Neuregulin‐1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension
Summary We have previously shown that treatment with recombinant human neuregulin‐1 (rhNRG‐1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)‐induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricu...
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| Veröffentlicht in: | Clinical and experimental pharmacology & physiology 2019-03, Vol.46 (3), p.255-265 |
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| creator | Adão, Rui Mendes‐Ferreira, Pedro Maia‐Rocha, Carolina Santos‐Ribeiro, Diana Rodrigues, Patrícia Gonçalves Vidal‐Meireles, André Monteiro‐Pinto, Cláudia Pimentel, Luís D. Falcão‐Pires, Inês De Keulenaer, Gilles W. Leite‐Moreira, Adelino F. Brás‐Silva, Carmen |
| description | Summary
We have previously shown that treatment with recombinant human neuregulin‐1 (rhNRG‐1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)‐induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function. Additionally, rhNRG‐1 treatment showed direct myocardial anti‐remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG‐1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG‐1 treatment on ventricular passive stiffness in RV and LV samples from MCT‐induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling‐associated genes and calcium handling proteins. Chronic rhNRG‐1 treatment decreased passive tension development in RV and LV isolated from animals with MCT‐induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers. Finally, we showed that rhNRG‐1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB‐induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac‐specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG‐1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling. |
| doi_str_mv | 10.1111/1440-1681.13043 |
| format | Article |
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We have previously shown that treatment with recombinant human neuregulin‐1 (rhNRG‐1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)‐induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function. Additionally, rhNRG‐1 treatment showed direct myocardial anti‐remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG‐1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG‐1 treatment on ventricular passive stiffness in RV and LV samples from MCT‐induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling‐associated genes and calcium handling proteins. Chronic rhNRG‐1 treatment decreased passive tension development in RV and LV isolated from animals with MCT‐induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers. Finally, we showed that rhNRG‐1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB‐induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac‐specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG‐1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling.</description><identifier>ISSN: 0305-1870</identifier><identifier>EISSN: 1440-1681</identifier><identifier>DOI: 10.1111/1440-1681.13043</identifier><identifier>PMID: 30339273</identifier><language>eng</language><publisher>Australia: Wiley Subscription Services, Inc</publisher><subject>Animals ; Attenuation ; Banding ; Calcium ; Calcium Signaling - drug effects ; Cardiomyocytes ; Diastole - physiology ; diastolic function ; diastolic stiffness ; Gene expression ; Gene Expression Regulation - drug effects ; Heart ; Humans ; Hypertension ; Hypertension, Pulmonary - pathology ; Hypertension, Pulmonary - physiopathology ; Hypertrophy ; Male ; Monocrotaline ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Neuregulin ; Neuregulin-1 - pharmacology ; Neuregulin-1 - therapeutic use ; neuregulin‐1 ; Phospholamban ; Phosphorylation ; Proteins ; pulmonary arterial hypertension ; Pulmonary arteries ; Pulmonary artery ; Pulmonary hypertension ; Rats ; Rats, Wistar ; Recombinant Proteins - pharmacology ; Recombinant Proteins - therapeutic use ; right ventricle ; Stiffness ; Tension ; Vascular Stiffness - drug effects ; Ventricle ; Ventricular Dysfunction, Right - drug therapy ; Ventricular Remodeling - drug effects</subject><ispartof>Clinical and experimental pharmacology & physiology, 2019-03, Vol.46 (3), p.255-265</ispartof><rights>2018 John Wiley & Sons Australia, Ltd</rights><rights>2018 John Wiley & Sons Australia, Ltd.