Activating soluble guanylate cyclase restores amyloid-beta and LDL clearance in aged rats
Cinaciguat reversed endothelial defenestration and restored paracrine signaling that enables rat hepatocytes to clear circulating lipids and amyloid-beta.
In aged rats, treating animals with the soluble guanylate cyclase activator cinaciguat for two weeks restored liver sinusoidal endothelial cell fenestration. This treatment halved circulating amyloid-beta 40 levels, returning them to levels found in young rats. Cinaciguat also reversed age-related increases in low-density lipoprotein. Further experiments showed that aged endothelial cells synthesize but fail to secrete heparin-binding epidermal growth factor-like growth factor, which is necessary for hepatocyte uptake function. Treating aged rats with cinaciguat rescued this paracrine signaling and restored endothelial secretion of the growth factor. The treatment also reversed the age-associated loss of LDLR and LRP1 surface expression on rat hepatocytes, permitting the cells to clear amyloid-beta 40 and low-density lipoprotein.
Why it matters
The findings demonstrate that structural and paracrine decline in liver sinusoidal endothelial cells directly limits the clearance of circulating macromolecules during aging. Targeting liver endothelial health may offer a way to address concurrent age-related increases in vascular and neurodegenerative risk factors.
Caveats
The investigation was performed entirely in aged rats and in vitro rat cell models, so it remains unknown if the same mechanism operates in humans.
- Cinaciguat
- Altered intercellular communication
- Cellular senescence
- Lipid and ceramide metabolism
- Hbegf
- Ldlr
- Lrp1
- LDL
- Amyloid-beta 40
- Rattus norvegicus
The paper
Reversing liver sinusoidal endothelial aging restores clearance of amyloid-beta and LDL
de Leve SJ, Wang X, Alavifard H et al.
The Journal of Biological Chemistry · 26 Sep 2026