Synergistic role of ADP and Ca(2+) in diastolic myocardial stiffness
Diastolic dysfunction in heart failure patients is evident from stiffening of the passive properties of the ventricular wall. Increased actomyosin interactions may significantly limit diastolic capacity, however, direct evidence is absent. From experiments at the cellular and whole organ level, in h...
Saved in:
Published in | The Journal of physiology Vol. 593; no. 17; p. 3899 |
---|---|
Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
01.09.2015
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Abstract | Diastolic dysfunction in heart failure patients is evident from stiffening of the passive properties of the ventricular wall. Increased actomyosin interactions may significantly limit diastolic capacity, however, direct evidence is absent. From experiments at the cellular and whole organ level, in humans and rats, we show that actomyosin-related force development contributes significantly to high diastolic stiffness in environments where high ADP and increased diastolic [Ca(2+) ] are present, such as the failing myocardium. Our basal study provides a mechanical mechanism which may partly underlie diastolic dysfunction. Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca(2+) ] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca(2+) handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca(2+) ] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca(2+) in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca(2+) both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathological levels of ADP and diastolic [Ca(2+) ] revealed a 76 ± 1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca(2+) overload. In isolated Langendorff-perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca(2+) ]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges, even at low Ca(2+) , and thereby increase myocardial stiffness. |
---|---|
AbstractList | Diastolic dysfunction in heart failure patients is evident from stiffening of the passive properties of the ventricular wall. Increased actomyosin interactions may significantly limit diastolic capacity, however, direct evidence is absent. From experiments at the cellular and whole organ level, in humans and rats, we show that actomyosin-related force development contributes significantly to high diastolic stiffness in environments where high ADP and increased diastolic [Ca(2+) ] are present, such as the failing myocardium. Our basal study provides a mechanical mechanism which may partly underlie diastolic dysfunction. Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca(2+) ] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca(2+) handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca(2+) ] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca(2+) in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca(2+) both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathological levels of ADP and diastolic [Ca(2+) ] revealed a 76 ± 1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca(2+) overload. In isolated Langendorff-perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca(2+) ]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges, even at low Ca(2+) , and thereby increase myocardial stiffness. |
Author | Kuster, Diederik W D McConnell, Mark van der Velden, Jolanda dos Remedios, Cris Fowler, Ewan D Stienen, Ger J M Tardiff, Jil Najafi, Aref Sequeira, Vasco Bollen, Ilse A E Wüst, Rob C I White, Ed Helmes, Michiel |
