Tadalafil induces antiproliferation, apoptosis, and phosphodiesterase type 5 downregulation in idiopathic pulmonary arterial hypertension in vitro
Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease of the pulmonary artery resulting from a currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Vascular remodeling is mediated by enhanc...
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description | Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease of the pulmonary artery resulting from a currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Vascular remodeling is mediated by enhanced proliferation and reduced apoptosis in pulmonary arterial smooth muscle cells (PASMCs). Based on its pathological mechanism, specific phosphodiesterase type 5 (PDE5) inhibitors have been used in the treatment of IPAH. In addition to sildenafil, tadalafil has been approved for the treatment of IPAH. However, the effects of tadalafil on excessive proliferation of IPAH-PASMCs currently remain unknown. In the present study, the in vitro pharmacological profiles of tadalafil for cell proliferation and apoptosis were assessed in IPAH-PASMCs using MTT, BrdU incorporation, and caspase 3/7 assays. Expression analyses revealed that PDE5 mRNA and protein expression levels were markedly higher in IPAH-PASMCs than in normal-PASMCs. The treatment with tadalafil inhibited the excessive proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC50 value of 4.5μM. On the other hand, tadalafil (0.03–100μM) did not affect cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). In addition, tadalafil induced apoptosis in IPAH-PASMCs. The antiproliferative and apoptotic effects of tadalafil were markedly stronger than those of sildenafil and vardenafil. The upregulated expression of PDE5 in IPAH-PASMCs was significantly attenuated by a long-term treatment with tadalafil. Taken together, these results indicate that tadalafil attenuates vascular remodeling by inhibiting cell proliferation, promoting apoptosis, and downregulating PDE5 in IPAH-PASMCs, thereby ameliorating IPAH. |
doi_str_mv | 10.1016/j.ejphar.2017.06.010 |
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IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Vascular remodeling is mediated by enhanced proliferation and reduced apoptosis in pulmonary arterial smooth muscle cells (PASMCs). Based on its pathological mechanism, specific phosphodiesterase type 5 (PDE5) inhibitors have been used in the treatment of IPAH. In addition to sildenafil, tadalafil has been approved for the treatment of IPAH. However, the effects of tadalafil on excessive proliferation of IPAH-PASMCs currently remain unknown. In the present study, the in vitro pharmacological profiles of tadalafil for cell proliferation and apoptosis were assessed in IPAH-PASMCs using MTT, BrdU incorporation, and caspase 3/7 assays. Expression analyses revealed that PDE5 mRNA and protein expression levels were markedly higher in IPAH-PASMCs than in normal-PASMCs. The treatment with tadalafil inhibited the excessive proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC50 value of 4.5μM. On the other hand, tadalafil (0.03–100μM) did not affect cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). In addition, tadalafil induced apoptosis in IPAH-PASMCs. The antiproliferative and apoptotic effects of tadalafil were markedly stronger than those of sildenafil and vardenafil. The upregulated expression of PDE5 in IPAH-PASMCs was significantly attenuated by a long-term treatment with tadalafil. Taken together, these results indicate that tadalafil attenuates vascular remodeling by inhibiting cell proliferation, promoting apoptosis, and downregulating PDE5 in IPAH-PASMCs, thereby ameliorating IPAH.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2017.06.010</identifier><identifier>PMID: 28603047</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Apoptosis - drug effects ; Cell Line ; Cell Proliferation - drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics ; Down-Regulation - drug effects ; Familial Primary Pulmonary Hypertension - drug therapy ; Familial Primary Pulmonary Hypertension - enzymology ; Familial Primary Pulmonary Hypertension - genetics ; Familial Primary Pulmonary Hypertension - pathology ; Humans ; Myocytes, Smooth Muscle - drug effects ; Myocytes, Smooth Muscle - pathology ; Phosphodiesterase 5 Inhibitors - pharmacology ; Phosphodiesterase 5 Inhibitors - therapeutic use ; Phosphodiesterase type 5 ; Pulmonary artery ; Pulmonary Artery - pathology ; Pulmonary hypertension ; Smooth muscle ; Tadalafil ; Tadalafil - pharmacology ; Tadalafil - therapeutic use ; Vascular remodeling</subject><ispartof>European journal of pharmacology, 