scholarly journals Enhanced store-operated Ca2+ entry and TRPC channel expression in pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats

2012 ◽  
Vol 302 (1) ◽  
pp. C77-C87 ◽  
Author(s):  
Xiao-Ru Liu ◽  
Ming-Fang Zhang ◽  
Na Yang ◽  
Qing Liu ◽  
Rui-Xing Wang ◽  
...  
Keyword(s):  
Time Course ◽  
Vascular Reactivity ◽  
Transient Receptor Potential ◽  
Pulmonary Arteries ◽  
Cyclopiazonic Acid ◽  
Receptor Potential ◽  
Treated Group ◽  
Channel Expression ◽  
Pulmonary Arterial ◽  
Transient Receptor

Pulmonary hypertension (PH) is associated with profound vascular remodeling and alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Previous studies show that canonical transient receptor potential (TRPC) genes are upregulated and store-operated Ca2+ entry (SOCE) is augmented in PASMCs of chronic hypoxic rats and patients of pulmonary arterial hypertension (PAH). Here we further examine the involvement of TRPC and SOCE in PH with a widely used rat model of monocrotaline (MCT)-induced PAH. Rats developed severe PAH, right ventricular hypertrophy, and significant increase in store-operated TRPC1 and TRPC4 mRNA and protein in endothelium-denuded pulmonary arteries (PAs) 3 wk after MCT injection. Contraction of PA and Ca2+ influx in PASMC evoked by store depletion using cyclopiazonic acid (CPA) were enhanced dramatically, consistent with augmented SOCE in the MCT-treated group. The time course of increase in CPA-induced contraction corresponded to that of TRPC1 expression. Endothelin-1 (ET-1)-induced vasoconstriction was also potentiated in PAs of MCT-treated rats. The response was partially inhibited by SOCE blockers, including Gd3+, La3+, and SKF-96365, as well as the general TRPC inhibitor BTP-2, suggesting that TRPC-dependent SOCE was involved. Moreover, the ET-1-induced contraction and Ca2+ response in the MCT group were more susceptible to the inhibition caused by the various SOCE blockers. Hence, our study shows that MCT-induced PAH is associated with increased TRPC expression and SOCE, which are involved in the enhanced vascular reactivity to ET-1, and support the hypothesis that TRPC-dependent SOCE is an important pathway for the development of PH.

Mibefradil suppresses the proliferation of pulmonary artery smooth muscle cells

2016 ◽  
Vol 64 (1) ◽  
pp. 45-49 ◽  
Author(s):  
Hong-Hong Li ◽  
Li-Jian Xie ◽  
Ting-Ting Xiao ◽  
Min Huang ◽  
Jie Shen
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Receptor Potential ◽  
Channel Expression ◽  
Intracellular Ca ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle ◽  
Transient Receptor

Intracellular Ca2+ levels play a critical role in the regulation of vasodilation and vasoconstriction by stimulating pulmonary artery smooth muscle cell (PASMC) proliferation, which is important in the pathogenesis of pulmonary arterial hypertension (PAH); however, L-type Ca2+ channel antagonists are useful in only few patients with PAH. The present study sought to assess the effect of mibefradil, which blocks T-type Ca2+ channels, on PASMC proliferation and Ca2+ channel profile. Human PASMCs were stimulated with 25 ng/mL platelet-derived growth factor-BB (PDGF-BB) with and without 10 µM mibefradil or 100 nM sildenafil. After 48 or 72 h, PASMC proliferation and Ca2+ channel expression were assessed by MTT assays and western blot analysis, respectively. PDGF-BB-induced PASMC proliferation at 72 h (p<0.01), which was inhibited by both sildenafil and mibefradil (p<0.01). Transient receptor potential Ca2+ channel 6 (TRPC6) expression was significantly increased with PDGF-BB stimulation (p=0.009); however, no changes in TRPC1, TRPC3, CAV1.2, and CAV3.2 levels were observed. Although both TRPC1 and CAV1.2 expression levels were increased in PDGF-stimulated PASMCs on mibefradil and sildenafil treatment, it was not statistically significant (p=0.086 and 1.000, respectively). Mibefradil inhibits PDGF-BB-stimulated PASMC proliferation; however, the mechanism through which it functions remains to be determined. Further studies are required to elucidate the full therapeutic value of mibefradil for PAH.

scholarly journals Transient Receptor Potential Melastatin 2 Enhances Vascular Reactivity During Development of Atherosclerosis in Mice

