PMID- 38474037
OWN - NLM
STAT- MEDLINE
DCOM- 20240314
LR  - 20240315
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 25
IP  - 5
DP  - 2024 Feb 28
TI  - Protein Kinase D Plays a Crucial Role in Maintaining Cardiac Homeostasis by 
      Regulating Post-Translational Modifications of Myofilament Proteins.
LID - 10.3390/ijms25052790 [doi]
LID - 2790
AB  - Protein kinase D (PKD) enzymes play important roles in regulating myocardial 
      contraction, hypertrophy, and remodeling. One of the proteins phosphorylated by 
      PKD is titin, which is involved in myofilament function. In this study, we aimed 
      to investigate the role of PKD in cardiomyocyte function under conditions of 
      oxidative stress. To do this, we used mice with a cardiomyocyte-specific 
      knock-out of Prkd1, which encodes PKD1 (Prkd1(loxP/loxP); (alphaMHC-Cre); PKD1 cKO), 
      as well as wild type littermate controls (Prkd1(loxP/loxP); WT). We isolated 
      permeabilized cardiomyocytes from PKD1 cKO mice and found that they exhibited 
      increased passive stiffness (F(passive)), which was associated with increased 
      oxidation of titin, but showed no change in titin ubiquitination. Additionally, 
      the PKD1 cKO mice showed increased myofilament calcium (Ca(2+)) sensitivity 
      (pCa(50)) and reduced maximum Ca(2+)-activated tension. These changes were 
      accompanied by increased oxidation and reduced phosphorylation of the small 
      myofilament protein cardiac myosin binding protein C (cMyBPC), as well as altered 
      phosphorylation levels at different phosphosites in troponin I (TnI). The 
      increased F(passive) and pCa(50), and the reduced maximum Ca(2+)-activated 
      tension were reversed when we treated the isolated permeabilized cardiomyocytes 
      with reduced glutathione (GSH). This indicated that myofilament protein oxidation 
      contributes to cardiomyocyte dysfunction. Furthermore, the PKD1 cKO mice 
      exhibited increased oxidative stress and increased expression of pro-inflammatory 
      markers interleukin (IL)-6, IL-18, and tumor necrosis factor alpha (TNF-alpha). Both 
      oxidative stress and inflammation contributed to an increase in 
      microtubule-associated protein 1 light chain 3 (LC3)-II levels and heat shock 
      response by inhibiting the mammalian target of rapamycin (mTOR) in the PKD1 cKO 
      mouse myocytes. These findings revealed a previously unknown role for PKD1 in 
      regulating diastolic passive properties, myofilament Ca(2+) sensitivity, and 
      maximum Ca(2+)-activated tension under conditions of oxidative stress. Finally, 
      we emphasized the importance of PKD1 in maintaining the balance of oxidative 
      stress and inflammation in the context of autophagy, as well as cardiomyocyte 
      function.
FAU - Herwig, Melissa
AU  - Herwig M
AUID- ORCID: 0000-0003-3245-5504
AD  - Department of Cellular and Translational Physiology, Institute of Physiology, 
      Ruhr University Bochum, 44801 Bochum, Germany.
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, 
      44791 Bochum, Germany.
FAU - Begovic, Merima
AU  - Begovic M
AD  - Department of Cellular and Translational Physiology, Institute of Physiology, 
      Ruhr University Bochum, 44801 Bochum, Germany.
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, 
      44791 Bochum, Germany.
FAU - Budde, Heidi
AU  - Budde H
AD  - Department of Cellular and Translational Physiology, Institute of Physiology, 
      Ruhr University Bochum, 44801 Bochum, Germany.
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, 
      44791 Bochum, Germany.
FAU - Delalat, Simin
AU  - Delalat S
AD  - Department of Cellular and Translational Physiology, Institute of Physiology, 
      Ruhr University Bochum, 44801 Bochum, Germany.
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, 
      44791 Bochum, Germany.
FAU - Zhazykbayeva, Saltanat
AU  - Zhazykbayeva S
AD  - Department of Cellular and Translational Physiology, Institute of Physiology, 
      Ruhr University Bochum, 44801 Bochum, Germany.
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, 
      44791 Bochum, Germany.
FAU - Sieme, Marcel
AU  - Sieme M
AD  - Department of Cellular and Translational Physiology, Institute of Physiology, 
      Ruhr University Bochum, 44801 Bochum, Germany.
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, 
      44791 Bochum, Germany.
FAU - Schneider, Luca
AU  - Schneider L
AUID- ORCID: 0009-0003-9612-7574
AD  - Department of Cellular and Translational Physiology, Institute of Physiology, 
      Ruhr University Bochum, 44801 Bochum, Germany.
