TRPM8 downregulation by angiotensin II in vascular smooth muscle cells is involved in hypertension

Huang, Fang; Ni, Min; Zhang, Jing‐Ming; Li, Dongjie; Shen, Fu‐Ming

doi:10.3892/mmr.2017.6158

Cited by 22 publications

(20 citation statements)

References 84 publications

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“…Several other cellular targets of menthol are also implicated in hypertension. For example, a recent study suggests that angiotensin II induces VSM TRPM8 channel down-regulation in renovascular hypertension (Huang et al, 2017) and in pulmonary hypertension (Liu et al, 2013). Therefore, it is logical that the activation of TRPM8 channels by menthol can also contribute to this blood pressure lowering response.…”

Section: Anti-hypertensive Effects Of Mentholmentioning

confidence: 99%

Current Knowledge on the Vascular Effects of Menthol

Silva

2020

Front. Physiol.

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Menthol is a monoterpene alcohol, widely used in several food and healthcare products for its particular odor and flavor. For some decades, menthol has been known to act on the vasculature directly in the endothelium and vascular smooth muscle, with recent studies showing that it also evokes an indirect vascular response via sensory fibers. The mechanisms underlying menthol's vascular action are complex due to the diversity of cellular targets, to the interplay between signaling pathways and to the variability in terms of response. Menthol can evoke either a perfusion increase or decrease in vivo in different vascular territories, an observation that warrants a critical discussion. Menthol vascular actions in vivo seem to depend on whether the vascular territory under analysis has been directly provoked with menthol or is located deep/distant to the application site. Menthol increases perfusion of directly provoked skin regions due to a complex interplay of increased nitric oxide (NO), endothelium-derived hyperpolarization factors (EDHFs) and sensory nerve responses. In non-provoked vascular beds menthol decreases perfusion which might be attributed to heat-conservation sympatheticallymediated vasoconstriction, although an increase in tissue evaporative heat loss due the formulation ethanol may also play a role. There is increasing evidence that several of menthol's cellular targets are involved in cardiovascular diseases, such as hypertension. Thus menthol and pharmacologically-similar drugs can play important preventive and therapeutic roles, which merits further investigation.

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Section: Anti-hypertensive Effects Of Mentholmentioning

confidence: 99%

Current Knowledge on the Vascular Effects of Menthol

Silva

2020

Front. Physiol.

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“…TRPM8 is thought to have a role in the inhibition of visceral pain signals and reduction of inflammatory conditions in irritable bowel syndrome (IBS) as TRPM8 activation reduces colon inflammation both in animal models [ 4 ] and human subjects [ 11 , 12 ]. TRPM8 channels have been implicated also in oropharyngeal dysphagia [ 13 ] and chronic cough [ 14 ], while the downregulation of TRPM8 by angiotensin II may be involved in hypertension [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

TRPM8 Channel Activation Reduces the Spontaneous Contractions in Human Distal Colon

Amato

Terzo

Lentini

et al. 2020

IJMS

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The transient receptor potential-melastatin 8 (TRPM8) is a non-selective Ca2+-permeable channel, activated by cold, membrane depolarization, and different cooling compounds. TRPM8 expression has been found in gut mucosal, submucosal, and muscular nerve endings. Although TRPM8 plays a role in pathological conditions, being involved in visceral pain and inflammation, the physiological functions in the digestive system remain unclear as yet. The aims of the present study were: (i) to verify the TRPM8 expression in human distal colon; (ii) to examine the effects of TRPM8 activation on colonic contractility; (iii) to characterize the mechanism of action. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting were used to analyze TRPM8 expression. The responses of human colon circular strips to different TRPM8 agonists [1-[Dialkyl-phosphinoyl]-alkane (DAPA) 2–5, 1-[Diisopropyl-phosphinoyl]-alkane (DIPA) 1–7, DIPA 1–8, DIPA 1–9, DIPA 1–10, and DIPA 1–12) were recorded using a vertical organ bath. The biomolecular analysis revealed gene and protein expression of TRPM8 in both mucosal and smooth muscle layers. All the agonists tested, except-DIPA 1–12, produced a concentration-dependent decrease in spontaneous contraction amplitude. The effect was significantly antagonized by 5-benzyloxytryptamine, a TRPM8 antagonist. The DIPA 1–8 agonist resulted in the most efficacious and potent activation among the tested molecules. The DIPA 1–8 effects were not affected by tetrodotoxin, a neural blocker, but they were significantly reduced by tetraethylammonium chloride, a non-selective blocker of K+ channels. Moreover, iberiotoxin, a blocker of the large-conductance Ca2+-dependent K+-channels, but not apamin, a blocker of small-conductance Ca2+-dependent K+ channels, significantly reduced the inhibitory DIPA 1–8 actions. The results of the present study demonstrated that TRPM8 receptors are also expressed in human distal colon in healthy conditions and that ligand-dependent TRPM8 activation is able to reduce the colonic spontaneous motility, probably by the opening of the large-conductance Ca2+-dependent K+-channels.

