PRDM16 deficiency in vascular smooth muscle cells aggravates abdominal aortic aneurysm
Zhenguo Wang, Xiangjie Zhao, Guizhen Zhao, Yanhong Guo, Haocheng Lu, Wenjuan Mu, Juan Zhong, Minerva Garcia-Barrio, Jifeng Zhang, Y. Eugene Chen, Lin Chang
Zhenguo Wang, Xiangjie Zhao, Guizhen Zhao, Yanhong Guo, Haocheng Lu, Wenjuan Mu, Juan Zhong, Minerva Garcia-Barrio, Jifeng Zhang, Y. Eugene Chen, Lin Chang
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Research Article Vascular biology

PRDM16 deficiency in vascular smooth muscle cells aggravates abdominal aortic aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is usually asymptomatic until life-threatening complications occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. The transcriptional regulator PR domain–containing protein 16 (PRDM16) is highly expressed in the aorta, but its functions in the aorta are largely unknown. By RNA-seq analysis, we found that vascular smooth muscle cell–specific (VSMC-specific) Prdm16-knockout (Prdm16SMKO) mice 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. Human AAA lesions displayed lower PRDM16 expression. Periadventitial elastase application to the suprarenal region of the abdominal aorta aggravated AAA formation in Prdm16SMKO 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 that can degrade various ECMs. 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.

Authors

Zhenguo Wang, Xiangjie Zhao, Guizhen Zhao, Yanhong Guo, Haocheng Lu, Wenjuan Mu, Juan Zhong, Minerva Garcia-Barrio, Jifeng Zhang, Y. Eugene Chen, Lin Chang

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Figure 4

Prdm16 knockdown exacerbates apoptosis in VSMCs.

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Prdm16 knockdown exacerbates apoptosis in VSMCs. (A) A7r5 cells were tr...
(A) A7r5 cells were transfected with siRNA-control (siCtrl, 10 nM) or siRNA-Prdm16 (siPrdm16, 10 nM) for 48 hours. The cells were then treated with TNF-α (5 ng/mL) for 6 hours. Expression of proinflammatory genes was determined by qPCR (the siCtrl + Vehicle group, set as 1 for each gene, serves as control). (B–D) A7r5 cells were transfected with siCtrl (10 nM) or siPrdm16 (10 nM) for 48 hours. The cells were then treated with TNF-α (10 ng/mL) plus cycloheximide (CHX, 20 mM) for 6 hours. (B) Cell survival was evaluated by MTT assay. (C) Apoptosis of A7r5 cells was assessed by the cleavage of caspase 3 using Western blotting. The level of cleaved caspase 3 relative to full-length caspase 3 is shown. (D) Apoptosis of A7r5 cells was determined by annexin V/PI staining followed by flow cytometry analysis. The histogram shows the percentage of annexin V+/PI– cells. Data are presented as mean ± SEM. P values were calculated using 2-way ANOVA with Holm-Šidák multiple-comparison test (A–D).