Ursodeoxycholic acid upregulates ERK and Akt in the protection of cardiomyocytes against CoCl2

Abstract

ABSTRACT. Ursodeoxycholic acid (UDCA) is used to treat liver diseases and demonstrates cardioprotective effects. Accumulation of the plasma membrane sphingolipid sphingomyelin in the heart can lead to atherosclerosis and coronary artery disease. Sphingomyelinases (SMases) break down sphingomyelin, producing ceramide, and inhibition of SMases activity can promote cell survival. We hypothesized that UDCA regulates activation of ERK and Akt survival signaling pathways and SMases in protecting cardiac cells against hypoxia. Neonatal cardiomyocytes were isolated from 0-to 2-day-old Sprague Dawley rats, and given 100 µM CoCl 2 , 150 µM H 2 O 2 , or placed in a hypoxia chamber for 24 h. The ameliorative effects of 100-µM UDCA treatment for 12 h were then assessed using MTS, QuantiGene Plex (for Smpd1 and Smpd2), and SMase assays, beating rate assessment, and western blotting (for ERK and Akt). Data were analyzed by the paired Student t-tests and one-way analyses of variance. Cell viability decreased significantly after H 2 O 2 (85%), CoCl 2 (50%), and hypoxia chamber (52%) treatments compared to the untreated control (100%). UDCA significantly counteracted the effects of chamber-and CoCl 2 -induced hypoxia on viability and beating rate. However, no significant differences were observed in acid SMase gene and protein expression between the untreated, CoCl 2 , and UDCA-CoCl 2 groups. In contrast, neutral SMase gene and protein expression did significantly differ between the latter two groups. ERK and Akt phosphorylation was higher in hypoxic cardiomyocytes treated with UDCA than those given CoCl 2 alone. In conclusion, UDCA regulates the activation of survival signaling proteins and SMases in neonatal rat cardiomyocytes during hypoxia.

Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein

“…Previously, we have reported that UDCA protects CMs against hypoxia induced by CoCl 2. While in here, we show the difference in the cardioprotection effects of UDCA given prior to hypoxia induction (pre‐UDCA) with CMs posttreated with UDCA after hypoxia induction (post‐UDCA). Our findings suggested similar protection of UDCA either given before or after hypoxia in cell viability and HIF‐1α protein activity.…”

“…In hepatocytes, UDCA activates various cell signalling pathways such as p53 and S1P receptor via Gα i ‐coupled receptor . Recently, our group has reported that UDCA protects CMs against chemically induced hypoxia through ERK, AKT, and ROS activity …”

“…6 Recently, our group has reported that UDCA protects CMs against chemically induced hypoxia through ERK, AKT, and ROS activity. 13,14 Although UDCA has been reported as a potential therapeutic agent to overcome myocardial injury, the effect of UDCA on HIF-1α and p53 expressions during hypoxia is still not well known. Therefore, this study was designed to investigate whether UDCA could protect CMs against hypoxia by regulating transcriptional mediators of cell stress: HIF-1α and p53.…”

Usage of ursodeoxycholic acid in cardiology (literature review and own data)

“…Anticholestatic, choleretic and litholytic effects of UDCA stipulate the main usage of this drug, namely, therapy of cholestasis, cholelithiasis, hepatitis, liver cirrhosis. But it was revealed that UDCA has a much wider spectrum of action because of its cytoprotective, anti-apoptotic, anti-inflammatory, antioxidative and immune-modulating effects, which are of especial value in cardiology [8,18,19].…”

“…This leads to membrane stabilization and increases cell resistance to various damages [13], which is especially important for protection against xenobiotics' action. UDCA also increases cardiomyocytes' resistance to hypoxia [19]. Anti-apoptotic effect of UDCA is provided mainly by decrease of Са 2+ concentration in the cells, prevention of cytochrome C exit from the mitochondria, decrease of caspases' activation [12,13].…”