Myocardin and myocardin-related transcription factor-A synergistically mediate actin cytoskeletal dependent inhibition of liver fibrogenesis.

Myocardin and myocardin-related transcription factor-A synergistically mediate actin cytoskeletal dependent inhibition of liver fibrogenesis. Am J Physiol Gastrointest Liver Physiol. 2020 Jan 13;: Authors: Shi Z, Ren M, Rockey DC Abstract Hepatic stellate cells (HSCs) activation, characterized by development of a robust actin cytoskeleton and expression of abundant extracellular matrix (ECM) proteins such as type 1 collagen (COL.1), is a central cellular and molecular event in liver fibrosis. It has been demonstrated that HSCs express both myocardin and myocardin-related transcription factor-A (MRTF-A). However, the biological effects of myocardin and MRTF-A on HSC activation and liver fibrosis as well as the molecular mechanism under the process remain unclear. Here, we report that myocardin and MRTF-A's expression and nuclear accumulation are prominently increased during HSC activation process, accompanied by robust activation of actin cytoskeleton dynamics. Targeting myocardin and MRTF-A binding and function with a novel small molecule, CCG-203971, led to dose dependent inhibition of HSC actin cytoskeleton dynamics and abrogated multiple functional features of HSC activation (i.e. HSC contraction, migration and proliferation), and decreased COL.1 expression in vitro and liver fibrosis in vivo. Mechanistically, blocking the myocardin and MRTF-A nuclear translocation pathway with CCG-203971 directly inhibited myocardin/MRTF-A mediat...
Source: American Journal of Physiology. Gastrointestinal and Liver Physiology - Category: Physiology Authors: Tags: Am J Physiol Gastrointest Liver Physiol Source Type: research