AI Article Synopsis
- Aberrant calcium handling is a key issue in heart failure, and understanding its molecular mechanisms is crucial for developing treatments. The study highlights the role of peptidyl-prolyl isomerase 1 (Pin1) as a new regulator of calcium dynamics in heart cells.
- Experiments show that deleting or inhibiting Pin1 slows down the decay of calcium in heart muscle cells, while unexpectedly increasing levels of calcium handling proteins like SERCA2a and Na/Ca exchanger 1, even though their actual activity is reduced.
- The findings suggest that Pin1 interacts directly with these proteins, influencing their function and calcium handling, which might contribute to impaired heart muscle relaxation and could be relevant in tackling heart
Article Abstract
Background: Aberrant Ca handling is a prominent feature of heart failure. Elucidation of the molecular mechanisms responsible for aberrant Ca handling is essential for the development of strategies to blunt pathological changes in calcium dynamics. The peptidyl-prolyl - isomerase peptidyl-prolyl isomerase 1 (Pin1) is a critical mediator of myocardial hypertrophy development and cardiac progenitor cell cycle. However, the influence of Pin1 on calcium cycling regulation has not been explored. On the basis of these findings, the aim of this study is to define Pin1 as a novel modulator of Ca handling, with implications for improving myocardial contractility and potential for ameliorating development of heart failure.
Methods And Results: Pin1 gene deletion or pharmacological inhibition delays cytosolic Ca decay in isolated cardiomyocytes. Paradoxically, reduced Pin1 activity correlates with increased sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) and Na/Ca exchanger 1 protein levels. However, SERCA2a ATPase activity and calcium reuptake were reduced in sarcoplasmic reticulum membranes isolated from Pin1-deficient hearts, suggesting that Pin1 influences SERCA2a function. SERCA2a and Na/Ca exchanger 1 associated with Pin1, as revealed by proximity ligation assay in myocardial tissue sections, indicating that regulation of Ca handling within cardiomyocytes is likely influenced through Pin1 interaction with SERCA2a and Na/Ca exchanger 1 proteins.
Conclusions: Pin1 serves as a modulator of SERCA2a and Na/Ca exchanger 1 Ca handling proteins, with loss of function resulting in impaired cardiomyocyte relaxation, setting the stage for subsequent investigations to assess Pin1 dysregulation and modulation in the progression of heart failure.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721875 | PMC |
| http://dx.doi.org/10.1161/JAHA.117.006837 | DOI Listing |
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