Relaxant Effect of Prostaglandin D2–Receptor DP Agonist on Liver Myofibroblast Contraction

Abstract

Abstract. Increased intrahepatic resistance causes portal hypertension in cirrhosis. Liver myofibroblasts (MFs) are now regarded as the principle cells involved in sinusoidal blood flow regulation. Many other prostaglandin-receptor agonists have been reported to regulate liver MF contraction, but the role of the prostaglandin D 2 -receptor DP is unknown. In this study, we investigated the effect of a synthetic agonist of prostanoid DP receptor, BW245C, on contractile properties of primary rat liver MFs. Collagen gel contraction assay revealed that BW245C alone (1 and 10 μM) did not induce contraction but induced cell relaxation. Pretreatment with BW245C (10 μM, 30 min) attenuated bradykinin (100 nM)-induced liver MF contraction. Elevation of [Ca 2+ ] i induced by bradykinin (100 nM) was partially suppressed by BW245C pretreatment (10 μM, 3 min). BW245C (1 and 10 μM) significantly increased intracellular cAMP level in a dose-dependent manner. Pretreatment with forskolin (30 -300 nM, 30 min) and dibutyryl-cAMP (3 -30 μM, 30 min) significantly reduced bradykinin-induced contraction. Furthermore, a protein kinase A (PKA) inhibitor KT5720 (10 nM to 1 μM, 30 min) blocked the relaxant effect of BW245C. These results suggest that prostanoid DP receptor agonism inhibits bradykinin-induced [Ca 2+ ] i elevation and contraction through cAMP-PKA signal activation in rat liver MFs.

Hepatic stellate cells relay inflammation signaling from sinusoids to parenchyma in mouse models of immune‐mediated hepatitis

“…Consistently, H&E staining showed decreased necrotic areas in the liver of BQ‐123‐adminstered mice compared with that of vehicle‐treated animals (http://onlinelibrary.wiley.com/doi/10.1002/hep.28112/suppinfo). As BW245C was reported to inhibit Ca 2+ elevation in rat myofibroblasts, we examined the possibility that BW245C inhibits ET‐1 action by suppressing Ca 2+ elevation. We used human HSCs and examined the effect of BW245C on ET‐1‐induced intracellular Ca 2+ elevation.…”

“…S8F). As BW245C was reported to inhibit Ca 21 elevation in rat myofibroblasts, (29) we examined the possibility that BW245C inhibits ET-1 action by suppressing Ca 21 elevation. We used human HSCs and examined the effect of BW245C on ET-1-induced intracellular Ca 21 elevation.…”

Tissue and Organ Regeneration in Adults

“…Among the several examples of chronic organ contraction in humans are the narrowing and sometimes complete obstruction of the duodenum following repeated ulceration (Billingham and Russell 1956) and the shrinking of heart valves in rheumatic heart disease (Peacock 1984;Rudolph et al 1992). A striking decrease in liver size, attributed to contraction, is a feature of terminal cases of liver cirrhosis (Rudolph et al 1979a;Rudolph 1980;Nimni 1983) and has been attributed to contractile cell (myofibroblast) activity (Maruyama et al 2011). …”