Abstract:
:Changes in the nonischemic remote myocardium of the heart contribute to left ventricular dysfunction after ischemia and reperfusion (I/R). Understanding the underlying mechanisms early after I/R is crucial to improve the adaptation of the viable myocardium to increased mechanical demands. Here, we investigated the role of myocyte Ca2+ handling in the remote myocardium 24 h after 60 min LAD occlusion. Cardiomyocytes isolated from the basal noninfarct-related parts of wild type mouse hearts demonstrated depressed beat-to-beat Ca2+ handling. The amplitude of the Ca2+ transients as well as the kinetics of Ca2+ transport were reduced by up to 25%. These changes were associated with impaired sarcomere contraction. While expression levels of Ca2+ regulatory proteins were unchanged in remote myocardium compared to the corresponding regions of sham-operated hearts, mobility shift analyses of phosphorylated protein showed 2.9 ± 0.4-fold more unphosphorylated phospholamban (PLN) monomers, the PLN species that inhibits the Ca2+ ATPase SERCA2a (P ≤ 0.001). Phospho-specific antibodies revealed normal phosphorylation of PLN at T17 in remote myocardium, but markedly reduced phosphorylation at its PKA-dependent phosphorylation site, S16 (P ≤ 0.01). The underlying cause involved enhanced activity of protein phosphatases, particularly PP2A (P ≤ 0.01). In contrast, overall PKA activity was normal. The PLN interactome, as determined by co-immunoprecipitation and mass spectrometry, and the phosphorylation state of PKA targets other than PLN were also unchanged. Isoproterenol enhanced cellular Ca2+ cycling much stronger in remote myocytes than in healthy controls and improved sarcomere function. We conclude that the reduced phosphorylation state of PLN at S16 impairs myocyte Ca2+ cycling in the remote myocardium 24 h after I/R and contributes to contractile dysfunction.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Kronenbitter A,Funk F,Hackert K,Gorreßen S,Glaser D,Boknik P,Poschmann G,Stühler K,Isić M,Krüger M,Schmitt JPdoi
10.1016/j.yjmcc.2018.04.004subject
Has Abstractpub_date
2018-06-01 00:00:00pages
28-39eissn
0022-2828issn
1095-8584pii
S0022-2828(18)30099-3journal_volume
119pub_type
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