Human hepatic stellate cells secrete adrenomedullin: potential autocrine factor in the regulation of cell contractility

• Published in: Journal of hepatology 2001-02, Vol.34 (2), p.222-229
• Main Authors: Nieves Görbig, M, Ginès, Pere, Bataller, Ramón, Nicolás, Josep M, Garcia-Ramallo, Eva, Cejudo, Pilar, Sancho-Bru, Pau, Jiménez, Wladimiro, Arroyo, Vicente, Rodés, Juan
• Format: Article
• Language: English
• Subjects: Adrenomedullin; Biological and medical sciences; Calcitonin Receptor-Like Protein; Calcium Signaling - drug effects; Cell Movement - physiology; Cells, Cultured; Cyclic AMP - metabolism; Endothelin-1 - pharmacology; Fundamental and applied biological sciences. Psychology; Hepatic blood flow; Hepatic microcirculation; Humans; Interleukin-1 - pharmacology; Liver - cytology; Liver - drug effects; Liver - metabolism; Liver - physiology; Liver. Bile. Biliary tracts; Peptides - metabolism; Peptides - pharmacology; Receptors, Adrenomedullin; Receptors, Calcitonin - metabolism; Receptors, Peptide - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Vertebrates: digestive system
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/S0168-8278(00)00016-7

Background/Aims : Hepatic stellate cells (HSCs) are perisinusoidal pericytes which have receptors for vasoactive factors, such as endothelin-1, which can regulate cell contractility in an autocrine manner. It is unknown whether human HSCs have receptors for and are able to synthesize the vasodilator peptide adrenomedullin (ADM), a peptide produced by most contractile cells. Methods and results : Stimulation of HSCs with ADM resulted in a dose-dependent raise in cAMP concentration (radioimmunoassay) and markedly blunted the endothelin-induced increase in [Ca 2+] i and cell contraction, as assessed in cells loaded with fura-2 using a morphometric method. The existence of the receptor CRLR for ADM and their associated proteins RAMP-1 and RAMP-2 was demonstrated by reverse transcriptase–polymerase chain reaction (RT–PCR). Moreover, activated human HSCs spontaneously secreted ADM in the culture medium in a time-dependent manner. ADM secretion was markedly enhanced by tumour necrosis factor-α and interleukin-1 β. Specific mRNA for ADM (RT–PCR and Northern blot) was detected in HSCs and increased after incubation of cells with cytokines. Conclusions : Human HSCs have functional receptors for ADM, the stimulation of which blunts the contractile effect of endothelin-1. Cultured human HSCs secrete ADM in baseline conditions. This secretion is markedly increased by cytokines. These results suggest that ADM can regulate HSCs’ contractility in an autocrine manner.