Sildenafil Potentiates Bone Morphogenetic Protein Signaling in Pulmonary Arterial Smooth Muscle Cells and in Experimental Pulmonary Hypertension

Yang, Jun; Li, Xiaohui; Al‐Lamki, Rafia S.; Wu, Changxin; Weiß, Astrid; Berk, Joachim; Schermuly, Ralph Theo; Morrell, Nicholas W.

doi:10.1161/atvbaha.112.300121

Cited by 60 publications

(55 citation statements)

References 25 publications

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confidence: 70%

“…Samples were electrophoresed by 12% SDS-PAGE and then transferred to PVDF membrane (GE Healthcare). For studies of BMPR2, Smad1/5, Id1, and Id3, blots were incubated with polyclonal mouse anti-BMPR2 (1:1,000, BD Biosciences), polyclonal rabbit antiphospho-Smad1/5 (1:1,000, Cell Signaling Technology), polyclonal rabbit anti-Id1 (1:1,000, Biocheck), polyclonal rabbit anti-Id3 (1:1,000, CalBioreagents), as previously described (39). To confirm equal protein loading, blots were stripped and reprobed using anti-␤-actin (1:4,000, Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…We further showed that Id1 and Id2 are involved in the inhibition of PASMC proliferation by BMP4. We have also shown that agents enhancing BMP/ Smad/Id signaling in PASMCs can restore the growth-suppressive effects of BMPs in BMPR-II mutant cells (38,39).In the present study, we undertook a systematic analysis of the regulation of Id1-4 in PASMCs via a range of growth factors, cytokines, and BMPs. Having identified Id1 and Id3 as major targets of BMP signaling in these cells, we show that the induction of both Id1 and Id3 is dependent on intact BMPR-II and that Id3 promotes PASMC growth suppression.…”

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Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

Yang

Li²,

Liu

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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bone morphogenetic protein type II receptor; cell cycle; Id; pulmonary arterial smooth muscle cell; pulmonary hypertension PULMONARY ARTERIAL HYPERTENSION (PAH) is a severe clinical condition associated with a poor prognosis and high mortality. Occlusive remodeling of the distal pulmonary vasculature is the major pathological finding in PAH. Proliferation of myofibroblasts and smooth muscle cells in the pulmonary arterial wall increases pulmonary vascular resistance and elevates pulmonary arterial pressure, ultimately leading to right ventricular failure and eventually death (20,26,29). A greater understanding of the molecular mechanisms involved in pulmonary vascular remodeling will facilitate new approaches for therapy.Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for the majority (Ͼ70%)of cases of heritable PAH and have been reported in 15-40% of apparently sporadic idiopathic cases (6, 15, 34). Loss of BMPR-II or dysfunction of BMP signaling are now recognized in several preclinical models of PAH, including those induced by hypoxia, monocrotaline, and high flow (10, 16). BMPs are pleiotropic cytokines involved in a wide range of vascular cell function including proliferation, migration, differentiation, and apoptosis, but how BMPR-II mutations cause these abnormalities remains uncertain.The inhibitor of DNA binding family of proteins (Id proteins) are major downstream mediators of BMP signaling (19). Id proteins are basic helix-loop-helix transcription factors that lack a DNA binding domain. These proteins bind to the ubiquitously expressed E protein family members with high affinity and inhibit their binding to target DNA (5, 11). This special function of Id proteins confers a central role in the regulation of gene expression and hence cell differentiation and proliferation (24,31). Until now, four members of the Id family, Id1-4, have been identified in mammalian cells. They are encoded by separate genes and demonstrate individual expression patterns and protein structure, which may contribute to their different functions. For example, Id2 is largely expressed in immune cells (8,40), and only Id1 lacks the consensus CDK2 phosphorylation site at its NH 2 terminus (5). Our recent study revealed that Id1 and Id2 are induced by BMPs in pulmonary artery smooth muscle cells (PASMCs) through a canonical Smad-dependent pathway (37) and that BMPR-II mutation reduced the BMP-stimulated induction of Id1 and Id2 in these cells. We further showed that Id1 and Id2 are involved in the inhibition of PASMC proliferation by BMP4. We have also shown that agents enhancing BMP/ Smad/Id signaling in PASMCs can restore the growth-suppressive effects of BMPs in BMPR-II mutant cells (38,39).In the present study, we undertook a systematic analysis of the regulation of Id1-4 in PASMCs via a range of growth factors, cytokines, and BMPs. Having identified Id1 and Id3 as major targets of BMP signaling in these cells, we show that the induction of both Id1 and Id3 is dependent on intact BMPR-II and that...

