NADPH oxidase 4 contributes to TRPV4-mediated endothelium-dependent vasodilation in human arterioles by regulating protein phosphorylation of TRPV4 channels

Xie, Yangjing; Nishijima, Yoshinori; Zinkevich, Natalya S.; Korishettar, Ankush; Fang, Juan; Mathison, Angela; Zimmermann, Michael T.; Wilcox, David A.; Gutterman, David D.; Shen, Yujun; Zhang, David X.

doi:10.1007/s00395-022-00932-9

Cited by 6 publications

(3 citation statements)

References 77 publications

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“…Since TRPV4 phosphorylation at serine 824 by PAM could be prevented by PKC inhibitors, 36,37 we further examined if activation of TRPV4 by CaSR is through PKC. First, as shown in Figure 9A, we found that after 48 hours pretreatment with LPS or LPS+cinacalcet, total TRPV4 was upregulated, which was significantly attenuated either by NPS2143 or by PKC inhibitor Gö6976, strongly suggesting the PKC-dependent regulation of TRPV4 in response to CaSR activation.…”

Section: Casr Regulation Of Trpv4 Phosphorylation Through Pkcmentioning

confidence: 99%

The CaSR/TRPV4 coupling mediates pro‐inflammatory macrophage function

et al. 2023

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Aim: Although calcium-sensing receptor (CaSR) and transient receptor potential vanilloid 4 (TRPV4) channels are functionally expressed on macrophages, it is unclear if they work coordinately to mediate macrophage function. The present study investigates whether CaSR couples to TRPV4 channels and mediates macrophage polarization via Ca 2+ signaling. Methods: The role of CaSR/TRPV4/Ca 2+ signaling was assessed in lipopolysaccharide (LPS)-treated peritoneal macrophages (PMs) from wild-type (WT) and TRPV4 knockout (TRPV4 KO) mice. The expression and function of CaSR and TRPV4 in PMs were analyzed by immunofluorescence and digital Ca 2+ imaging. The correlation factors of M1 polarization, CCR7, IL-1β, and TNFα were detected using q-PCR, western blot, and ELISA. Results: We found that PMs expressed CaSR and TRPV4, and CaSR activationinduced marked Ca 2+ signaling predominately through extracellular Ca 2+ entry, which was inhibited by selective pharmacological blockers of CaSR and TRPV4 channels. The CaSR activation-induced Ca 2+ signaling was significantly attenuated in PMs from TRPV4 KO mice compared to those from WT mice. Moreover, the CaSR activation-induced Ca 2+ entry via TRPV4 channels was inhibited by blocking phospholipases A2 (PLA2)/cytochromeP450 (CYP450) and phospholipase C (PLC)/Protein kinase C (PKC) pathways. Finally, CaSR activation promoted the expression and release of M1-associated cytokines IL-1β and TNFɑ, which were attenuated in PMs from TRPV4 KO mice. Conclusion: We reveal a novel coupling of the CaSR and TRPV4 channels via PLA2/CYP450 and PLC/PKC pathways, promoting a Ca 2+ -dependent M1 macrophage polarization. Modulation of this coupling and downstream pathways may become a potential strategy for the prevention/treatment of immune-related disease.

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Section: Casr Regulation Of Trpv4 Phosphorylation Through Pkcmentioning

confidence: 99%

The CaSR/TRPV4 coupling mediates pro‐inflammatory macrophage function

et al. 2023

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“…Zinc-finger C4H2-type containing protein was identified as a positive modulator interacting with TRPV4 [ 228 ]. NADPH oxidase 4 increased TRPV4 phosphorylation in endothelial cells, subsequently enhancing Ca 2+ entry [ 229 ]. Carbenoxolone inhibited TRPV4-initiated oxidative stress and cell injury in the urothelium, thus relieving CYP-induced bladder dysfunction in mice [ 230 ].…”

Section: Mechanoreceptors In the Urotheliummentioning

confidence: 99%

Mechanotransduction in the urothelium: ATP signalling and mechanoreceptors

Li,

Hu,

Yin

et al. 2023

Heliyon

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“…Previous work demonstrated that NOX4-derived H 2 O 2 contributes to endothelium-dependent-vasodilation in mouse mesenteric arteries and rat intrarenal arteries [ 31 , 32 ] and that bradykinin (BK)-induced dilation in human arterioles depends on Nox-derived H 2 O 2 [ 33 ]. A recent study demonstrated that NOX4 regulates the activity of TRPV4 endothelium-dependent dilation in human adipose and coronary arterioles via phosphorylation of Ser824 [ 34 ]. GKT137831, a NOX1/NOX4 inhibitor, reduced Ach-induced dilation as did the TRPV4 inhibitor HC067047, but GKT137831 did not further reduce vasodilation following application of HC067047, indicating a similar signaling pathway.…”

Section: Role Of Nadph Oxidasesmentioning

confidence: 99%

Inhibiting NADPH Oxidases to Target Vascular and Other Pathologies: An Update on Recent Experimental and Clinical Studies

et al. 2022

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Reactive oxygen species (ROS) can be beneficial or harmful in health and disease. While low levels of ROS serve as signaling molecules to regulate vascular tone and the growth and proliferation of endothelial cells, elevated levels of ROS contribute to numerous pathologies, such as endothelial dysfunctions, colon cancer, and fibrosis. ROS and their cellular sources have been extensively studied as potential targets for clinical intervention. Whereas various ROS sources are important for different pathologies, four NADPH oxidases (NOX1, NOX2, NOX4, and NOX5) play a prominent role in homeostasis and disease. NOX1-generated ROS have been implicated in hypertension, suggesting that inhibition of NOX1 may be a promising therapeutic approach. NOX2 and NOX4 oxidases are of specific interest due to their role in producing extra- and intracellular hydrogen peroxide (H2O2). NOX4-released hydrogen peroxide activates NOX2, which in turn stimulates the release of mitochondrial ROS resulting in ROS-induced ROS release (RIRR) signaling. Increased ROS production from NOX5 contributes to atherosclerosis. This review aims to summarize recent findings on NOX enzymes and clinical trials inhibiting NADPH oxidases to target pathologies including diabetes, idiopathic pulmonary fibrosis (IPF), and primary biliary cholangitis (PBC).

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NADPH oxidase 4 contributes to TRPV4-mediated endothelium-dependent vasodilation in human arterioles by regulating protein phosphorylation of TRPV4 channels

Cited by 6 publications

References 77 publications

The CaSR/TRPV4 coupling mediates pro‐inflammatory macrophage function

The CaSR/TRPV4 coupling mediates pro‐inflammatory macrophage function

Mechanotransduction in the urothelium: ATP signalling and mechanoreceptors

Inhibiting NADPH Oxidases to Target Vascular and Other Pathologies: An Update on Recent Experimental and Clinical Studies

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