Cyclophilin A contributes to aortopathy induced by postnatal loss of smooth muscle TGFBR1.

ABSTRACT: Recent recognition that TGF-β signaling disruption is involved in the development of aortic aneurysms has led to renewed investigations into the role of TGF-β biology in the aortic wall. We previously found that the type I receptor of TGF-β (TGFBR2) receptor contributes to formation of ascending aortic aneurysms and dissections (AADs) induced by smooth muscle cell (SMC)-specific, postnatal deletion of Tgfbr1 (Tgfbr1^iko). Here, we aimed to decipher the mechanistic signaling pathway underlying the pathogenic effects of TGFBR2 in this context. Gene expression profiling demonstrated that Tgfbr1^iko triggers an acute inflammatory response in developing AADs, and Tgfbr1^iko SMCs express an inflammatory phenotype in culture. Comparative proteomics profiling and mass spectrometry revealed that Tgfbr1^iko SMCs respond to TGF-β1 stimulation via robust up-regulation of cyclophilin A (CypA). This up-regulation is abrogated by inhibition of TGFBR2 kinase activity, small interfering RNA silencing of Tgfbr2 expression, or inhibition of SMAD3 activation. In mice, Tgfbr1^iko rapidly promotes CypA production in SMCs of developing AADs, whereas treatment with a CypA inhibitor attenuates aortic dilation by 56% (P = 0.003) and ameliorates aneurysmal degeneration (P = 0.016). These protective effects are associated with reduced aneurysm-promoting inflammation. Collectively, these results suggest a novel mechanism, wherein loss of type I receptor of TGF-β triggers promiscuous, proinflammatory TGFBR2 signaling in SMCs, thereby promoting AAD formation.-Zhou, G., Liao, M., Wang, F., Qi, X., Yang, P., Berceli, S. A., Sharma, A. K., Upchurch, G. R., Jr., Jiang, Z. Cyclophilin A contributes to aortopathy induced by postnatal loss of smooth muscle TGFBR1.

SUBMITTER: Zhou G 

PROVIDER: S-EPMC6766662 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature