (ECM) remodeling and inflammation in the abdominal aorta under normal housing conditions without any pathological stimuli. We found that human AAA lesions displayed decreased PRDM16 expression in the aortic medial layer. Periadventitial elastase application to the suprarenal region of the abdominal aorta aggravated AAA formation in Prdm16 SMKO mice. During AAA development, VSMCs undergo apoptosis because of both intrinsic and environmental changes including inflammation and ECM remodeling. Prdm16 deficiency promoted inflammation and apoptosis in VSMCs. A disintegrin and metalloproteinase 12 (ADAM12) is a gelatinase which can degrade various ECM. We found that ADAM12 is a target of transcriptional repression by PRDM16. Adam12 knockdown reversed VSMC apoptosis induced by Prdm16 deficiency. Our study demonstrated that PRDM16 deficiency in VSMCs promoted ADAM12 expression and aggravates AAA formation, which may provide potential targets for AAA treatment. This work was partially supported by National Institutes of Health grants HL151524 (L. Chang) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.