Oxidative Stress Regulates Left Ventricular PDE5 Expression in the Failing Heart
Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased...
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| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2010-04, Vol.121 (13), p.1474-1483 |
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| creator | ZHONGBING LU XIN XU PRITZKER, Marc HALL, Jennifer L GARRY, Daniel J YINGJIE CHEN XINLI HU LEE, Sangjin TRAVERSE, Jay H GUANGSHUO ZHU FASSETT, John YI TAO PING ZHANG DOS REMEDIOS, Cris |
| description | Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF.
Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)-induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased approximately equal 4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3'-nitrotyrosine or 4-hydroxynonenal expression (P |
| doi_str_mv | 10.1161/circulationaha.109.906818 |
| format | Article |
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Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)-induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased approximately equal 4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3'-nitrotyrosine or 4-hydroxynonenal expression (P<0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (P<0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF.
Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/circulationaha.109.906818</identifier><identifier>PMID: 20308615</identifier><identifier>CODEN: CIRCAZ</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Animals ; Antioxidants - pharmacology ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cardiovascular system ; Cyclic GMP-Dependent Protein Kinases - metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics ; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism ; Disease Models, Animal ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Heart Failure - drug therapy ; Heart Failure - metabolism ; Heart Failure - physiopathology ; Humans ; Hypertrophy, Left Ventricular - drug therapy ; Hypertrophy, Left Ventricular - metabolism ; Hypertrophy, Left Ventricular - physiopathology ; Investigative techniques of hemodynamics ; Investigative techniques, diagnostic techniques (general aspects) ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocytes, Cardiac - enzymology ; Nitric Oxide Synthase Type II - genetics ; Nitric Oxide Synthase Type II - metabolism ; Organometallic Compounds - pharmacology ; Oxidative Stress - drug effects ; Oxidative Stress - physiology ; Phosphodiesterase 5 Inhibitors ; Phosphodiesterase Inhibitors - pharmacology ; Phosphorylation - drug effects ; Phosphorylation - physiology ; Piperazines - pharmacology ; Proto-Oncogene Proteins c-akt - metabolism ; Purines - pharmacology ; Signal Transduction - drug effects ; Signal Transduction - physiology ; Sildenafil Citrate ; Sulfones - pharmacology ; Superoxide Dismutase - genetics ; Superoxide Dismutase - metabolism</subject><ispartof>Circulation (New York, N.Y.), 2010-04, Vol.121 (13), p.1474-1483</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c518t-9b60b0c06051fa9583ced93fe1aefbb2334d34e8a0b82ececb9b4e8887d556ad3</citedby><cites>FETCH-LOGICAL-c518t-9b60b0c06051fa9583ced93fe1aefbb2334d34e8a0b82ececb9b4e8887d556ad3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3687,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22635617$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20308615$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ZHONGBING LU</creatorcontrib><creatorcontrib>XIN XU</creatorcontrib><creatorcontrib>PRITZKER, Marc</creatorcontrib><creatorcontrib>HALL, Jennifer L</creatorcontrib><creatorcontrib>GARRY, Daniel J</creatorcontrib><creatorcontrib>YINGJIE CHEN</creatorcontrib><creatorcontrib>XINLI HU</creatorcontrib><creatorcontrib>LEE, Sangjin</creatorcontrib><creatorcontrib>TRAVERSE, Jay H</creatorcontrib><creatorcontrib>GUANGSHUO ZHU</creatorcontrib><creatorcontrib>FASSETT, John</creatorcontrib><creatorcontrib>YI TAO</creatorcontrib><creatorcontrib>PING ZHANG</creatorcontrib><creatorcontrib>DOS REMEDIOS, Cris</creatorcontrib><title>Oxidative Stress Regulates Left Ventricular PDE5 Expression in the Failing Heart</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF.
Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)-induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased approximately equal 4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3'-nitrotyrosine or 4-hydroxynonenal expression (P<0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (P<0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF.
Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF.</description><subject>Animals</subject><subject>Antioxidants - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Cardiovascular system</subject><subject>Cyclic GMP-Dependent Protein Kinases - metabolism</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism</subject><subject>Disease Models, Animal</subject><subject>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Heart Failure - drug therapy</subject><subject>Heart Failure - metabolism</subject><subject>Heart Failure - physiopathology</subject><subject>Humans</subject><subject>Hypertrophy, Left Ventricular - drug therapy</subject><subject>Hypertrophy, Left Ventricular - metabolism</subject><subject>Hypertrophy, Left Ventricular - physiopathology</subject><subject>Investigative techniques of hemodynamics</subject><subject>Investigative techniques, diagnostic techniques (general aspects)</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myocytes, Cardiac - enzymology</subject><subject>Nitric Oxide Synthase Type II - genetics</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>Organometallic Compounds - pharmacology</subject><subject>Oxidative Stress - drug effects</subject><subject>Oxidative Stress - physiology</subject><subject>Phosphodiesterase 5 Inhibitors</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Phosphorylation - drug effects</subject><subject>Phosphorylation - physiology</subject><subject>Piperazines - pharmacology</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Purines - pharmacology</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Sildenafil Citrate</subject><subject>Sulfones - pharmacology</subject><subject>Superoxide Dismutase - genetics</subject><subject>Superoxide Dismutase - metabolism</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUFvEzEQhS0EoqHlLyBzQJw2tdex174gRSFtIkVNVVqu1qx3NjHa7AZ7U5V_j1dJWziNZuab90Z6hHzmbMy54pfOB3dooPddC1sYc2bGhinN9Rsy4jKfZBMpzFsyYoyZrBB5fkY-xPgrtUoU8j05y5lgWnE5IrfrJ18lpUekP_qAMdI73AzaGOkK657-xLYPfrAL9Pb7XNL5037gkjf1Le23SK_AN77d0AVC6C_IuxqaiB9P9Zw8XM3vZ4tstb5ezqarzEmu-8yUipXMMcUkr8FILRxWRtTIAeuyzIWYVGKCGlipc3ToSlOmVuuiklJBJc7Jt6Pu_lDusHLDm9DYffA7CH9sB97-v2n91m66Rys4ZwXjSeDrSSB0vw8Ye7vz0WHTQIvdIdpCCGmYzFUizZF0oYsxYP3iwpkdArGz5d3sYTW9X65vpotpGht7DCTdfvr3zZfL5wQS8OUEQHTQ1AFa5-Mrl_yl4oX4C2DumPs</recordid><startdate>20100406</startdate><enddate>20100406</enddate><creator>ZHONGBING LU</creator><creator>XIN XU</creator><creator>PRITZKER, Marc</creator><creator>HALL, Jennifer L</creator><creator>GARRY, Daniel J</creator><creator>YINGJIE CHEN</creator><creator>XINLI HU</creator><creator>LEE, Sangjin</creator><creator>TRAVERSE, Jay H</creator><creator>GUANGSHUO ZHU</creator><creator>FASSETT, John</creator><creator>YI TAO</creator><creator>PING ZHANG</creator><creator>DOS REMEDIOS, Cris</creator><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><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><scope>5PM</scope></search><sort><creationdate>20100406</creationdate><title>Oxidative Stress Regulates Left Ventricular PDE5 Expression in the Failing Heart</title><author>ZHONGBING LU ; XIN XU ; PRITZKER, Marc ; HALL, Jennifer L ; GARRY, Daniel J ; YINGJIE CHEN ; XINLI HU ; LEE, Sangjin ; TRAVERSE, Jay H ; GUANGSHUO ZHU ; FASSETT, John ; YI TAO ; PING ZHANG ; DOS REMEDIOS, Cris</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c518t-9b60b0c06051fa9583ced93fe1aefbb2334d34e8a0b82ececb9b4e8887d556ad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Antioxidants - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Cardiology. Vascular system</topic><topic>Cardiovascular system</topic><topic>Cyclic GMP-Dependent Protein Kinases - metabolism</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism</topic><topic>Disease Models, Animal</topic><topic>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Heart Failure - drug therapy</topic><topic>Heart Failure - metabolism</topic><topic>Heart Failure - physiopathology</topic><topic>Humans</topic><topic>Hypertrophy, Left Ventricular - drug therapy</topic><topic>Hypertrophy, Left Ventricular - metabolism</topic><topic>Hypertrophy, Left Ventricular - physiopathology</topic><topic>Investigative techniques of hemodynamics</topic><topic>Investigative techniques, diagnostic techniques (general aspects)</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Myocytes, Cardiac - enzymology</topic><topic>Nitric Oxide Synthase Type II - genetics</topic><topic>Nitric