Clinical Studies
Human SERCA2a levels correlate inversely with age in senescent human myocardium

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Abstract

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 tauin 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.

Abbreviations

SERCA2a
sarcoendoplasmic reticulum Ca2+-ATPase
I/R
ischemia-reperfusion
T
tau, the time constant of force decay
SI
simulated ischemia
[Ca2+]i
intramyocellular calcium
CAD
coronary artery disease
HTN
hypertension
IDDM
insulin-dependent diabetes mellitus
NIDDM
non–insulin-dependent diabetes mellitus
GERD
gastro-esophageal reflux disease
COPD
chronic obstructive pulmonary disease
CHF
congestive heart failure
LAD
left anterior descending coronary artery
RCA
right coronary artery
Cx
circumflex coronary artery
LVEF
left ventricular ejection fraction

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This work was supported in part by National Institutes of Health Grants HL-43696, HL-44186, and GM-08315.