Urotensin-#receptor antagonist SB-706375 protected isolated rat heart from ischaemia-reperfusion injury by attenuating myocardial necrosis via RhoA/ROCK/RIP3 signalling pathway.

Abstract

SB-706375 is a selective receptor antagonist of human urotensin-II (hU-II), which can block the aorta contraction induced by hU-II in rats. The effect of SB-706375 on myocardial ischaemia-reperfusion (I/R) injury is unclear. The major objective of this study was to investigate whether SB-706375 has a protective effect on myocardial I/R injury in rats and explore its possible mechanisms. Isolated hearts of Adult Sprague-Dawley were perfused in a Langendorff apparatus, and haemodynamic parameters, lactate dehydrogenase (LDH), creatine phosphokinase-MB (CK-MB), cardiac troponin I (cTnI), RhoA, and the protein expressions of U-II receptor (UTR), receptor-interacting protein 3 (RIP3), Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) and Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) were assessed. We found that SB-706375 (1 × 10-6 and 1 × 10-5 mol/L) significantly inhibited the changes of haemodynamic parameters and reduced LDH and CK-MB activities and also cTnI level in the coronary effluents in the heart subjected to myocardial I/R injury. Further experiments studies showed that SB-706375 obviously prevented myocardial I/R increased RhoA activity and UTR, RIP3, ROCK1, and ROCK2 protein expressions. ROCK inhibition abolished the improving effect of SB-706375 on myocardial I/R-induced haemodynamic change in the isolated perfused rat heart. These findings suggested that SB-706375 provides cardio-protection against I/R injury in isolated rats by blocking UTR-RhoA/ROCK-RIP3 pathway.

• Authors: Jing-Si Duan, Shuo Chen, Xiao-Qing Sun, Juan Du, Zhi-Wu Chen
• Journal: Inflammopharmacology (Inflammopharmacology) Vol. 27 Issue 6 Pg. 1309-1318 (Dec 2019) ISSN: 1568-5608 [Electronic] Switzerland
• PMID: 31168686 (Publication Type: Journal Article)

Chemical References

• Pyrrolidines
• Receptors, G-Protein-Coupled
• SB-706375
• Sulfonamides
• Uts2r protein, rat
• Receptor-Interacting Protein Serine-Threonine Kinases
• receptor-interacting protein 3, rat
• rho-Associated Kinases
• RhoA protein, rat
• rho GTP-Binding Proteins

Topics

• Animals
• Female
• Male
• Myocardial Reperfusion Injury (prevention & control)
• Myocardium (pathology)
• Necrosis
• Pyrrolidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor-Interacting Protein Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• Receptors, G-Protein-Coupled (analysis, antagonists & inhibitors)
• Signal Transduction (physiology)
• Sulfonamides (pharmacology)
• rho GTP-Binding Proteins (antagonists & inhibitors, physiology)
• rho-Associated Kinases (antagonists & inhibitors, physiology)