National Institutes of Health 5R01HL151524-04

Smooth muscle cell PRDM16 and aortic aneurysm

This award funds research on the role of PRDM16 in smooth muscle cells to understand and develop therapeutic targets for aortic aneurysm, a disease with high mortality. The study investigates PRDM16's protective mechanisms and potential treatments involving NO2-cLA.

Description

Aortic aneurysm (AA) is a major medical concern due to the increasing prevalence and high mortality rate. The pathophysiology of this disease is largely unknown which limits the development of drug targets. The proposed project is relevant for public health because it will establish a novel therapeutic target aimed to manage this asymptomatic disease with a high mortality rate. PR domain containing 16 (PRDM16) is a transcriptional regulator and plays crucial roles in the determination and development of cells including hematopoietic, cardiomyocytes, and smooth muscle cells. Preliminary data indicate that PRDM16 is significantly reduced in the aorta of AAA patients and the PRDM16 SNP is associated with human AA rupture. Tamoxifen-induced VSMC-selective Prdm16 knockout in mice results in increased elastin degradation in AAA lesions, suggesting that loss of PRDM16 promotes AAA formation. PRDM16 negatively regulates TGF-β and ADAM12 in VSMC, which are involved in cell apoptosis and aneurysm progression. The study aims to determine the protective role of PRDM16 in AAA, its mechanism involving TGF-β/ADAM12 signaling, and the protective effect of endogenous NO2-cLA, a nitrated fatty acid that stabilizes PRDM16 and inhibits VSMC apoptosis and inflammation.

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