Oxide Synthase Type II - metabolism</topic><topic>Organometallic Compounds - pharmacology</topic><topic>Oxidative Stress - drug effects</topic><topic>Oxidative Stress - physiology</topic><topic>Phosphodiesterase 5 Inhibitors</topic><topic>Phosphodiesterase Inhibitors - pharmacology</topic><topic>Phosphorylation - drug effects</topic><topic>Phosphorylation - physiology</topic><topic>Piperazines - pharmacology</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Purines - pharmacology</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>Sildenafil Citrate</topic><topic>Sulfones - pharmacology</topic><topic>Superoxide Dismutase - genetics</topic><topic>Superoxide Dismutase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>ZHONGBING LU</creatorcontrib><creatorcontrib>XIN XU</creatorcontrib><creatorcontrib>PRITZKER, Marc</creatorcontrib><creatorcontrib>HALL, Jennifer L</creatorcontrib><creatorcontrib>GARRY, Daniel J</creatorcontrib><creatorcontrib>YINGJIE CHEN</creatorcontrib><creatorcontrib>XINLI HU</creatorcontrib><creatorcontrib>LEE, Sangjin</creatorcontrib><creatorcontrib>TRAVERSE, Jay H</creatorcontrib><creatorcontrib>GUANGSHUO ZHU</creatorcontrib><creatorcontrib>FASSETT, John</creatorcontrib><creatorcontrib>YI TAO</creatorcontrib><creatorcontrib>PING ZHANG</creatorcontrib><creatorcontrib>DOS REMEDIOS, Cris</creatorcontrib><collection>Pascal-Francis</collection><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>ZHONGBING LU</au><au>XIN XU</au><au>PRITZKER, Marc</au><au>HALL, Jennifer L</au><au>GARRY, Daniel J</au><au>YINGJIE CHEN</au><au>XINLI HU</au><au>LEE, Sangjin</au><au>TRAVERSE, Jay H</au><au>GUANGSHUO ZHU</au><au>FASSETT, John</au><au>YI TAO</au><au>PING ZHANG</au><au>DOS REMEDIOS, Cris</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oxidative Stress Regulates Left Ventricular PDE5 Expression in the Failing Heart</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2010-04-06</date><risdate>2010</risdate><volume>121</volume><issue>13</issue><spage>1474</spage><epage>1483</epage><pages>1474-1483</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><coden>CIRCAZ</coden><abstract>Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF.
Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)-induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased approximately equal 4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3'-nitrotyrosine or 4-hydroxynonenal expression (P<0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (P<0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF.
Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>20308615</pmid><doi>10.1161/circulationaha.109.906818</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Circulation (New York, N.Y.), 2010-04, Vol.121 (13), p.1474-1483 |
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| source | MEDLINE; American Heart Association; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antioxidants - pharmacology Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cardiovascular system Cyclic GMP-Dependent Protein Kinases - metabolism Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism Disease Models, Animal Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Extracellular Signal-Regulated MAP Kinases - metabolism Heart Failure - drug therapy Heart Failure - metabolism Heart Failure - physiopathology Humans Hypertrophy, Left Ventricular - drug therapy Hypertrophy, Left Ventricular - metabolism Hypertrophy, Left Ventricular - physiopathology Investigative techniques of hemodynamics Investigative techniques, diagnostic techniques (general aspects) Male Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Myocytes, Cardiac - enzymology Nitric Oxide Synthase Type II - genetics Nitric Oxide Synthase Type II - metabolism Organometallic Compounds - pharmacology Oxidative Stress - drug effects Oxidative Stress - physiology Phosphodiesterase 5 Inhibitors Phosphodiesterase Inhibitors - pharmacology Phosphorylation - drug effects Phosphorylation - physiology Piperazines - pharmacology Proto-Oncogene Proteins c-akt - metabolism Purines - pharmacology Signal Transduction - drug effects Signal Transduction - physiology Sildenafil Citrate Sulfones - pharmacology Superoxide Dismutase - genetics Superoxide Dismutase - metabolism |
| title | Oxidative Stress Regulates Left Ventricular PDE5 Expression in the Failing Heart |
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