scholarly journals Sildenafil Inhibits Hypoxia-Induced Transient Receptor Potential Canonical Protein Expression in Pulmonary Arterial Smooth Muscle via cGMP-PKG-PPARγ Axis

2013 ◽  
Vol 49 (2) ◽  
pp. 231-240 ◽  
Author(s):  
Jian Wang ◽  
Kai Yang ◽  
Lei Xu ◽  
Yi Zhang ◽  
Ning Lai ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Expression ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Arterial Smooth Muscle ◽  
Transient Receptor Potential Canonical ◽  
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 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.

Hydrogen peroxide is a critical regulator of the hypoxia-induced alterations of store-operated Ca2+ entry into rat pulmonary arterial smooth muscle cells

2017 ◽  
Vol 312 (4) ◽  
pp. L477-L487 ◽  
Author(s):  
Tao-Xiang Chen ◽  
Xiao-Ya Xu ◽  
Zhao Zhao ◽  
Fang-Yu Zhao ◽  
Yi-Mei Gao ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

To investigate the association between store-operated Ca2+ entry (SOCE) and reactive oxygen species (ROS) during hypoxia, this study determined the changes of transient receptor potential canonical 1 (TRPC1) and Orai1, two candidate proteins for store-operated Ca2+ (SOC) channels and their gate regulator, stromal interaction molecule 1 (STIM1), in a hypoxic environment and their relationship with ROS in pulmonary arterial smooth muscle cells (PASMCs). Exposure to hypoxia caused a transient Ca2+ spike and subsequent Ca2+ plateau of SOCE to be intensified in PASMCs when TRPC1, STIM1, and Orai1 were upregulated. SOCE in cells transfected with specific short hairpin RNA (shRNA) constructs was almost completely eliminated by the knockdown of TRPC1, STIM1, or Orai1 alone and was no longer affected by hypoxia exposure. Hypoxia-induced SOCE enhancement was further strengthened by PEG-SOD but was attenuated by PEG-catalase, with correlated changes to intracellular hydrogen peroxide (H2O2) levels and protein levels of TRPC1, STIM1, and Orai1. Exogenous H2O2 could mimic alterations of the interactions of STIM1 with TRPC1 and Orai1 in hypoxic cells. These findings suggest that TRPC1, STIM1, and Orai1 are essential for the initiation of SOCE in PASMCs. Hypoxia-induced ROS promoted the expression and interaction of the SOC channel molecules and their gate regulator via their converted product, H2O2.

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