2017-09, Vol.810, p.44-50</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-57f239c96d378b8af54fafcf8e007ab09477fa5156b1ba18f8ebf53f78a028833</citedby><cites>FETCH-LOGICAL-c428t-57f239c96d378b8af54fafcf8e007ab09477fa5156b1ba18f8ebf53f78a028833</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejphar.2017.06.010$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28603047$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yamamura, Aya</creatorcontrib><creatorcontrib>Fujitomi, Eri</creatorcontrib><creatorcontrib>Ohara, Naoki</creatorcontrib><creatorcontrib>Tsukamoto, Kikuo</creatorcontrib><creatorcontrib>Sato, Motohiko</creatorcontrib><creatorcontrib>Yamamura, Hisao</creatorcontrib><title>Tadalafil induces antiproliferation, apoptosis, and phosphodiesterase type 5 downregulation in idiopathic pulmonary arterial hypertension in vitro</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease of the pulmonary artery resulting from a currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Vascular remodeling is mediated by enhanced proliferation and reduced apoptosis in pulmonary arterial smooth muscle cells (PASMCs). Based on its pathological mechanism, specific phosphodiesterase type 5 (PDE5) inhibitors have been used in the treatment of IPAH. In addition to sildenafil, tadalafil has been approved for the treatment of IPAH. However, the effects of tadalafil on excessive proliferation of IPAH-PASMCs currently remain unknown. In the present study, the in vitro pharmacological profiles of tadalafil for cell proliferation and apoptosis were assessed in IPAH-PASMCs using MTT, BrdU incorporation, and caspase 3/7 assays. Expression analyses revealed that PDE5 mRNA and protein expression levels were markedly higher in IPAH-PASMCs than in normal-PASMCs. The treatment with tadalafil inhibited the excessive proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC50 value of 4.5μM. On the other hand, tadalafil (0.03–100μM) did not affect cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). In addition, tadalafil induced apoptosis in IPAH-PASMCs. The antiproliferative and apoptotic effects of tadalafil were markedly stronger than those of sildenafil and vardenafil. The upregulated expression of PDE5 in IPAH-PASMCs was significantly attenuated by a long-term treatment with tadalafil. Taken together, these results indicate that tadalafil attenuates vascular remodeling by inhibiting cell proliferation, promoting apoptosis, and downregulating PDE5 in IPAH-PASMCs, thereby ameliorating IPAH.</description><subject>Apoptosis - drug effects</subject><subject>Cell Line</subject><subject>Cell Proliferation - drug effects</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics</subject><subject>Down-Regulation - drug effects</subject><subject>Familial Primary Pulmonary Hypertension - drug therapy</subject><subject>Familial Primary Pulmonary Hypertension - enzymology</subject><subject>Familial Primary Pulmonary Hypertension - genetics</subject><subject>Familial Primary Pulmonary Hypertension - pathology</subject><subject>Humans</subject><subject>Myocytes, Smooth Muscle - drug effects</subject><subject>Myocytes, Smooth Muscle - pathology</subject><subject>Phosphodiesterase 5 Inhibitors - pharmacology</subject><subject>Phosphodiesterase 5 Inhibitors - therapeutic use</subject><subject>Phosphodiesterase type 5</subject><subject>Pulmonary artery</subject><subject>Pulmonary Artery - pathology</subject><subject>Pulmonary hypertension</subject><subject>Smooth muscle</subject><subject>Tadalafil</subject><subject>Tadalafil - pharmacology</subject><subject>Tadalafil - therapeutic use</subject><subject>Vascular remodeling</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9u1DAQxi0EotvCGyDkIwcSxkkc2xckVAFFqsSlnK2J_7BeeeNgJ0V9DZ4Yl104crA80vy-GX3zEfKKQcuAje8OrTsse8xtB0y0MLbA4AnZMSlUA4J1T8kOgA1Np5S6IJelHACAq44_JxedHKGHQezIrzu0GNGHSMNsN-MKxXkNS04xeJdxDWl-S3FJy5pKKLWcLV32qdRngytrZYqj68PiKKc2_Zyz-77FP7o6kQYb0oLrPhi6bPGYZswPFHOVBYx0X2W1nsuZvg9rTi_IM4-xuJfn_4p8-_Tx7vqmuf36-cv1h9vGDJ1cGy581yujRtsLOUn0fPDojZcOQOAEahDCI2d8nNiETNbG5HnvhUTopOz7K_LmNLea_bFVK_oYinEx4uzSVjRTUG-pGO8qOpxQk1Mp2Xm95HCsVjQD_ZiGPuhTGvoxDQ2jrmlU2evzhm06OvtP9Pf8FXh_Alz1eR9c1sUENxtnQ3Zm1TaF_2_4DTqcohM</recordid><startdate>20170905</startdate><enddate>20170905</enddate><creator>Yamamura, Aya</creator><creator>Fujitomi, Eri</creator><creator>Ohara, Naoki</creator><creator>Tsukamoto, Kikuo</creator><creator>Sato, Motohiko</creator><creator>Yamamura, Hisao</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20170905</creationdate><title>Tadalafil induces antiproliferation, apoptosis, and phosphodiesterase type 5 downregulation in idiopathic pulmonary arterial hypertension in vitro</title><author>Yamamura, Aya ; Fujitomi, Eri ; Ohara, Naoki ; Tsukamoto, Kikuo ; Sato, Motohiko ; Yamamura, Hisao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c428t-57f239c96d378b8af54fafcf8e007ab09477fa5156b1ba18f8ebf53f78a028833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Apoptosis - drug effects</topic><topic>Cell Line</topic><topic>Cell Proliferation - drug effects</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics</topic><topic>Down-Regulation - drug effects</topic><topic>Familial Primary Pulmonary Hypertension - drug therapy</topic><topic>Familial Primary Pulmonary Hypertension - enzymology</topic><topic>Familial Primary Pulmonary Hypertension - genetics</topic><topic>Familial Primary Pulmonary Hypertension - pathology</topic><topic>Humans</topic><topic>Myocytes, Smooth Muscle - drug effects</topic><topic>Myocytes, Smooth Muscle - pathology</topic><topic>Phosphodiesterase 5 Inhibitors - pharmacology</topic><topic>Phosphodiesterase 5 Inhibitors - therapeutic use</topic><topic>Phosphodiesterase type 5</topic><topic>Pulmonary artery</topic><topic>Pulmonary Artery - pathology</topic><topic>Pulmonary hypertension</topic><topic>Smooth muscle</topic><topic>Tadalafil</topic><topic>Tadalafil - pharmacology</topic><topic>Tadalafil - therapeutic use</topic><topic>Vascular remodeling</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yamamura, Aya</creatorcontrib><creatorcontrib>Fujitomi, Eri</creatorcontrib><creatorcontrib>Ohara, Naoki</creatorcontrib><creatorcontrib>Tsukamoto, Kikuo</creatorcontrib><creatorcontrib>Sato, Motohiko</creatorcontrib><creatorcontrib>Yamamura, Hisao</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yamamura, Aya</au><au>Fujitomi, Eri</au><au>Ohara, Naoki</au><au>Tsukamoto, Kikuo</au><au>Sato, Motohiko</au><au>Yamamura, Hisao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tadalafil induces antiproliferation, apoptosis, and phosphodiesterase type 5 downregulation in idiopathic pulmonary arterial hypertension in vitro</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2017-09-05</date><risdate>2017</risdate><volume>810</volume><spage>44</spage><epage>50</epage><pages>44-50</pages><issn>0014-2999</issn><eissn>1879-0712</eissn><abstract>Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease of the pulmonary artery resulting from a currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Vascular remodeling is mediated by enhanced proliferation and reduced apoptosis in pulmonary arterial smooth muscle cells (PASMCs). Based on its pathological mechanism, specific phosphodiesterase type 5 (PDE5) inhibitors have been used in the treatment of IPAH. In addition to sildenafil, tadalafil has been approved for the treatment of IPAH. However, the effects of tadalafil on excessive proliferation of IPAH-PASMCs currently remain unknown. In the present study, the in vitro pharmacological profiles of tadalafil for cell proliferation and apoptosis were assessed in IPAH-PASMCs using MTT, BrdU incorporation, and caspase 3/7 assays. Expression analyses revealed that PDE5 mRNA and protein expression levels were markedly higher in IPAH-PASMCs than in normal-PASMCs. The treatment with tadalafil inhibited the excessive proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC50 value of 4.5μM. On the other hand, tadalafil (0.03–100μM) did not affect cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). In addition, tadalafil induced apoptosis in IPAH-PASMCs. The antiproliferative and apoptotic effects of tadalafil were markedly stronger than those of sildenafil and vardenafil. The upregulated expression of PDE5 in IPAH-PASMCs was significantly attenuated by a long-term treatment with tadalafil. Taken together, these results indicate that tadalafil attenuates vascular remodeling by inhibiting cell proliferation, promoting apoptosis, and downregulating PDE5 in IPAH-PASMCs, thereby ameliorating IPAH.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>28603047</pmid><doi>10.1016/j.ejphar.2017.06.010</doi><tpages>7</tpages></addata></record> |
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subjects | Apoptosis - drug effects Cell Line Cell Proliferation - drug effects Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics Down-Regulation - drug effects Familial Primary Pulmonary Hypertension - drug therapy Familial Primary Pulmonary Hypertension - enzymology Familial Primary Pulmonary Hypertension - genetics Familial Primary Pulmonary Hypertension - pathology Humans Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - pathology Phosphodiesterase 5 Inhibitors - pharmacology Phosphodiesterase 5 Inhibitors - therapeutic use Phosphodiesterase type 5 Pulmonary artery Pulmonary Artery - pathology Pulmonary hypertension Smooth muscle Tadalafil Tadalafil - pharmacology Tadalafil - therapeutic use Vascular remodeling |
title | Tadalafil induces antiproliferation, apoptosis, and phosphodiesterase type 5 downregulation in idiopathic pulmonary arterial hypertension in vitro |
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