Targeting integrin αvβ3 by a rationally designed protein for chronic liver disease treatment.
Ravi Chakra TuragaGanesh SatyanarayanaMalvika SharmaJenny J YangShiyuan WangChunfeng LiuSun LiHua YangHans E GrossniklausAlton Brad FarrisJordi Gracia-SanchoZhi-Ren LiuPublished in: Communications biology (2021)
Chronic Liver Diseases (CLD) are characterized by abnormal accumulation of collagen fibrils, neo-angiogenesis, and sinusoidal remodeling. Collagen deposition along with intrahepatic angiogenesis and sinusoidal remodeling alters sinusoid structure resulting in portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for CLDs. However, the success of such treatments is limited and unpredictable. We report a strategy for CLD treatment by induction of integrin αvβ3 mediated cell apoptosis using a rationally designed protein (ProAgio). ProAgio is designed to target integrin αvβ3 at a novel site. Integrin αvβ3 is highly expressed in activated Hepatic Stellate Cells (HSC), angiogenic endothelium, and capillarized Liver Sinusoidal Endothelial Cells (LSEC). ProAgio induces apoptosis of these disease causative cells. Tests with liver fibrosis mouse models demonstrate that ProAgio reverses liver fibrosis and relieves blood flow resistance by depleting activated HSC and capillarized LSEC. Our studies demonstrate an effective approach for CLD treatment.
Keyphrases
- liver fibrosis
- endothelial cells
- blood flow
- induced apoptosis
- liver failure
- blood pressure
- cell cycle arrest
- vascular endothelial growth factor
- mouse model
- cell proliferation
- wound healing
- cell adhesion
- cell migration
- protein protein
- signaling pathway
- quality improvement
- endoplasmic reticulum stress
- small molecule
- drug delivery
- pi k akt
- tissue engineering