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“…At least 10 images per group were included and analysed. The levels of H 2 O 2 , superoxide anion and total‐antioxidant capacity (T‐AOC) in VSMCs were measured using commercial kits from Beyotime Institute of Biotechnology (Haimen, China) and performed according to the manufacturer's instructions (Huang et al, ).…”

Section: Methodsmentioning

confidence: 99%

Nicotinic ACh receptor α7 inhibits PDGF‐induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3

Tong

Zeng

et al. 2018

British J Pharmacology

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Background and Purpose PDGF‐BB is an angiogenic factor involved in cardiovascular diseases. Here, we investigated the possible effects of activation of the nicotinic ACh receptor α7 subtype (α7nAChR) on PDGF‐BB‐induced proliferation and migration in vascular smooth muscle cells (VSMCs). Experimental Approach PNU‐282987, a selective α7nAChR pharmacological agonist, was used to activate α7nAChR. The influences of α7nAChR activation on PDGF‐BB‐induced proliferation and migration, as well as the phosphorylation of focal adhesion kinase (FAK)/Src, a pro‐migration signalling pathway, were determined in VSMCs. A variety of biochemical assays were applied to explore the underlying molecular mechanisms. Key Results PDGF‐BB induced pronounced migration and proliferation of VSMCs. Activation of α7nAChRs by PNU‐282987 blocked PDGF‐BB‐induced migration but not proliferation in wild‐type (WT) VSMCs, whereas this effect was absent in α7nAChR‐knockout VSMCs. Accordingly, PNU‐282987 attenuated PDGF‐BB‐induced phosphorylation of FAKTyr397 and SrcTyr416 in WT VSMCs. Mechanistically, PNU‐282987 suppressed PDGF‐BB‐induced oxidative stress, as demonstrated by the alterations in ROS, H2O2 content, superoxide anion and total antioxidant activity. A sirtuin 3 (SIRT3) inhibitor 3‐(1H‐1,2,3‐triazol‐4‐yl) pyridine or shRNA‐mediated SIRT3 knockdown abolished the inhibitory effect of PNU‐282987. PNU‐282987 did not modulate SIRT3 protein expression but enhanced mitochondrial SIRT3 deacetylase activity. In line with this action, PNU‐282987 enhanced the deacetylation of mitochondrial FoxO3. Lastly, PNU‐282987 corrected the PDGF‐BB‐induced mitochondrial dysfunction by increasing mitochondrial citrate synthase activity, ATP content and nicotinamide adenine dinucleotide pool. Conclusions Pharmacological activation of α7nAChRs inhibits PDGF‐BB‐induced VSMC migration by activating the mitochondrial deacetylase SIRT3, implying an important role for α7nAChRs in mitochondria biology and PDGF‐related diseases. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

show abstract

TRPM8 downregulation by angiotensin II in vascular smooth muscle cells is involved in hypertension

Cited by 22 publications

References 84 publications

Current Knowledge on the Vascular Effects of Menthol

Current Knowledge on the Vascular Effects of Menthol

TRPM8 Channel Activation Reduces the Spontaneous Contractions in Human Distal Colon

Nicotinic ACh receptor α7 inhibits PDGF‐induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3

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