Angiotensin receptor blockers retard the progression and fibrosis via inhibiting the viability of ^AGTR1+CAFs in intrahepatic cholangiocarcinoma

Abstract

Background Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy characterized by massive fibrosis and has ineffective adjuvant therapies. Here, we demonstrate the potential of angiotensin receptor blockers (ARBs) in targeting iCCA. Methods Masson's trichrome staining was used to assess the effect of ARBs in iCCA specimens, CCK8 and gel contraction assays in vitro and in xenograft models in vivo. RNA‐seq and ATAC‐seq were used for mechanistic investigations. Results Patients with iCCA who were administered ARBs had a better prognosis and a lower proportion of tumour stroma, indicating alleviated fibrosis. The presence of AGTR1, the ARBs receptor, is associated with a poor prognosis of iCCA and is highly expressed in tumour tissues and cancer‐associated fibroblasts (CAFs). The ARBs strongly attenuated the viability of AGTR1+ CAFs in vitro and retarded tumour progression and fibrosis in xenograft models of co‐cultured CAFs and iCCA cells. Still, they did not have a significant effect on AGTR1− CAFs. Moreover, ARBs decreased the secretion of AGTR1+ CAF‐derived MFAP5 via the Hippo pathway, weakened the interaction between CAFs and iCCA cells, and impaired the aggressiveness of iCCA cells by attenuating the activation of the Notch1 pathway in iCCA cells. Conclusions ARBs exhibit anti‐fibrotic function by inhibiting the viability of AGTR1+ CAFs. These findings support using ARBs as a novel therapeutic option for targeting iCCA.

Recovery from Heart Failure is a Vascular Recovery

“…Our detailed snRNA-seq analyses have revealed an important interplay between cellular transitions and gene expression alterations within the cardiac tissue microenvironment. Notably, we observed a downregulation of fibrosis markers/mediators, including COL1A1, COL3A1, TGF-β1 and AGTR1 [60][61][62] particularly in the EC5 subset. As each of these genes play a role in the accumulation of ECM, and their reduced expression in the post-LVAD specimens may facilitate a recovery from cardiac fibrosis.…”