Upregulation of canonical transient receptor potential channel in the pulmonary arterial smooth muscle of a chronic thromboembolic pulmonary hypertension rat model

2015 ◽  
Vol 38 (12) ◽  
pp. 821-828 ◽  
Author(s):  
Xin Yun ◽  
Yuqin Chen ◽  
Kai Yang ◽  
Sabrina Wang ◽  
Wenju Lu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Transient Receptor Potential ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Canonical Transient Receptor Potential ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Transient Receptor

scholarly journals Sildenafil inhibits chronically hypoxic upregulation of canonical transient receptor potential expression in rat pulmonary arterial smooth muscle

2010 ◽  
Vol 298 (1) ◽  
pp. C114-C123 ◽  
Author(s):  
Wenju Lu ◽  
Pixin Ran ◽  
Dandan Zhang ◽  
Gongyong Peng ◽  
Bing Li ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Tone ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Arterial Smooth Muscle ◽  
Canonical Transient Receptor Potential ◽  
Mrna And Protein Expression ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Transient Receptor

In pulmonary arterial smooth muscle cells (PASMCs), Ca2+ influx through store-operated Ca2+ channels thought to be composed of canonical transient receptor potential (TRPC) proteins is an important determinant of intracellular free calcium concentration ([Ca2+]i) and pulmonary vascular tone. Sildenafil, a type V phosphodiesterase inhibitor that increases cellular cGMP, is recently identified as a promising agent for treatment of pulmonary hypertension. We previously demonstrated that chronic hypoxia elevated basal [Ca2+]i in PASMCs due in large part to enhanced store-operated Ca2+ entry (SOCE); moreover, ex vivo exposure to prolonged hypoxia (4% O2 for 60 h) upregulated TRPC1 and TRPC6 expression in PASMCs. We examined the effect of sildenafil on basal [Ca2+]i, SOCE, and the expression of TRPC in PASMCs under prolonged hypoxia exposure. We also examined the effect of sildenafil on TRPC1 and TRPC6 expression in pulmonary arterial smooth muscle (PA) from rats that developed chronically hypoxic pulmonary hypertension (CHPH). Compared with vehicle control, treatment with sildenafil (300 nM) inhibited prolonged hypoxia induced increases of 1) basal [Ca2+]i, 2) SOCE, and 3) mRNA and protein expression of TRPC in PASMCs. Moreover, sildenafil (50 mg · kg−1 · day−1) inhibited mRNA and protein expression of TRPC1 and TRPC6 in PA from chronically hypoxic (10% O2 for 21 days) rats, which was associated with decreased right ventricular pressure and right ventricular hypertrophy. Furthermore, we found, in PASMCs exposed to prolonged hypoxia, that knockdown of TRPC1 or TRPC6 by their specific small interference RNA attenuated the hypoxic increases of SOCE and basal [Ca2+]i, suggesting a cause and effect link between increases of TRPC1 and TRPC6 expression and the hypoxic increases of SOCE and basal [Ca2+]i. These results suggest that sildenafil may alter basal [Ca2+]i in PASMCs by decreasing SOCE through downregulation of TRPC1 and TRPC6 expression, thereby contributing to decreased vascular tone of pulmonary arteries during the development of CHPH.

scholarly journals Bone morphogenetic protein 4 enhances canonical transient receptor potential expression, store-operated Ca2+ entry, and basal [Ca2+]i in rat distal pulmonary arterial smooth muscle cells

2010 ◽  
Vol 299 (6) ◽  
pp. C1370-C1378 ◽  
Author(s):  
Wenju Lu ◽  
Pixin Ran ◽  
Dandan Zhang ◽  
Ning Lai ◽  
Nanshan Zhong ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Pulmonary Vascular Remodeling ◽  
Canonical Transient Receptor Potential ◽  
Morphogenetic Protein ◽  
Mrna And Protein Expression ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle ◽  
Transient Receptor