Author_xml | – sequence: 1 givenname: Vasco surname: Sequeira fullname: Sequeira, Vasco organization: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands – sequence: 2 givenname: Aref surname: Najafi fullname: Najafi, Aref organization: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands – sequence: 3 givenname: Mark surname: McConnell fullname: McConnell, Mark organization: Sarver Heart Center, University of Arizona, Tucson, AZ, USA – sequence: 4 givenname: Ewan D surname: Fowler fullname: Fowler, Ewan D organization: School of Biomedical Sciences, Garstang Building, University of Leeds, Leeds, UK – sequence: 5 givenname: Ilse A E surname: Bollen fullname: Bollen, Ilse A E organization: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands – sequence: 6 givenname: Rob C I surname: Wüst fullname: Wüst, Rob C I organization: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands – sequence: 7 givenname: Cris surname: dos Remedios fullname: dos Remedios, Cris organization: Muscle Research Unit, Bosch Institute, University of Sydney, Sydney, Australia – sequence: 8 givenname: Michiel surname: Helmes fullname: Helmes, Michiel organization: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands – sequence: 9 givenname: Ed surname: White fullname: White, Ed organization: School of Biomedical Sciences, Garstang Building, University of Leeds, Leeds, UK – sequence: 10 givenname: Ger J M surname: Stienen fullname: Stienen, Ger J M organization: Department of Physics and Astronomy, VU University, Amsterdam, The Netherlands – sequence: 11 givenname: Jil surname: Tardiff fullname: Tardiff, Jil organization: Sarver Heart Center, University of Arizona, Tucson, AZ, USA – sequence: 12 givenname: Diederik W D surname: Kuster fullname: Kuster, Diederik W D organization: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands – sequence: 13 givenname: Jolanda surname: van der Velden fullname: van der Velden, Jolanda organization: ICIN-Netherlands Heart Institute, Utrecht, The Netherlands |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26096258$$D View this record in MEDLINE/PubMed |
BookMark | eNo1j8tKxDAARYMozkPBL5AslaGad5rl0NFRGXBAXQ95SqVNhqQu-vcW1NXlwrkH7gKcxhQ9AFcY3WGM6f3LnkhEOTsBc8yEqqRUdAYWpXwhhClS6hzMiEBKEF7PweZtjD5_tmVoLcyp8zAFuN7soY4ONvqGrG5hG6FrdRlSNzH9mKzOU-_gtAkh-lIuwFnQXfGXf7kEH48P781TtXvdPjfrXWWx4EMVhHLMMcVrI21NtBMIa8MZldZihr2wyDEjODFICut9qIlRIhjttVQmGLoE17_e47fpvTscc9vrPB7-79AfEnVKcQ |
CitedBy_id | crossref_primary_10_3389_fphys_2020_00815 crossref_primary_10_37349_ec_2024_00018 crossref_primary_10_1007_s00395_020_0777_3 crossref_primary_10_1007_s10741_020_10042_0 |
ContentType | Journal Article |
Copyright | 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society. |
Copyright_xml | – notice: 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society. |
DBID | CGR CUY CVF ECM EIF NPM |
DOI | 10.1113/JP270354 |
DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed |
DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) |
DatabaseTitleList | MEDLINE |
Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: EIF name: MEDLINE url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search sourceTypes: Index Database |
DeliveryMethod | fulltext_linktorsrc |
Discipline | Anatomy & Physiology |
EISSN | 1469-7793 |
ExternalDocumentID | 26096258 |
Genre | Research Support, Non-U.S. Gov't Journal Article |
GrantInformation_xml | – fundername: British Heart Foundation grantid: PG/13/3/29924 – fundername: NHLBI NIH HHS grantid: T32 HL007955 – fundername: NHLBI NIH HHS grantid: R01 HL075619 |