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, 
      44791 Bochum, Germany.
FAU - Jaquet, Kornelia
AU  - Jaquet K
AD  - Department of Cellular and Translational Physiology, Institute of Physiology, 
      Ruhr University Bochum, 44801 Bochum, Germany.
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, 
      44791 Bochum, Germany.
FAU - Mugge, Andreas
AU  - Mugge A
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, 
      44791 Bochum, Germany.
AD  - Department of Cardiology and Angiology, Bergmannsheil University Hospitals, UK 
      RUB, Ruhr University Bochum, 44789 Bochum, Germany.
FAU - Akin, Ibrahim
AU  - Akin I
AD  - Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, 
      University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg 
      University, 68167 Mannheim, Germany.
FAU - El-Battrawy, Ibrahim
AU  - El-Battrawy I
AD  - Department of Cellular and Translational Physiology, Institute of Physiology, 
      Ruhr University Bochum, 44801 Bochum, Germany.
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology and Angiology, Bergmannsheil University Hospitals, UK 
      RUB, Ruhr University Bochum, 44789 Bochum, Germany.
FAU - Fielitz, Jens
AU  - Fielitz J
AUID- ORCID: 0000-0001-8522-1045
AD  - Department of Molecular Cardiology, DZHK (German Center for Cardiovascular 
      Research), Partner Site, 17475 Greifswald, Germany.
AD  - Department of Internal Medicine B, Cardiology, University Medicine Greifswald, 
      17475 Greifswald, Germany.
FAU - Hamdani, Nazha
AU  - Hamdani N
AUID- ORCID: 0000-0002-3053-0008
AD  - Department of Cellular and Translational Physiology, Institute of Physiology, 
      Ruhr University Bochum, 44801 Bochum, Germany.
AD  - Institut fur Forschung und Lehre (IFL), Molecular and Experimental Cardiology, 
      Ruhr University Bochum, 44791 Bochum, Germany.
AD  - Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, 
      44791 Bochum, Germany.
AD  - Department of Physiology, University Maastricht, 6211 LK Maastricht, The 
      Netherlands.
AD  - HCEMM-SU Cardiovascular Comorbidities Research Group, Department of Pharmacology 
      and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary.
LA  - eng
GR  - HA 7512/2-4/Deutsche Forschungsgemeinschaft/
GR  - HA 7512/2-1/Deutsche Forschungsgemeinschaft/
GR  - 739593/EU's Horizon 2020 research and innovation program/
GR  - IF-023-22/InnovationsForum program of the Medical Faculty, RUB/
GR  - IF-034-22/InnovationsForum program of the Medical Faculty, RUB/
GR  - FI 965/9-1/Deutsche Forschungsgemeinschaft/
GR  - FI 965/10-1/Deutsche Forschungsgemeinschaft/
GR  - DZHK 81Z5400153/German Center for Cardiovascular Research, partner site 
      Greifswald/
PT  - Journal Article
DEP - 20240228
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - EC 2.7.10.- (protein kinase D)
RN  - 0 (Connectin)
RN  - 0 (Microfilament Proteins)
RN  - SY7Q814VUP (Calcium)
RN  - EC 2.7.11.13 (Protein Kinase C)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Connectin/metabolism
MH  - *Myofibrils/metabolism
MH  - *Protein Processing, Post-Translational
MH  - Myocytes, Cardiac/metabolism
MH  - Phosphorylation
MH  - Microfilament Proteins/metabolism
MH  - Homeostasis
MH  - Inflammation/metabolism
MH  - Calcium/metabolism
MH  - Mammals/metabolism
MH  - *Protein Kinase C
PMC - PMC10932171
OTO - NOTNLM
OT  - autophagy
OT  - inflammation
OT  - myofilament proteins
OT  - protein kinase D
OT  - protein oxidation
COIS- The authors declare no conflict of interest.
EDAT- 2024/03/13 06:46
MHDA- 2024/03/14 06:47
PMCR- 2024/02/28
CRDT- 2024/03/13 01:23
PHST- 2024/01/09 00:00 [received]
PHST- 2024/02/21 00:00 [revised]
PHST- 2024/02/25 00:00 [accepted]
PHST- 2024/03/14 06:47 [medline]
PHST- 2024/03/13 06:46 [pubmed]
PHST- 2024/03/13 01:23 [entrez]
PHST- 2024/02/28 00:00 [pmc-release]
AID - ijms25052790 [pii]
AID - ijms-25-02790 [pii]
AID - 10.3390/ijms25052790 [doi]
PST - epublish
SO  - Int J Mol Sci. 2024 Feb 28;25(5):2790. doi: 10.3390/ijms25052790.