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confidence: 99%

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confidence: 89%

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Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

Yang

Li²,

Liu

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…None activated BRE-luciferase, although iloprost can induce ID1 by a pSMAD1/5-independent, cAMP-mediated mechanism (54). Recent data suggest that other medications approved and effective for PAH, such as the vasodilator and phosphodiesterase inhibitor sildenafil, can partially restore BMPR2 defective signaling (55), underscoring the importance of this pathway in PAH.…”

Section: Discussionmentioning

confidence: 99%

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension

Spiekerkoetter

Tian²,

Cai³

et al. 2013

J. Clin. Invest.

385

370

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Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH. IntroductionIdiopathic pulmonary arterial hypertension (IPAH) is a rare disorder thought to develop following a genetic and/or environmental insult that triggers endothelial cell (EC) apoptosis, loss of distal vessels, and occlusive vascular remodeling (1). These pathological changes increase resistance to pulmonary flow and cause progressive right heart failure. Current therapies mainly include drugs with vasodilatory properties that improve cardiopulmonary function (2). However, the obliterative vascular pathology usually continues to progress (3), leaving heart-lung transplantation as the only option for many patients. Therefore, new approaches are needed that focus on activating cellular mechanisms to reverse vascular remodeling. One strategy could be to improve function of the bone morphogenetic protein receptor-2 (BMPR2) signaling pathway. Germline mutations causing loss of BMPR2 function are found in >80% of familial and approximately 20% of sporadic cases of IPAH (4, 5). Acquired somatic chromosomal abnormalities in the BMPR2 signaling pathway have also been described (6). The low penetrance of pulmonary arterial hypertension (PAH) found in nonaffected family members with a BMPR2 mutation has been attributed to a higher level of

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“…Yang et al (34) reported that sildenafil enhances standard bone morphogenetic protein signaling through c-GMP and c-GMP-dependent protein kinase I in vivo and in vitro. Yaman et al (35) reported that, in rats, sildenafil could be used as a supporting factor to accelerate the healing process of defective bone in oral and maxillofacial surgeries.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Sildenafil on Recuperation from Sciatic Nerve Injury in Rats

et al. 2016

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Background: Severe functional and anatomical defects can be detected after the peripheral nerve injury. Pharmacological approaches are preferred rather than surgical treatment in the treatment of nerve injuries. Aims: The aim of this study is to perform histopathological, functional and bone densitometry examinations of the effects of sildenafil on nerve regeneration in a rat model of peripheral nerve crush injury. Study Design: Animal experiment. Methods: The study included a total of thirty adult Sprague-Dawley rats that were divided into three groups of ten rats each. In all rats, a crush injury was created by clamping the right sciatic nerve for one minute. One day before the procedure, rats in group 1 were started on a 28-day treatment consisting of a daily dose of 20 mg/kg body weight sildenafil citrate given orally via a nasogastric tube, while the rats in group 2 were started on an every-other-day dose of 10 mg/kg body weight sildenafil citrate. Rats from group 3 were not administered any drugs. Forty-two days after the nerve damage was created, functional and histopathological examination of both sciatic nerves and bone densitometric evaluation of the extremities were conducted.

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Sildenafil Potentiates Bone Morphogenetic Protein Signaling in Pulmonary Arterial Smooth Muscle Cells and in Experimental Pulmonary Hypertension

Abstract: Key Words: BMP signaling pathway ◼ cGKI ◼ PDE5 inhibitor ◼ pulmonary hypertension ◼ smooth muscle cell

Cited by 60 publications

References 25 publications

Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension

The Effect of Sildenafil on Recuperation from Sciatic Nerve Injury in Rats

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