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

Lu, Wenju; Ran, Pixin; Zhang, Dandan; Lai, Ning; Zhong, Nanshan; Wang, Jian

doi:10.1152/ajpcell.00040.2010

Cited by 27 publications

(33 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with our previous results (29,33) 0.042 (hypoxia; P , 0.001 versus normoxia) ( Figure 1C) and increases on the ratio of right ventricle to body weight (RV/body weight) from 0.46 6 0.01 (normoxia) to 1.09 6 0.07 (hypoxia; P , 0.001 versus normoxia) ( Figure 1D). Injection of STS (10 mg/kg/d) significantly reduced these characteristic changes of CHPH.…”

Section: Sts Inhibited the Characteristic Changes Of Chph In Ratssupporting

confidence: 92%

“…In channel expression (29,33,41,(45)(46)(47) and up-regulates TRPC expression in PASMCs (29). Therefore, we focused on investigating the effects of STS on SOCE.…”

Section: Discussionmentioning

confidence: 99%

“…Reverse transcription and real-time PCR were performed as described previously (30,33,34). Details are provided in the online supplement.…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

“…Rat distal PA or PASMCs were sonicated or lysed in TPER lysis buffer (Pierce, Rockford, IL) with a protease inhibitor cocktail tablet, and protein expression was measured by immunoblotting assay as described previously (27,29,33). Details are provided in the online supplement.…”

Section: Western Blottingmentioning

confidence: 99%

See 3 more Smart Citations

Sodium Tanshinone IIA Sulfonate Inhibits Canonical Transient Receptor Potential Expression in Pulmonary Arterial Smooth Muscle from Pulmonary Hypertensive Rats

Wang

Qian

Wan

et al. 2013

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Danshen, the dried root of Salvia miltiorrhiza, is widely used in clinics in China for treating various diseases, including cardiovascular diseases. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA isolated as the major active component from Danshen, was recently reported to be effective in attenuating the characteristic pulmonary vascular changes associated with chronically hypoxic pulmonary hypertension (CHPH); however, the underlying detailed mechanisms are poorly understood. In this study, we investigated the effects of STS on basal intracellular Ca 21 concentration ([Ca 21 ] i ) and store-operated Ca 21 entry (SOCE) in distal pulmonary arterial smooth muscle cells (PASMCs) exposed to prolonged hypoxia or isolated from CHPH rats. SOCE measured by Mn 21 quenching of Fura-2 fluorescence in PASMCs from rats exposed to chronic hypoxia (10% O 2 , 21 d) was increased by 59%, and basal [Ca 21 ] i was increased by 119%; this effect was inhibited by intraperitoneal injection of STS. These inhibitory effects of STS on hypoxic increases of SOCE and basal [Ca 21 ] i were associated with reduced expression of canonical transient receptor potential (TRPC)1 and TRPC6 in distal pulmonary arterial smooth muscle and decreases on right ventricular pressure, right ventricular hypertrophy, and peripheral pulmonary vessel thickening. In ex vivo cultured distal PASMCs from normoxic rats, STS (0-25 mM) dose-dependently inhibited hypoxiainduced cell proliferation and migration, paralleled with attenuation in increases of basal [Ca 21 ] i , SOCE, mRNA, and protein expression of TRPC1 and TRPC6. STS also relieved right ventricular systolic pressure, right ventricular hypertrophy, and TRPC1 and TRPC6 protein expression in distal pulmonary arteries in a monocrotaline-induced rat model of pulmonary arterial hypertension. These results indicate that STS prevents pulmonary arterial hypertension development likely by inhibiting TRPC1 and TRPC6 expression, resulting in normalized basal [Ca 21 ] i and attenuated proliferation and migration of PASMCs.Keywords: STS; TRPC; SOCE; pulmonary hypertension Pulmonary arterial hypertension (PAH) is a rare yet life-threatening disease that affects 15 per 1 million adults, according to the most recent estimation in 2008 (1). It is physiologically defined by mean pulmonary arterial pressure of 25 mm Hg or greater at rest and is pathologically characterized by pulmonary vascular remodeling, including smooth muscle hypertrophy and intima thickening. Although significant progress has been made in the past decades in our understanding of PAH and in disease management, the prognosis is still poor, with a 1-year survival rate of 91.0% (2) and 3-year survival rate of 77% or less according to recent investigations (3-5). The principal treatments for PAH rely on approaches targeting the prostacyclin, endothelin, or NO pathways (phosphodiesterase inhibition) or, increasingly, on a combination of them (6-11). Few patients show indication for treatment with calcium channel...

show abstract

Section: Sts Inhibited the Characteristic Changes Of Chph In Ratssupporting

confidence: 92%

“…In channel expression (29,33,41,(45)(46)(47) and up-regulates TRPC expression in PASMCs (29). Therefore, we focused on investigating the effects of STS on SOCE.…”

Section: Discussionmentioning

confidence: 99%

“…Reverse transcription and real-time PCR were performed as described previously (30,33,34). Details are provided in the online supplement.…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

Section: Western Blottingmentioning

confidence: 99%

See 2 more Smart Citations

Sodium Tanshinone IIA Sulfonate Inhibits Canonical Transient Receptor Potential Expression in Pulmonary Arterial Smooth Muscle from Pulmonary Hypertensive Rats

Wang

Qian

Wan

et al. 2013

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previously we found that BMP4 increased TRPC1, TRPC4, and TRPC6 expression in rat distal PASMCs (19). To examine whether these effects were mediated through the activation of p38 and ERK1/2, we pretreated cells with SB203580 (10 mM) or PD98059 (5 mM) for 30 minutes, followed by treatment with BMP4 (50 ng/ml) for 60 hours.…”

