Transforming growth factor ?1 suppresses proinflammatory gene program independent of its regulation on vascular smooth muscle differentiation and autophagy.

ABSTRACT: Transforming growth factor ? (TGF?) signaling plays crucial roles in maintaining vascular integrity and homeostasis, and is established as a strong activator of vascular smooth muscle cell (VSMC) differentiation. Chronic inflammation is a hallmark of various vascular diseases. Although TGF? signaling has been suggested to be protective against inflammatory aortic aneurysm progression, its exact effects on VSMC inflammatory process and the underlying mechanisms are not fully unraveled. Here we revealed that TGF?1 suppressed the expression of a broad array of proinflammatory genes while potently induced the expression of contractile genes in cultured primary human coronary artery SMCs (HCASMCs). The regulation of TGF?1 on VSMC contractile and proinflammatory gene programs appeared to occur in parallel and both processes were through a SMAD4-dependent canonical pathway. We also showed evidence that the suppression of TGF?1 on VSMC proinflammatory genes was mediated, at least partially through the blockade of signal transducer and activator of transcription 3 (STAT3) and NF-?B pathways. Interestingly, our RNA-seq data also revealed that TGF?1 suppressed gene expression of a battery of autophagy mediators, which was validated by western blot for the conversion of microtubule-associated protein light chain 3 (LC3) and by immunofluo-rescence staining for LC3 puncta. However, impairment of VSMC autophagy by ATG5 deletion failed to rescue TGF?1 influence on both VSMC contractile and proinflammatory gene programs, suggesting that TGF?1-regulated VSMC differentiation and inflammation are not attributed to TGF?1 suppression on autophagy. In summary, our results demonstrated an important role of TGF? signaling in suppressing proinflammatory gene program in cultured primary human VSMCs via the blockade on STAT3 and NF-?B pathway, therefore providing novel insights into the mechanisms underlying the protective role of TGF? signaling in vascular diseases.

SUBMITTER: Gao P 

PROVIDER: S-EPMC6389266 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature