PRDM16 Deficiency in Vascular Smooth Muscle Cells Aggravates Abdominal Aortic Aneurysm

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. Prdm16flox/flox mice (stock number 024992) and Myh11-CreERT2 mice (stock number 019079) were from the Jackson Laboratory and were backcrossed to C57BL/6 background. Prdm16flox/flox mice were crossbred with Myh11-CreERT2 mice (carrying the CreER cassette on the Y chromosome) to generate VSMCs specific Prdm16 knockout (Prdm16SMKO) mice. Eight- to ten-week-old male mice were treated with tamoxifen (75 mg/kg/day) in corn oil for 5 consecutive days by gavage. Two weeks later, total RNA from abdominal aorta were isolated with the RNeasy® micro kit (Cat# 74004, Qiagen).