endothelin-1 and 4-phenylbutyric-acid

We investigated the regulation of endothelin-1 (ET-1) expression in in vivo high-fat diet (HFD)-fed mice and in vitro cultured human aortic endothelial cells (HAECs).. Male C57BL/6 mice were fed on standard chow, serum was prepared, and ET-1 levels were analyzed using an ELISA kit. Quantitative PCR was performed using iQ SYBR Green Supermix. Statistical significance was assessed using SPSS, with p < 0.05 considered significant.. The serum ET-1 content and endothelial expression of ET-1 mRNA were increased in the HFD-fed mice compared to the chow-fed control mice. Moreover, the mRNA expression of ET-1 was significantly increased in cultured HAECs in response to acute (< 24 h) and chronic (12-16 days) treatments with palmitic acid (PA), one of the most abundant saturated fatty acids in obesity. We found that the induction of ET-1 expression by PA was abolished by pretreating the cells with the endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid or the protein kinase C (PKC) inhibitor Gö 6850.. Our findings demonstrate for the first time that PA increases ET-1 expression in endothelial cells through the induction of ER stress and the activation of PKC, providing novel mechanistic insights into the pathogenesis of obesity-associated hypertension and cardiovascular diseases.

Topics: Animals; Cells, Cultured; Diet, High-Fat; Endoplasmic Reticulum Stress; Endothelial Cells; Endothelin-1; Humans; Indoles; Male; Maleimides; Mice; Mice, Inbred C57BL; Obesity; Palmitic Acid; Phenylbutyrates; Protein Kinase C; Signal Transduction

As hydroxyurea (HU), sodium phenyl butyrate (SPB) is known to induce fetal hemoglobin (HbF) expression and thus shows potentials for sickle-cell disease (SCD) treatment. More recently, few studies suggested that endothelial cells (ECs), a major pathophysiological actor of SCD, are also a target of SPB. Here, we show that SPB, as HU, reduces endothelin-1 mRNA expression and peptide release by human ECs in culture. SPB increases VCAM-1 and ICAM-1 mRNAs and soluble ICAM-1 release. Both drugs have a cumulative effect on ICAM-1 expression. We conclude that SPB, as HU, also affects the expression of molecules important to the pathophysiology of SCD, in addition to its effect on HbF. Its potential as an alternative or adjuvant drug in SCD treatment warrants further investigations.

Topics: Anemia, Sickle Cell; Cell Line, Transformed; Drug Evaluation, Preclinical; Drug Synergism; Endothelial Cells; Endothelin-1; Gene Expression Regulation; Humans; Hydroxyurea; Intercellular Adhesion Molecule-1; Interferon-gamma; Phenylbutyrates; RNA, Messenger; Solubility; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1