Dexamethasone attenuated thoracic aortic aneurysm and dissection in vascular smooth muscle cell Tgfbr2 disrupted mice with CCL8 suppression.

What is the central question of this study? The aim of this study was to investigate the relationship of CCL8 and the thoracic aortic aneurysm and dissection (TAAD) formation in postnatal mice with vascular smooth muscle cell (VSMC) Tgfbr2 disruption and whether dexamethasone could be a potential treatment. What is the main finding and its importance? CCL8 was associated with the formation of TAAD in VSMC Tgfbr2 disrupted mice. Dexamethasone reduced TAAD formation and inhibited MAPK (p-p38) and NF-κB (p-p65) signaling pathways. CCL8 might be an important promoter in aortic inflammation. DEX provided potential therapeutic effects in TAAD treatment.Aortic inflammation plays a vital role in initiation and progression of thoracic aortic aneurysm and dissection (TAAD). The disturbance of transforming growth factor-β (TGF-β) signaling pathway is believed to be one of the pathogenic mechanisms of TAAD. Initially, Myh11-CreERT2 .Tgfbr2f/f male mice were used to build TAAD mice model. And bioinformatics analyses revealed the enriched inflammatory signal pathways and upregulated chemokine CCL8. So we hypothesized that vascular smooth muscle cell (VSMC) Tgfbr2 disruption in postnatal mice resulted in aortic inflammation associated with CCL8 secretion. Then real-time quantitative PCR and serum ELISA results confirmed that CCL8 expression began to increase after VSMC Tgfbr2 disruption. Next, we cultured mouse thoracic aortas ex vivo, and observed that the protein expressions of CCL8 in culture supernatants were increased by ELISA. Subsequently, the co-localization of CCL8 with α-smooth muscle actin (α-SMA) orCD68 was found significantly increased by immunofluorescence. Then, dexamethasone (DEX) was used to treat TAAD in VSMC Tgfbr2 disrupted mice The results of histochemical, immunofluorescence and immunohistochemical staining indicated that DEX therapy reduced CCL8 secretion, inflammatory cell recruitment, aortic medial thickening, elastic fiber fragmentating, extracellular matrix degradation, contractile apparatus impairment, thereby ameliorated TAAD formation. Western blot showed that MAPK and NF-κB signaling pathways in aorta were overactivated after VSMC Tgfbr2 disruption, but inhibited by DEX therapy. Altogether, CCL8 might be an important promoter in TAAD formation of VSMC Tgfbr2 disrupted mice. And DEX provided potential therapeutic effects in TAAD treatment. This article is protected by copyright. All rights reserved.