Propofol induces excessive vasodilation of aortic rings by inhibiting protein kinase Cβ2 and θ in spontaneously hypertensive rats

Wang, Yan; Zhou, Quanhong; Wu, Bin; Zhou, Huixuan; Zhang, Xiaoli; Jiang, Wei; Wang, Li; Wang, Aizhong

doi:10.1111/bph.13797

Cited by 8 publications

(4 citation statements)

References 55 publications

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“…Hypotension caused by propofol in the process of anesthesia induction is very common and requires the attention of anesthesiologists. Especially for patients with chronic hypertension, the antihypertensive effect of propofol is more significant, which may endanger the life of patients [ 38 ]. Cx37, Cx40, Cx43 and Cx45 are expressed in VSMCs.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of connexin 43-based gap junctions underlies propofol-induced excessive relaxation in hypertensive vascular smooth muscle cells

et al. 2023

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Background Postinduction hypotension caused by propofol remains a non-negligible problem for anesthesiologists, and is especially severe in chronic hypertensive patients with long-term vasoconstriction and decreased vascular elasticity. The functional change in gap junctions composed of Cx43 (Cx43-GJs) is reported as the biological basis of synchronized contraction or relaxation of blood vessels. Thus, we investigated the role of Cx43-GJs in propofol-induced dramatic blood pressure fluctuations in chronic hypertensive patients, and their internal mechanisms. Methods Human umbilical artery smooth muscle cells (HUASMCs) were pretreated with long-term angiotensin II (Ang II), with or without propofol, to simulate the contraction and relaxation of normal and hypertensive VSMCs during anesthesia induction. The levels of F-actin polymerization and MLC2 phosphorylation were used as indicators to observe the contraction and relaxation of HUASMCs. Different specific activators, inhibitors and siRNAs were used to explore the role of Cx43-GJs and Ca2+ as well as the RhoA/ LIMK2/cofilin and RhoA/MLCK signaling pathways in the contraction and relaxation of normal and hypertensive HUASMCs. Results Both F-actin polymerization and MLC2 phosphorylation were significantly enhanced in Ang II-pretreated HUASMCs, along with higher expression of Cx43 protein and stronger function of Cx43-GJs than in normal HUASMCs. However, with propofol administration, similar to Gap26 and Cx43-siRNA, the function of Cx43-GJs in Ang II-pretreated HUASMCs was inhibited compared with that in normal HUASMCs, accompanied by a larger decrease in intracellular Ca2+ and the RhoA/LIMK2/cofilin and RhoA/MLCK signaling pathways. Eventually F-actin polymerization and MLC2 phosphorylation were more dramatically decreased. However, these effects could be reversed by RA with enhanced Cx43-GJ function. Conclusion Long-term exposure to Ang II significantly enhanced the expression of the Cx43 protein and function of Cx43-GJs in HUASMCs, resulting in the accumulation of intracellular Ca2+ and the activation of its downstream RhoA/LIMK2/cofilin and RhoA/MLCK signaling pathways, which maintained HUASMCs in a state of excessive-contraction. With inhibition of Cx43-GJs by propofol in Ang II-pretreated HUASMCs, intracellular Ca2+ and its downstream signaling pathways were dramatically inhibited, which ultimately excessively relaxed HUASMCs. This is the reason why the blood pressure fluctuation of patients with chronic hypertension was more severe after receiving propofol induction.

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Section: Discussionmentioning

confidence: 99%

Downregulation of connexin 43-based gap junctions underlies propofol-induced excessive relaxation in hypertensive vascular smooth muscle cells

et al. 2023

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“…[39][40][41] Previous studies have demonstrated that activation of PKCb 2 and PKCu is enhanced in the aorta of SHRs. 42 This further increases the phosphorylation of the Ca 2+ -sensitization pathway, such as CPI-17-MYPT1-MLC, causing the contraction of vascular smooth muscles. 43 The findings of our study indicated that a high dose of rosuvastatin could decrease the phosphorylation of PKCa in SHRs, suggesting that it might be mediated by the inhibition of PKC.…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin Reverses Hypertension-Induced Changes in the Aorta Structure and Endothelium-Dependent Relaxation in Rats Through Suppression of Apoptosis and Inflammation

Wang²,

Li³

et al. 2020

Journal of Cardiovascular Pharmacology

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Vascular remodeling is one of the most critical complications caused by hypertension. Previous studies have demonstrated that rosuvastatin has anti-inflammatory, antioxidant, and antiplatelet effects and therefore can be used to treat cardiovascular disease. In this study, we explored the beneficial effects of rosuvastatin in reversing aortic remodeling in spontaneously hypertensive rats. After treating with different doses of rosuvastatin, its antilipid, antiapoptosis, and anti-inflammatory effects were determined. We also examined whether rosuvastatin can improve the structure and function of the aorta. We found that rosuvastatin treatment of spontaneously hypertensive rats for 2 months at 2 different doses can effectively reduce the media thickness of the aorta compared with the control group. Similarly, rosuvastatin improved the vascular relaxation function of the aortic rings at a high level of acetylcholine in vitro. Mechanistically, it was found that rosuvastatin increased the expression of endothelial nitric oxide synthase and plasma nitrite/nitrate levels. Besides, rosuvastatin suppressed the apoptosis and inflammation and upregulated the expression of gap-junction complex connexin 43 both in media and endothelium. Finally, rosuvastatin inhibited the AT 1 R/PKCa/HSP70 signaling transduction pathway. In summary, these findings demonstrated that rosuvastatin could improve the vascular structure and function mainly by increasing endothelial nitric oxide synthase expression and preventing apoptosis and inflammation. This study provided evidence that rosuvastatin has beneficial effects in reversing the remodeling of the aorta due to hypertension.

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“…Phosphorylation of Akt and PKCII at these sites increases their kinase activities (55,56). To test their kinase activities, we examined the phosphorylation of their two respective endogenous substrates GSK3 at Ser-9 and myristoylated alanine rich protein kinase C substrate (MARCKS) at Ser-152/156, which elicit many effects of Akt and PKCII, respectively (57)(58)(59). TGF significantly increased the phosphorylation J o u r n a l P r e -p r o o f of GSK3 and MARCKS (Fig.…”

Section: Tgf Increases the Expression Of Dj-1mentioning

confidence: 99%

Oncoprotein DJ-1 interacts with mTOR complexes to effect transcription factor Hif1α-dependent expression of collagen I (α2) during renal fibrosis

Das¹,

Ghosh‐Choudhury²,

Maity³

et al. 2022

Journal of Biological Chemistry

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Propofol induces excessive vasodilation of aortic rings by inhibiting protein kinase Cβ2 and θ in spontaneously hypertensive rats

Cited by 8 publications

References 55 publications

Downregulation of connexin 43-based gap junctions underlies propofol-induced excessive relaxation in hypertensive vascular smooth muscle cells

Downregulation of connexin 43-based gap junctions underlies propofol-induced excessive relaxation in hypertensive vascular smooth muscle cells

Rosuvastatin Reverses Hypertension-Induced Changes in the Aorta Structure and Endothelium-Dependent Relaxation in Rats Through Suppression of Apoptosis and Inflammation

Oncoprotein DJ-1 interacts with mTOR complexes to effect transcription factor Hif1α-dependent expression of collagen I (α2) during renal fibrosis

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