</rights><rights>Copyright © 2019 John Wiley & Sons Australia, Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4393-109b71cb2868ae01062644b45eb35b3d777a98923ac3cec06fbfb9bae037c70c3</citedby><cites>FETCH-LOGICAL-c4393-109b71cb2868ae01062644b45eb35b3d777a98923ac3cec06fbfb9bae037c70c3</cites><orcidid>0000-0003-2528-142X ; 0000-0002-4238-4183 ; 0000-0003-1937-3782 ; 0000-0001-7808-3596 ; 0000-0001-6438-3248 ; 0000-0001-6538-1420 ; 0000-0003-3616-6785 ; 0000-0003-2203-436X ; 0000-0001-9381-7420 ; 0000-0003-1527-3776 ; 0000-0003-3767-2559 ; 0000-0001-7056-9508</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2F1440-1681.13043$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2F1440-1681.13043$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30339273$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Adão, Rui</creatorcontrib><creatorcontrib>Mendes‐Ferreira, Pedro</creatorcontrib><creatorcontrib>Maia‐Rocha, Carolina</creatorcontrib><creatorcontrib>Santos‐Ribeiro, Diana</creatorcontrib><creatorcontrib>Rodrigues, Patrícia Gonçalves</creatorcontrib><creatorcontrib>Vidal‐Meireles, André</creatorcontrib><creatorcontrib>Monteiro‐Pinto, Cláudia</creatorcontrib><creatorcontrib>Pimentel, Luís D.</creatorcontrib><creatorcontrib>Falcão‐Pires, Inês</creatorcontrib><creatorcontrib>De Keulenaer, Gilles W.</creatorcontrib><creatorcontrib>Leite‐Moreira, Adelino F.</creatorcontrib><creatorcontrib>Brás‐Silva, Carmen</creatorcontrib><title>Neuregulin‐1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension</title><title>Clinical and experimental pharmacology & physiology</title><addtitle>Clin Exp Pharmacol Physiol</addtitle><description>Summary
We have previously shown that treatment with recombinant human neuregulin‐1 (rhNRG‐1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)‐induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function. Additionally, rhNRG‐1 treatment showed direct myocardial anti‐remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG‐1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG‐1 treatment on ventricular passive stiffness in RV and LV samples from MCT‐induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling‐associated genes and calcium handling proteins. Chronic rhNRG‐1 treatment decreased passive tension development in RV and LV isolated from animals with MCT‐induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers. Finally, we showed that rhNRG‐1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB‐induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac‐specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG‐1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling.</description><subject>Animals</subject><subject>Attenuation</subject><subject>Banding</subject><subject>Calcium</subject><subject>Calcium Signaling - drug effects</subject><subject>Cardiomyocytes</subject><subject>Diastole - physiology</subject><subject>diastolic function</subject><subject>diastolic stiffness</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Heart</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Hypertension, Pulmonary - pathology</subject><subject>Hypertension, Pulmonary - physiopathology</subject><subject>Hypertrophy</subject><subject>Male</subject><subject>Monocrotaline</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Neuregulin</subject><subject>Neuregulin-1 - pharmacology</subject><subject>Neuregulin-1 - therapeutic use</subject><subject>neuregulin‐1</subject><subject>Phospholamban</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>pulmonary arterial hypertension</subject><subject>Pulmonary arteries</subject><subject>Pulmonary artery</subject><subject>Pulmonary hypertension</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Recombinant Proteins - therapeutic use</subject><subject>right ventricle</subject><subject>Stiffness</subject><subject>Tension</subject><subject>Vascular Stiffness - drug effects</subject><subject>Ventricle</subject><subject>Ventricular