Palmitic Acid Increases Endothelin-1 Expression in Vascular Endothelial Cells through the Induction of Endoplasmic Reticulum Stress and Protein Kinase C Signaling

Abstract

Objective: 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). Methods: 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. Results: 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. Conclusion: 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.

Protective effects of phenolic acid extract from ginseng on vascular endothelial cell injury induced by palmitate via activation of PI3K/Akt/eNOS pathway

“…Spectrophotometry and immunofluorescence were used to detect the insulin induced‐NO production and expressions of ET‐1. As shown in Figure 4 and 5, PA increased the expression of ET‐1 (Zhang, Zhao, Wang, Xu, & Yang, 2018) and inhibited the insulin‐induced NO production (Fratantonio et al., 2017), which is consistent with previous reports. However, when cotreated with PG2, NO content was similar to the insulin‐treated group without PA, and the expression of ET‐1 was similar to the control.…”

“…This relationship is precipitated by a pathway‐selective inhibition of insulin signaling to eNOS via PI3K/Akt/eNOS, whereas MAPK signaling to ET‐1 is unaltered or increased (Jiang et al., 1999). The resulting endothelial cell dysfunction reduces agonist‐induced vasodilation and renders the vascular wall more susceptible to atherosclerosis (Maeno et al., 2012; Rask‐Madsen et al., 2010), which is consistent with related literature (Zhang et al., 2018). NO, an antithrombotic product for endothelial cells, plays a crucial role in vascular homeostasis.…”

<p>Loxoprofen Sodium Alleviates Oxidative Stress and Apoptosis Induced by Angiotensin II in Human Umbilical Vein Endothelial Cells (HUVECs)</p>

“…1,2 The vasoactive factors released by the vascular endothelial cells, such as nitric oxide, prostaglandin, and endothelin, exert important roles in regulating the vasomotor function of blood vessels, maintaining the homeostasis of vascular walls and the steady flow of blood. [3][4][5] Therefore, the integrity and functional normality of vascular endothelial cells are of great significance in protecting us from cardiovascular diseases, such as arterial stiffness. [6][7][8] Angiotensin II, which is a peptide transformed from angiotensin I, is reported to be involved in the process and development of arterial stiffness by stimulating the vessels to release excessive free radicals, which contribute to the damage inflammation, and dysfunction of vascular endothelial cells.…”

Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells

“…Furthermore, hypoxia stimulates human preproendothelin-1 promoter activity in transgenic mice and in microvascular endothelial cells through interaction of transcription factor HIF with specific hypoxia responsible element in EDN1 promoter (Aversa et al 1997;Minchenko and Caro 2000). However, hypoxic regulation of the EDN1 gene expression is associated with protein kinases and functional activity of other transcriptional factors as well as with signaling pathways of endoplasmic reticulum stress (Minchenko and Caro 2000;Stow et al 2011;Minchenko et al 2015bMinchenko et al , 2017Tsymbal et al 2017;Zhang et al 2018).…”

“…It is interesting to note that palmitic acid increases ET-1 expression in endothelial cells through the induction of endoplasmic reticulum stress and the activation of protein kinase C, providing novel mechanistic insights into the pathogenesis of obesity-associated hypertension and cardiovascular diseases including atherosclerosis (Zhang et al 2018). The primary mechanism thought to control EDN1 bioavailability is the rate of transcription from the EDN1 gene.…”