2021 ◽  
Vol 34 (1) ◽  
pp. 121-122
Author(s):  
Yi-quan Dai ◽  
Xiao-xiao Yan ◽  
Yi-chen Lin ◽  
Hong-yu Chen ◽  
Xiao-ru Liu
Keyword(s):  
Knockout Mice ◽  
Vascular Reactivity ◽  
Transient Receptor Potential ◽  
Gene Knockout ◽  
Receptor Potential ◽  
Blood Lipid ◽  
Normal Diet ◽  
Protein Levels ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Abstract Background To investigate the function of transient receptor potential melastatin 2 (TRPM2) in vascular reactivity induced by 5-hydroxytryptamine (5-HT) in the aorta during development of atherosclerosis in mice. Methods Forty mice were randomly divided into 4 groups: C57BL/6J on normal diet (C57 + ND), C57BL/6J on high-fat diet (C57 + HFD), apolipoprotein E gene knockout mice (ApoE−/−) on ND (ApoE−/− + ND), and ApoE−/− on HFD (ApoE−/− + HFD). They were fed with a ND or HFD for 16 weeks. Aortic TRPM2 expression and isometric contractions were analyzed. Results In the ApoE−/− + HFD group, body weight, blood glucose, and blood lipid concentrations were increased, and aortic plaques were developed. Compared with the other 3 groups, aortic TRPM2 mRNA and protein levels were significantly increased in the ApoE−/− + HFD group (P &lt; 0.01). Aortic reactivity to 5-HT was enhanced in ApoE−/− + HFD mice with lower EC50 values. The enhanced reactivity to 5-HT was significantly inhibited by TRPM2 inhibitors, N-p-amylcinnamoyl anthranilic acid (1 µmol/l) and 2-aminoethyl diphenylborinate (10 µmol/l). Conclusions Aortic TRPM2 expression is upregulated in ApoE knockout mice fed with a HFD. Upregulation of TRPM2 enhances 5-HT vascular reactivity during development of atherosclerosis.

scholarly journals Human transient receptor potential (TRP) channel expression profiling in carcinogenesis

2015 ◽  
Vol 59 (7-8-9) ◽  
pp. 399-406 ◽  
Author(s):  
Michela Bernardini ◽  
Alessandra Fiorio Pla ◽  
Natalia Prevarskaya ◽  
Dimitra Gkika
Keyword(s):  
Expression Profiling ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Trp Channel ◽  
Channel Expression ◽  
Transient Receptor

Endothelin-mediated in vivo pressor responses following TRPV1 activation

2011 ◽  
Vol 301 (3) ◽  
pp. H1135-H1142 ◽  
Author(s):  
Vahagn A. Ohanyan ◽  
Giacinta Guarini ◽  
Charles K. Thodeti ◽  
Phani K. Talasila ◽  
Priya Raman ◽  
...  
Keyword(s):  
Vascular Function ◽  
Vascular Reactivity ◽  
Transient Receptor Potential ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Receptor Potential ◽  
Immunoblot Analysis ◽  
Trpv1 Channels ◽  
Transient Receptor

Transient receptor potential vanilliod 1 (TRPV1) channels have recently been postulated to play a role in the vascular complications/consequences associated with diabetes despite the fact that the mechanisms through which TRPV1 regulates vascular function are not fully known. Accordingly, our goal was to define the mechanisms by which TRPV1 channels modulate vascular function and contribute to vascular dysfunction in diabetes. We subjected mice lacking TRPV1 [TRPV1(−/−)], db/ db, and control C57BLKS/J mice to in vivo infusion of the TRPV1 agonist capsaicin or the α-adrenergic agonist phenylephrine (PE) to examine the integrated circulatory actions of TRPV1. Capsaicin (1, 10, 20, and 100 μg/kg) dose dependently increased MAP in control mice (5.7 ± 1.6, 11.7 ± 2.1, 25.4 ± 3.4, and 51.6 ± 3.9%), which was attenuated in db/db mice (3.4 ± 2.1, 3.9 ± 2.1, 7.0 ± 3.3, and 17.9 ± 6.2%). TRPV1(−/−) mice exhibited no changes in MAP in response to capsaicin, suggesting the actions of this agonist are specific to TRPV1 activation. Immunoblot analysis revealed decreased aortic TRPV1 protein expression in db/db compared with control mice. Capsaicin-induced responses were recorded following inhibition of endothelin A and B receptors (ETA /ETB). Inhibition of ETA receptors abolished the capsaicin-mediated increases in MAP. Combined antagonism of ETA and ETB receptors did not further inhibit the capsaicin response. Cultured endothelial cell exposure to capsaicin increased endothelin production as shown by an endothelin ELISA assay, which was attenuated by inhibition of TRPV1 or endothelin-converting enzyme. TRPV1 channels contribute to the regulation of vascular reactivity and MAP via production of endothelin and subsequent activation of vascular ETA receptors. Impairment of TRPV1 channel function may contribute to vascular dysfunction in diabetes.

scholarly journals Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs

2016 ◽  
Vol 311 (3) ◽  
pp. C482-C497 ◽  
Author(s):  
Jun Zhang ◽  
Wenju Lu ◽  
Yuqin Chen ◽  
Qian Jiang ◽  
Kai Yang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Transient Receptor Potential ◽  
Hypoxia Inducible Factor ◽  
Pulmonary Arteries ◽  
Receptor Potential ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Canonical Transient Receptor Potential ◽  
Transient Receptor

The ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca2+ concentration ([Ca2+]i) and store-operated Ca2+ entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling. In this study we aim to determine whether BTZ attenuates the hypoxia-induced elevation of [Ca2+] in PASMCs and the signaling pathway involved in this mechanism. Our results showed that 1) in hypoxia- and monocrotaline-induced rat pulmonary hypertension (PH) models, BTZ markedly attenuated the development and progression of PH, 2) BTZ inhibited the hypoxia-induced increase in cell proliferation, basal [Ca2+]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregulated expression of hypoxia-inducible factor-1α, bone morphogenetic protein 4, canonical transient receptor potential isoforms 1 and 6, and the hypoxia-downregulated expression of peroxisome proliferator-activated receptor-γ in rat distal pulmonary arteries and PASMCs. These results indicate that BTZ exerts its protective role in the development of PH potentially by inhibiting the canonical transient receptor potential-SOCE-[Ca2+]i signaling axis in PASMCs.

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