Dysfunction, Right - drug therapy</subject><subject>Ventricular Remodeling - drug effects</subject><issn>0305-1870</issn><issn>1440-1681</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkbFuFDEQhi0EIpdAnQ5ZSpNmk_HO7nq3jE4JRIqAAmrL9s0mjnzew14HruMReEaeBB-XpKDBkmVp9PnTzD-MHQs4E-Wci6aBSnS9OBMIDb5gi-fKS7YAhLYSvYQDdpjSPQC00OFrdoCAONQSF2z8SDnSbfYu_P75S3A9zxSyninx6G7vZv5AYY7OZq8jXzmd5sk7y9PsxjFQStwFTj82FN26gNrzTfbrKei45XfbUi625Kbwhr0atU_09vE9Yl-vLr8sP1Q3n95fLy9uKtvggJWAwUhhTd13vSYQ0NVd05imJYOtwZWUUg_9UKO2aMlCN5rRDKagKK0Ei0fsdO_dxOlbpjSrtUuWvNeBppxULWqUQvYCCnryD3o_5RhKd4XqUeyuLNT5nrJxSinSqDZl1DKeEqB2K1C7wNUucPV3BeXHu0dvNmtaPfNPmReg3QPfnaft_3xqefl5L_4D4dGSeA</recordid><startdate>201903</startdate><enddate>201903</enddate><creator>Adão, Rui</creator><creator>Mendes‐Ferreira, Pedro</creator><creator>Maia‐Rocha, Carolina</creator><creator>Santos‐Ribeiro, Diana</creator><creator>Rodrigues, Patrícia Gonçalves</creator><creator>Vidal‐Meireles, André</creator><creator>Monteiro‐Pinto, Cláudia</creator><creator>Pimentel, Luís D.</creator><creator>Falcão‐Pires, Inês</creator><creator>De Keulenaer, Gilles W.</creator><creator>Leite‐Moreira, Adelino F.</creator><creator>Brás‐Silva, Carmen</creator><general>Wiley Subscription Services, Inc</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>7QP</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2528-142X</orcidid><orcidid>https://orcid.org/0000-0002-4238-4183</orcidid><orcidid>https://orcid.org/0000-0003-1937-3782</orcidid><orcidid>https://orcid.org/0000-0001-7808-3596</orcidid><orcidid>https://orcid.org/0000-0001-6438-3248</orcidid><orcidid>https://orcid.org/0000-0001-6538-1420</orcidid><orcidid>https://orcid.org/0000-0003-3616-6785</orcidid><orcidid>https://orcid.org/0000-0003-2203-436X</orcidid><orcidid>https://orcid.org/0000-0001-9381-7420</orcidid><orcidid>https://orcid.org/0000-0003-1527-3776</orcidid><orcidid>https://orcid.org/0000-0003-3767-2559</orcidid><orcidid>https://orcid.org/0000-0001-7056-9508</orcidid></search><sort><creationdate>201903</creationdate><title>Neuregulin‐1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension</title><author>Adão, Rui ; Mendes‐Ferreira, Pedro ; Maia‐Rocha, Carolina ; Santos‐Ribeiro, Diana ; Rodrigues, Patrícia Gonçalves ; Vidal‐Meireles, André ; Monteiro‐Pinto, Cláudia ; Pimentel, Luís D. ; Falcão‐Pires, Inês ; De Keulenaer, Gilles W. ; Leite‐Moreira, Adelino F. ; Brás‐Silva, Carmen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4393-109b71cb2868ae01062644b45eb35b3d777a98923ac3cec06fbfb9bae037c70c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Attenuation</topic><topic>Banding</topic><topic>Calcium</topic><topic>Calcium Signaling - drug effects</topic><topic>Cardiomyocytes</topic><topic>Diastole - physiology</topic><topic>diastolic function</topic><topic>diastolic stiffness</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Heart</topic><topic>Humans</topic><topic>Hypertension</topic><topic>Hypertension, Pulmonary - pathology</topic><topic>Hypertension, Pulmonary - physiopathology</topic><topic>Hypertrophy</topic><topic>Male</topic><topic>Monocrotaline</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - pathology</topic><topic>Neuregulin</topic><topic>Neuregulin-1 - pharmacology</topic><topic>Neuregulin-1 - therapeutic use</topic><topic>neuregulin‐1</topic><topic>Phospholamban</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>pulmonary arterial hypertension</topic><topic>Pulmonary arteries</topic><topic>Pulmonary artery</topic><topic>Pulmonary hypertension</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Recombinant Proteins - therapeutic use</topic><topic>right ventricle</topic><topic>Stiffness</topic><topic>Tension</topic><topic>Vascular Stiffness - drug effects</topic><topic>Ventricle</topic><topic>Ventricular Dysfunction, Right - drug therapy</topic><topic>Ventricular Remodeling - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Adão, Rui</creatorcontrib><creatorcontrib>Mendes‐Ferreira, Pedro</creatorcontrib><creatorcontrib>Maia‐Rocha, Carolina</creatorcontrib><creatorcontrib>Santos‐Ribeiro, Diana</creatorcontrib><creatorcontrib>Rodrigues, Patrícia Gonçalves</creatorcontrib><creatorcontrib>Vidal‐Meireles, André</creatorcontrib><creatorcontrib>Monteiro‐Pinto, Cláudia</creatorcontrib><creatorcontrib>Pimentel, Luís D.