Section: Pretreatment With P38 and Erk1/2 Inhibitors Prevented Their mentioning

confidence: 99%

BMP4 Increases Canonical Transient Receptor Potential Protein Expression by Activating p38 MAPK and ERK1/2 Signaling Pathways in Pulmonary Arterial Smooth Muscle Cells

et al. 2013

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Abnormal bone morphogenetic protein (BMP) signaling has been implicated in the pathogenesis of pulmonary hypertension. We previously found that BMP4 elevated basal intracellular Ca 21 ([Ca 21 ] i ) concentrations in distal pulmonary arterial smooth muscle cells (PASMCs), attributable in large part to enhanced store-operated Ca 21 entry through store-operated Ca 21 channels (SOCCs). Moreover, BMP4 up-regulated the expression of canonical transient receptor potential (TRPC) proteins thought to compose SOCCs. The present study investigated the signaling pathways through which BMP4 regulates TRPC expression and basal [Ca 21 ] i in distal PASMCs. Real-time quantitative PCR was used for the measurement of mRNA, Western blotting was used for the measurement of protein, and fluorescent microscopic for [Ca 21 ] i was used to determine the involvement of p38 and extracellular regulated kinase (ERK)-1/2 mitogen-activated protein kinase (MAPK) signaling in BMP4-induced TRPC expression and the elevation of [Ca 21 ] i in PASMCs. We found that the treatment of BMP4 led to the activation of both p38 MAPK and ERK1/2 in rat distal PASMCs. The induction of TRPC1, TRPC4, and TRPC6 expression, and the increases of [Ca 21 ] i caused by BMP4 in distal PASMCs, were inhibited by treatment with either SB203580 (10 mM), the selective inhibitor for p38 activation, or the specific p38 small interfering RNA (siRNA). Similarly, those responses induced by BMP4 were also abolished by treatment with PD98059 (5 mM), the selective inhibitor of ERK1/2, or by the knockdown of ERK1/2 using its specific siRNA. These results indicate that BMP4 participates in the regulation of Ca 21 signaling in PASMCs by modulating TRPC channel expression via activating p38 and ERK1/2 MAPK pathways. [Ca 21 ] i in PASMCs during chronic hypoxia, and relaxed arteries in chronically hypoxic rats (5). Store-operated calcium channels (SOCCs) are believed to be composed of members of transient receptor potential canonical (TRPC) family, which assemble as either homotetramer or heterotetramer channels and mediate store-operated calcium entry (SOCE) (6). We recently demonstrated the predominant expression of TRPC1, TRPC4, and TRPC6, and the presence of SOCE in PASMCs (7). Exposure to chronic hypoxia enhanced the expressions of TRPC1, TRPC6, and SOCE in rat distal PASMCs (1, 2). Using a specific small interfering (si)RNA individually targeted to TRPC1 and TRPC6, we found they both contributed to the hypoxic enhancement of SOCE and the maintenance of elevated basal [Ca 21 ] i in PASMCs (8). These studies provided fundamental information indicating that the elevation of basal [Ca 21 ] i in PASMCs during chronic hypoxia are in large part caused by enhanced SOCE via the up-regulation of TRPC proteins.Bone morphogenetic protein (BMP) family members comprise multifunctional cytokines that play crucial roles during embryonic development, organogenesis, and adult tissue remodeling by regulating cell proliferation, growth, differentiation, and apoptosis (9). BMP4,...

show abstract

Lung Circulation

Suresh

Shimoda

2016

Comprehensive Physiology

100

View full text Add to dashboard Cite

The circulation of the lung is unique both in volume and function. For example, it is the only organ with two circulations: the pulmonary circulation, the main function of which is gas exchange, and the bronchial circulation, a systemic vascular supply that provides oxygenated blood to the walls of the conducting airways, pulmonary arteries and veins. The pulmonary circulation accommodates the entire cardiac output, maintaining high blood flow at low intravascular arterial pressure. As compared with the systemic circulation, pulmonary arteries have thinner walls with much less vascular smooth muscle and a relative lack of basal tone. Factors controlling pulmonary blood flow include vascular structure, gravity, mechanical effects of breathing, and the influence of neural and humoral factors. Pulmonary vascular tone is also altered by hypoxia, which causes pulmonary vasoconstriction. If the hypoxic stimulus persists for a prolonged period, contraction is accompanied by remodeling of the vasculature, resulting in pulmonary hypertension. In addition, genetic and environmental factors can also confer susceptibility to development of pulmonary hypertension. Under normal conditions, the endothelium forms a tight barrier, actively regulating interstitial fluid homeostasis. Infection and inflammation compromise normal barrier homeostasis, resulting in increased permeability and edema formation. This article focuses on reviewing the basics of the lung circulation (pulmonary and bronchial), normal development and transition at birth and vasoregulation. Mechanisms contributing to pathological conditions in the pulmonary circulation, in particular when barrier function is disrupted and during development of pulmonary hypertension, will also be discussed.

show abstract

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

Cited by 27 publications

References 54 publications

Sodium Tanshinone IIA Sulfonate Inhibits Canonical Transient Receptor Potential Expression in Pulmonary Arterial Smooth Muscle from Pulmonary Hypertensive Rats

Sodium Tanshinone IIA Sulfonate Inhibits Canonical Transient Receptor Potential Expression in Pulmonary Arterial Smooth Muscle from Pulmonary Hypertensive Rats

BMP4 Increases Canonical Transient Receptor Potential Protein Expression by Activating p38 MAPK and ERK1/2 Signaling Pathways in Pulmonary Arterial Smooth Muscle Cells

Lung Circulation

Contact Info

Product

Resources

About