GroupedDBID | --- -DZ -~X .3N .GA 05W 0R~ 0YM 10A 123 18M 1OB 1OC 24P 29L 2WC 33P 36B 3SF 4.4 50Y 50Z 51W 51X 52M 52N 52O 52P 52R 52S 52T 52U 52V 52W 52X 53G 5GY 5HH 5LA 5RE 5VS 66C 702 7PT 8-0 8-1 8-3 8-4 8-5 8UM 930 A01 A03 AAESR AAEVG AAFWJ AAHHS AANLZ AAONW AASGY AAXRX AAZKR ABCQN ABCUV ABEML ABITZ ABIVO ABJNI ABOCM ABPPZ ABPVW ABQWH ABXGK ACAHQ ACCFJ ACCZN ACFBH ACGFO ACGFS ACGOF ACIWK ACMXC ACNCT ACPOU ACPRK ACSCC ACXBN ACXQS ADBBV ADBTR ADEOM ADIZJ ADKYN ADMGS ADOZA ADXAS ADZMN AEEZP AEGXH AEIGN AEIMD AEQDE AEUQT AEUYR AFBPY AFEBI AFFPM AFGKR AFPWT AFZJQ AHBTC AI. AIACR AIAGR AITYG AIURR AIWBW AJBDE ALAGY ALMA_UNASSIGNED_HOLDINGS ALUQN AMBMR AMYDB AOIJS ATUGU AZBYB AZVAB BAFTC BAWUL BFHJK BHBCM BMXJE BROTX BRXPI BY8 C45 CGR CS3 CUY CVF D-6 D-7 D-E D-F DCZOG DIK DPXWK DR2 DRFUL DRMAN DRSTM E3Z EBS ECM EIF EJD EMOBN EX3 F00 F01 F04 F5P FIJ FUBAC G-S G.N GODZA GX1 H.X HGLYW HZI HZ~ IHE IX1 J0M K48 KBYEO LATKE LC2 LC3 LEEKS LH4 LITHE LOXES LP6 LP7 LUTES LW6 LYRES MEWTI MK4 MRFUL MRMAN MRSTM MSFUL MSMAN MSSTM MXFUL MXMAN MXSTM N04 N05 N9A NF~ NPM O66 O9- OIG OK1 OVD P2P P2W P2X P2Z P4B P4D Q.N Q11 QB0 R.K RIG ROL RPM RX1 SUPJJ TEORI TLM TN5 TR2 UB1 UPT V8K VH1 W8F W8V W99 WBKPD WH7 WIH WIJ WIK WIN WNSPC WOHZO WOQ WOW WQJ WRC WXI WXSBR WYISQ XG1 YBU YHG YKV YQT YSK YZZ ZZTAW ~IA ~WT |
ID | FETCH-LOGICAL-c165t-f69d4d4958b7c82ad601ab5437cc141e6c0d4b652b076ceef82b96fbaea79bfb3 |
IngestDate | Sat Sep 28 08:23:18 EDT 2024 |
IsPeerReviewed | true |
IsScholarly | true |
Issue | 17 |
Language | English |
License | 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society. |
LinkModel | OpenURL |
MergedId | FETCHMERGED-LOGICAL-c165t-f69d4d4958b7c82ad601ab5437cc141e6c0d4b652b076ceef82b96fbaea79bfb3 |
PMID | 26096258 |
ParticipantIDs | pubmed_primary_26096258 |
PublicationCentury | 2000 |
PublicationDate | 2015-Sep-01 |
PublicationDateYYYYMMDD | 2015-09-01 |
PublicationDate_xml | – month: 09 year: 2015 text: 2015-Sep-01 day: 01 |
PublicationDecade | 2010 |
PublicationPlace | England |
PublicationPlace_xml | – name: England |
PublicationTitle | The Journal of physiology |
PublicationTitleAlternate | J Physiol |
PublicationYear | 2015 |
SSID | ssj0013099 |
Score | 2.4531007 |
Snippet | Diastolic dysfunction in heart failure patients is evident from stiffening of the passive properties of the ventricular wall. Increased actomyosin interactions... |
SourceID | pubmed |
SourceType | Index Database |
StartPage | 3899 |
SubjectTerms | Actomyosin - physiology Adenosine Diphosphate - physiology Animals Calcium - physiology Cardiomyopathy, Dilated - physiopathology Creatine Kinase - antagonists & inhibitors Creatine Kinase - physiology Diastole Heart - physiology Humans Iodoacetamide - pharmacology Isometric Contraction Male Myocytes, Cardiac - physiology Rats, Wistar |
Title | Synergistic role of ADP and Ca(2+) in diastolic myocardial stiffness |
URI | https://www.ncbi.nlm.nih.gov/pubmed/26096258 |
Volume | 593 |
hasFullText | 1 |
inHoldings | 1 |
isFullTextHit | |
isPrint | |
link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1LSwMxEA5aL17E91tyUFFkdTebfR1rayk9SKEqvZUkm0AL3YquSP31TrJPxYJ6Wfa9kC_MfDM78wWhU6WARLvStZSymUW5YBYHt2sRPw7t2LEjwkyV773ffaS9oTeslrcy3SUpvxYfP_aV_AdVOAe46i7ZPyBbvhROwD7gC1tAGLa_wngw1517Rmq5LBNstvvmh0ALWGFIzsitjvt1yeuYAc_TktbTOfivlzjrFBkrlRRFGJNq5tR4qsl9fEm-D3T59dgsUHT1xF7FrMwoswlTpjygCY63SvnVqmnqvUEdnc7L2m3ewcy06xkIxytLrMCBZFYTYmyg6dlSh4VZ9fLDfP4ENSupNf0WmG8tI9HrE7BDmbZ0DcXnqYERArAIgrawcmBlWWFxaRmtaF1EWiRvip9KwIZz_WH40E3xGa0HnT_4LbYwHONhHa3lg46bGdIbaEkmm2irmbB0Np3jc9wvodhC7Rr4WIOPZwoD-BjAxy12Qa4u8TjBJey4gh2XsG-jx87dQ6tr5UtiWMLxvdRSfhTTGILakAciJCyGeJpxj7qBEA51pC_smHLfI9wOfOA_KiQ88hVnkgURV9zdQY1klsg9hLnwKA-0dpDklFK4xXVoHEnpKRUGrruPdrOxGD1nuiejYpQOFl45RKvVBDlCjfTlTR4DaUv5iYHiE0hnQPY |
link.rule.ids | 314,780,784,27924,27925 |
linkProvider | National Library of Medicine |
openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Synergistic+role+of+ADP+and+Ca%282%2B%29+in+diastolic+myocardial+stiffness&rft.jtitle=The+Journal+of+physiology&rft.au=Sequeira%2C+Vasco&rft.au=Najafi%2C+Aref&rft.au=McConnell%2C+Mark&rft.au=Fowler%2C+Ewan+D&rft.date=2015-09-01&rft.eissn=1469-7793&rft.volume=593&rft.issue=17&rft.spage=3899&rft_id=info:doi/10.1113%2FJP270354&rft_id=info%3Apmid%2F26096258&rft.externalDocID=26096258 |