Function of connexin 43 and RhoA/LIMK2/Cofilin signaling pathway in transient changes of contraction and dilation of human umbilical arterial smooth muscle cells

Deng, Zhizhao; Zhang, Yanling; Zhang, Qian; Li, Xianlong; Zeng, Weiqi; Cai, Jianfei; Yuan, Ding

doi:10.1016/j.biocel.2022.106326

Cited by 2 publications

(6 citation statements)

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“…Cells were serum-starved for 24 h in DMEM before drug treatment, to switch the cell phenotype from proliferating to contractile [ 29 ]. Treatment with 1 μM Ang II for 12 h has been found to significantly promote VSMC proliferation and migration, which are indicators of vascular remodeling and are thought to be the main causes of hypertension [ 30 ]; hence, 1 μM Ang II (G-CLONE, Beijing, China) was administered to HUASMCs for 12 h. In accordance with an earlier study [ 15 ], we pretreated cells with 30 μM propofol (Kelun, Sichuang, China) to explore the changes in VSMCs in patients with hypertension and with propofol administration at the early stage of anesthesia induction. In addition, cells were treated with an intracellular calcium chelator (BAPTA-AM, 10 μM, APExBIO, Houston, USA), the specific Cx43 gap junction agonist retinoic acid (RA, 1 μM, MedChemExpress, New Jersey, USA) [ 31 ], a specific Cx43 gap junction blocker (Gap26, 0.25 mg/ml, APExBIO, Houston, USA), and a selective RhoA inhibitor (50 μM, Rhosin hydrochloride, APExBIO).…”

Section: Methodsmentioning

confidence: 67%

“…As reported, both the RhoA/LIMK2/cofolin and RhoA/MLCK pathways can lead to cell contraction [ 15 , 24 ]. Our results demonstrated that Ang II exposure significantly activated the RhoA/LIMK2/cofilin and RhoA/MLCK signaling pathways, manifested as an increase in key molecules, such as p-LIMK2, p-cofilin and MLCK, which was reversed by propofol and Rhosin (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…Cx43-siRNA (CAGUCUGCCUUUCGUUGUA, RiboBio, Guangzhou, CN) was applied to modify the communicating function of Cx43-GJs [ 15 ]. The control group was given a sequence-scrambled siRNA as a negative control (NC-siRNA) for comparison.…”

Section: Methodsmentioning

confidence: 99%

“…In our previous study, gap junctions (GJs) composed of connexin 43 (Cx43-GJs) were found to be pivotal in propofol-regulated expression of contractile proteins [ 15 ]. Cx37, Cx40, Cx43 and Cx45 are expressed in the cardiovascular system, among which Cx43 is the most highly expressed [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Notably, RhoA can be activated by Ca 2+ and regulate the relaxation and contraction of VSMCs through dual regulation [ 23 ]. Activated RhoA can stimulate LIMK2 and cofilin phosphorylation,inhibit the degradation of the F-actin cytoskeleton and lead to stable cell contraction [ 15 ]. RhoA activation also inhibits the function of myosin light chain phosphatase, which is responsible for the dephosphorylation of MLC2, and thus keeps MLC2 phosphorylated [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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The Potential Role of Connexins in the Pathogenesis of Atherosclerosis

Kiełbowski

Bakinowska

Pawlik

2023

IJMS

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Connexins (Cx) are members of a protein family which enable extracellular and intercellular communication through hemichannels and gap junctions (GJ), respectively. Cx take part in transporting important cell–cell messengers such as 3′,5′-cyclic adenosine monophosphate (cAMP), adenosine triphosphate (ATP), and inositol 1,4,5-trisphosphate (IP3), among others. Therefore, they play a significant role in regulating cell homeostasis, proliferation, and differentiation. Alterations in Cx distribution, degradation, and post-translational modifications have been correlated with cancers, as well as cardiovascular and neurological diseases. Depending on the isoform, Cx have been shown either to promote or suppress the development of atherosclerosis, a progressive inflammatory disease affecting large and medium-sized arteries. Cx might contribute to the progression of the disease by enhancing endothelial dysfunction, monocyte recruitment, vascular smooth muscle cell (VSMC) activation, or by inhibiting VSMC autophagy. Inhibition or modulation of the expression of specific isoforms could suppress atherosclerotic plaque formation and diminish pro-inflammatory conditions. A better understanding of the complexity of atherosclerosis pathophysiology linked with Cx could result in developing novel therapeutic strategies. This review aims to present the role of Cx in the pathogenesis of atherosclerosis and discusses whether they can become novel therapeutic targets.

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Function of connexin 43 and RhoA/LIMK2/Cofilin signaling pathway in transient changes of contraction and dilation of human umbilical arterial smooth muscle cells

Cited by 2 publications

References 43 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

The Potential Role of Connexins in the Pathogenesis of Atherosclerosis

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