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Human SERCA2a levels correlate inversely with age in senescent human myocardium
Open accessAbstract
Objectives This study sought to characterize functional impairment after simulated ischemia-reperfusion (I/R) or Ca2+ bolus in senescent human myocardium and to determine if age-related alterations in myocardial concentrations of SERCA2a, phospholamban, or calsequestrin participate in senescent myocardial dysfunction.Background Candidates for elective cardiac interventions are aging, and an association between age and impairment of relaxation has been reported in experimental animals. Function of the sarcoplasmic reticulum resulting in diastolic dysfunction could be dysregulated at the level of cytosolic Ca2+ uptake by SERCA2a, its inhibitory subunit (phospholamban), or at the level of Ca2+ binding by calsequestrin.Methods Human atrial trabeculae from 17 patients (45-75 years old) were suspended in organ baths, field simulated at 1 Hz, and force development was recorded during I/R (45/120 min). Trabeculae from an additional 12 patients (53-73 years old) were exposed to Ca2+ bolus (2-3 mmol/L bath concentration). Maximum +/- dF/dt and the time constant of force decay (tau) were measured before and after I/R or Ca2+ bolus and related to age. SERCA2a, phospholamban, and calsequestrin from 12 patients (39-77 years old) were assessed by immunoblot.Results Functional results indicated that maximum +/-dF/dt and tau were prolonged in senescent (>60 years) human myocardium after I/R (p < 0.05). Calcium bolus increased the maximum +/-dF/dt and decreased tau in younger, but not older patients (p < 0.05). SERCA2a and the ratio of SERCA2a to either phospholamban or calsequestrin were decreased in senescent human myocardium (p < 0.05).Conclusions Senescent human myocardium exhibits decreased myocardial SERCA2a content with age, which may, in part, explain impaired myocardial function after either I/R or Ca2+ exposure.
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“Furthermore, SERCA2a protein levels were found to be significantly decreased in senescent human myocardium that is characterized by HFpEF, 50 which was associated with myocardial function impairment at baseline that was exacerbated by hypoxic conditions and higher heart rates.[51][52][53]”
From Reversal of contractile defects by mediating calcium homeostasis in human mini-heart models of heart failure with preserved ejection fraction (HFpEF) leads to first-in-human gene therapy clinical trial (2024) · cites this paper as [50]
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Metadata
- Authors
- Cain, B. S., Meldrum, D. R., Joo, K. S., Wang, J.-F., Meng, X., Cleveland, J. C., Banerjee, A., & Harken, A. H.
- Corresponding author
- Cain, Brian S
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 1998-08
- Volume
- 32
- Issue
- 2
- Pages
- 458-467
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2032602706
- Cited by
- 129
- References
- 77
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 2 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 3 · 2015: 3 · 2014: 6 · 2013: 2 · 2012: 4
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29hl043696-03, 5r01hl044186-04)
- National Heart, Lung, and Blood Institute (HL-44186, HL 43696)
- National Institute of General Medical Sciences (GM 08315, T32GM008315)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- SERCA2a, cardiac aging, sarcoplasmic reticulum, phospholamban, calsequestrin, ischemia-reperfusion injury, diastolic dysfunction, calcium uptake
- MeSH terms
- Phospholamban, Calcium-Transporting ATPases, Adult, Aged, Aging, Analysis of Variance, Calcium, Calcium-Binding Proteins, Calsequestrin, Cytosol, Diastole, Dose-Response Relationship, Drug, Female, Heart Atria, Humans, Male, Middle Aged, Myocardial Contraction, Myocardium, Sarcoplasmic Reticulum, Blotting, Western, Cohort Studies, Myocardial Reperfusion, Linear Models, Myocardial Ischemia
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