Recent advances have identified an important role of bone morphogenetic protein 4 (BMP4) in pulmonary vascular remodeling, yet the underlying mechanisms remain largely unexplored. We have previously found that Ca2+ influx through store-operated calcium channels (SOCC), which are mainly thought to be composed of canonical transient receptor potential (TRPC) proteins, likely contribute to the pathogenic development of chronic hypoxic pulmonary hypertension. In this study, we investigated the effect of BMP4 on expression of TRPC and store-operated Ca2+ entry (SOCE) in pulmonary arterial smooth muscle cells (PASMCs). Real-time quantitative PCR and Western blotting revealed that treatment with BMP4 (50 ng/ml, 60 h) increased TRPC1, TRPC4, and TRPC6 mRNA and protein expression in growth-arrested rat distal PASMCs. Moreover, in comparison to vehicle control, cells treated with BMP4 also exhibited enhanced SOCE, and elevated basal intracellular calcium concentration ([Ca2+]i) as determined by fluorescent microscopy using the Ca2+ indicator Fura-2 AM. Perfusing cells with Ca2+-free Krebs-Ringer bicarbonate solution (KRBS) or KRBS containing SOCC antagonists SKF-96365 or NiCl2 attenuated the increases in basal [Ca2+]i caused by BMP4. Specific knockdown of BMP4 by small interference RNA significantly decreased the mRNA and protein expression of TRPC1, TRPC4, and TRPC6 and reduced SOCE and basal [Ca2+]i in serum-stimulated PASMCs. We conclude that BMP4 regulates calcium signaling in PASMCs likely via upregulation of TRPC expression, leading to enhanced SOCE and basal [Ca2+]i in PASMCs, and by this mechanism contributes to pulmonary vascular remodeling during pulmonary arterial hypertension.

scholarly journals Effects of chronic exposure to cigarette smoke on canonical transient receptor potential expression in rat pulmonary arterial smooth muscle

2014 ◽  
Vol 306 (4) ◽  
pp. C364-C373 ◽  
Author(s):  
Jian Wang ◽  
Yuqin Chen ◽  
Chunyi Lin ◽  
Jing Jia ◽  
Lichun Tian ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Arterial Smooth Muscle ◽  
Nicotine Treatment ◽  
Canonical Transient Receptor Potential ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Transient Receptor

To clarify the possible mechanism of cigarette smoke (CS)-induced pulmonary hypertension and furthermore provide effective targets for prevention and treatment, the effects of chronic CS on rat pulmonary arterial smooth muscle in vivo and nicotine treatment on rat pulmonary arterial smooth muscle cells (PASMCs) in vitro were investigated. In this study, we demonstrated that chronic CS exposure led to rat weight loss, right ventricular hypertrophy, and pulmonary arterial remodeling. A fluorescence microscope was used to measure intracellular calcium concentration ([Ca2+]i) in rat distal PASMCs. Results showed that basal [Ca2+]i and store-operated calcium entry (SOCE) levels in PASMCs from 3- and 6-mo CS-exposed rats were markedly higher than those in cells from the unexposed control animals (the increases in 6-mo CS group were more significant than that in 3-mo group), accompanied with increased canonical transient receptor potential 1 (TRPC1) and TRPC6 expression at both mRNA and protein levels in isolated distal PA. Simultaneously, in vitro study showed that nicotine treatment (10 nM) significantly increased basal [Ca2+]i and SOCE and upregulated TRPC1 and TRPC6 expression in cultured rat distal PASMCs. TRPC siRNA knockdown strategies revealed that the elevations of basal [Ca2+]i and SOCE induced by nicotine in PASMCs were TRPC1 and TRPC6 dependent. These results suggested that chronic CS-induced changes in vascular tone and structure in PA and the development of pulmonary hypertension might be largely due to upregulation of TRPC1 and TRPC6 expression in PASMCs, in which nicotine played an important role.

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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