</creatorcontrib><creatorcontrib>Falcão‐Pires, Inês</creatorcontrib><creatorcontrib>De Keulenaer, Gilles W.</creatorcontrib><creatorcontrib>Leite‐Moreira, Adelino F.</creatorcontrib><creatorcontrib>Brás‐Silva, Carmen</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical and experimental pharmacology & physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Adão, Rui</au><au>Mendes‐Ferreira, Pedro</au><au>Maia‐Rocha, Carolina</au><au>Santos‐Ribeiro, Diana</au><au>Rodrigues, Patrícia Gonçalves</au><au>Vidal‐Meireles, André</au><au>Monteiro‐Pinto, Cláudia</au><au>Pimentel, Luís D.</au><au>Falcão‐Pires, Inês</au><au>De Keulenaer, Gilles W.</au><au>Leite‐Moreira, Adelino F.</au><au>Brás‐Silva, Carmen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neuregulin‐1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension</atitle><jtitle>Clinical and experimental pharmacology & physiology</jtitle><addtitle>Clin Exp Pharmacol Physiol</addtitle><date>2019-03</date><risdate>2019</risdate><volume>46</volume><issue>3</issue><spage>255</spage><epage>265</epage><pages>255-265</pages><issn>0305-1870</issn><eissn>1440-1681</eissn><abstract>Summary
We have previously shown that treatment with recombinant human neuregulin‐1 (rhNRG‐1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)‐induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function. Additionally, rhNRG‐1 treatment showed direct myocardial anti‐remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG‐1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG‐1 treatment on ventricular passive stiffness in RV and LV samples from MCT‐induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling‐associated genes and calcium handling proteins. Chronic rhNRG‐1 treatment decreased passive tension development in RV and LV isolated from animals with MCT‐induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers. Finally, we showed that rhNRG‐1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB‐induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac‐specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG‐1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling.</abstract><cop>Australia</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30339273</pmid><doi>10.1111/1440-1681.13043</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-2528-142X</orcidid><orcidid>https://orcid.org/0000-0002-4238-4183</orcidid><orcidid>https://orcid.org/0000-0003-1937-3782</orcidid><orcidid>https://orcid.org/0000-0001-7808-3596</orcidid><orcidid>https://orcid.org/0000-0001-6438-3248</orcidid><orcidid>https://orcid.org/0000-0001-6538-1420</orcidid><orcidid>https://orcid.org/0000-0003-3616-6785</orcidid><orcidid>https://orcid.org/0000-0003-2203-436X</orcidid><orcidid>https://orcid.org/0000-0001-9381-7420</orcidid><orcidid>https://orcid.org/0000-0003-1527-3776</orcidid><orcidid>https://orcid.org/0000-0003-3767-2559</orcidid><orcidid>https://orcid.org/0000-0001-7056-9508</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Attenuation Banding Calcium Calcium Signaling - drug effects Cardiomyocytes Diastole - physiology diastolic function diastolic stiffness Gene expression Gene Expression Regulation - drug effects Heart Humans Hypertension Hypertension, Pulmonary - pathology Hypertension, Pulmonary - physiopathology Hypertrophy Male Monocrotaline Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Neuregulin Neuregulin-1 - pharmacology Neuregulin-1 - therapeutic use neuregulin‐1 Phospholamban Phosphorylation Proteins pulmonary arterial hypertension Pulmonary arteries Pulmonary artery Pulmonary hypertension Rats Rats, Wistar Recombinant Proteins - pharmacology Recombinant Proteins - therapeutic use right ventricle Stiffness Tension Vascular Stiffness - drug effects Ventricle Ventricular Dysfunction, Right - drug therapy Ventricular Remodeling - drug effects |
| title | Neuregulin‐1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension |
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