Alpha-1 Adrenergic Receptor Agonist Phenylephrine Inhibits Sepsis-Induced Cardiomyocyte Apoptosis and Cardiac Dysfunction via Activating ERK1/2 Signal Pathway
| Autor: | Xiangxu Tang, Hongmei Li, Hua-dong Wang, Duomeng Yang, Da-xiang Lu, Yun Xing |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Lipopolysaccharides
Male Lipopolysaccharide p38 mitogen-activated protein kinases Blotting Western Apoptosis Enzyme-Linked Immunosorbent Assay 030204 cardiovascular system & hematology Pharmacology Critical Care and Intensive Care Medicine p38 Mitogen-Activated Protein Kinases Rats Sprague-Dawley Phenylephrine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine NF-KappaB Inhibitor alpha Troponin T Sepsis In Situ Nick-End Labeling medicine Prazosin Animals Myocytes Cardiac Phosphorylation bcl-2-Associated X Protein Alpha-1 adrenergic receptor biology Tumor Necrosis Factor-alpha Cytochrome c Cytochromes c 030208 emergency & critical care medicine Rats IκBα Proto-Oncogene Proteins c-bcl-2 chemistry Caspases Emergency Medicine biology.protein Adrenergic alpha-1 Receptor Agonists Signal Transduction medicine.drug |
| Zdroj: | Shock. 52:122-133 |
| ISSN: | 1540-0514 1073-2322 |
| DOI: | 10.1097/shk.0000000000001205 |
| Popis: | It was demonstrated that α1 adrenergic receptor (α1-AR) activation by phenylephrine (PE) attenuated cardiac dysfunction in lipopolysaccharide (LPS)-challenged mice. However, it is unclear whether PE suppresses sepsis-induced cardiomyocyte apoptosis. Here, we investigated the effects of PE on cardiomyocyte apoptosis in LPS-treated adult rat ventricular myocytes (ARVMs) and septic rats induced by cecal ligation and puncture. Cardiomyocyte apoptosis and caspase activity were detected by TUNEL and spectrophotometrical assay, respectively. Bax, Bcl-2 and cytochrome c (Cyt c) levels as well as IκBα, ERK1/2, p38 MAPK, JNK and cardiac troponin I (cTnI) phosphorylation were analyzed by Western blotting, and TNF-α concentration was analyzed by ELISA. PE inhibited LPS-induced caspase-3 activation in ARVMs, which was reversed by prazosin (a membrane permeable α1-AR antagonist), but not by CGP12177A (a membrane impermeable α1-AR antagonist). PE upregulated phosphorylated ERK1/2 and Bcl-2 contents, decreased TNF-α and Bax levels, Cyt c release, caspase-8/-9 activities as well as IκBα, p38MAPK and JNK phosphorylation in LPS-treated ARVMs, all of which were abolished by prazosin. Treatment with U0126 (a specific ERK1/2 inhibitor) reversed the effects of PE on IκBα, p38MAPK and JNK phosphorylation as well as caspase-3/-8/-9 activation in LPS-treated ARVMs. In septic rats, PE not only inhibited myocardial apoptosis as well as IκBα, p38MAPK, and JNK phosphorylation, but also upregulated myocardial phosphorylated ERK1/2. Furthermore, PE inhibited myocardial cTnI phosphorylation and improved cardiac function in septic rats. Taken together, our data suggest that α1-AR activation by PE inhibits sepsis-induced cardiomyocyte apoptosis and cardiac dysfunction via activating ERK1/2 signal pathway. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|