Browning of perivascular adipose tissue protects against thoracic aortic aneurysm

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PROJECT SUMMARY/ABSTRACT Thoracic aortic aneurysm (TAA) is a life-threatening disease and has a high mortality rate if rupture occurs. Currently, apart from endovascular or open surgery repair, no drug has been demonstrated to be effective for TAA treatment. Even though some patients with TAA have evidence of a heritable aortopathy, about 75% of TAA patients have severe aortic damage without a clear genetic etiology. The scant mechanistic knowledge is limiting the development of medications for the treatment of TAA, thus highlighting a pressing need for better understanding TAA formation and progression. Aorta is naturally surrounded by perivascular adipose tissue (PVAT). Recent large-scale epidemiological studies demonstrated that PVAT was highly associated with a significantly higher adjusted risk of all-cause cardiac mortality. We and others documented that brown-like PVAT contributes to vascular homeostasis in health, while whitening of PVAT is dysfunctional and contributes to development of the vascular diseases. A causal relationship between PVAT and TAA and the underlying mechanisms remain unknown. Our preliminary studies indicate that the PVAT near the TAA lesion in patients lost brown characteristics, and that TAA formation was dramatically increased in mice that lack normal PVAT, suggesting that dysfunctional PVAT is associated with TAA. The conditioned medium from PVAT of TAA patients induced apoptosis and inflammation in human aortic smooth muscle cells, suggesting that signaling from PVAT can cause loss of vascular smooth muscle cells (VSMC) in the aorta, which may promote TAA lesion. It is unknown whether browning of PVAT could protect against TAA. PR-domain containing 16 (PRDM16) is a determinant of browning gene programs. We show that PRDM16 expression in PVAT of TAA patients is significantly reduced when compared to that in normal PVAT. PRDM16 inhibited resistin expression in PVAT. We found that nitrated conjugated linoleic acid (NO2-CLA) induced the browning of human PVAT adipocytes by mediating PRDM16 signaling. Based on these data, we hypothesize that PRDM16-mediated PVAT browning prevents TAA formation. We will determine that 1) PRDM16 in PVAT prevents and reverses TAA in mice; 2) PRDM16 inhibits TAA by regulating PVAT crosstalk with VSMC; 3) NO2-CLA prevents TAA by targeting PRDM16. Outcomes will demonstrate that a previously unrecognized process involving loss of browning features in PVAT promotes TAA formation through crosstalk to VSMC. This work will accelerate clinical translation of a nitro-fatty acid-based treatment for TAA targeting PVAT homeostasis with this new class of drugs, currently on clinical trials for other diseases.