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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
Published on: September 18, 2017
Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with
Regis R Lamberts1, Shivanjali J Lingam, Heng-Yu Wang
1Department of Physiology - HeartOtago, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand. regis.lamberts@otago.ac.nz.
Insights
Diabetic heart muscle shows increased fibrosis and impaired relaxation, particularly under stress. Compensatory calcium handling mechanisms attempt to maintain diastolic function despite these changes.
Area of Science:
- Cardiology
- Diabetology
- Molecular Biology
Background:
- Diastolic dysfunction is a significant complication of diabetes, yet its human mechanisms are unclear.
- Diabetes-associated cardiac dysfunction involves impaired myocardial contraction and relaxation.
- Understanding these mechanisms is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the mechanisms of diastolic dysfunction in human type 2 diabetes.
- To measure myocardial contraction, relaxation, calcium-handling protein expression, and fibrosis in diabetic patients.
- To assess the impact of diabetes on myocardial response to beta-adrenergic stimulation.
Main Methods:
- Analysis of right atrial appendages from type 2 diabetes mellitus (DM) and non-diabetic (non-DM) patients undergoing coronary artery bypass grafting (CABG).
- Measurement of basal and beta-adrenergic stimulated myocardial function in isolated cardiac trabeculae.
- Western blot analysis of calcium-handling proteins (SERCA2a, PLB) and beta1-adrenoreceptors.
- Picro-sirius red staining to quantify collagen deposition (fibrosis).
Main Results:
- Diabetic trabeculae exhibited preserved contractile function but prolonged relaxation (increased Tau).
- Increased SERCA2a and decreased PLB expression were observed in diabetic myocardium, suggesting accelerated calcium reuptake.
- Diabetic samples showed increased collagen deposition and unresponsiveness to beta-adrenergic stimulation.
Conclusions:
- Human type 2 diabetic atrial myocardium presents with increased fibrosis and impaired relaxation, especially under beta-adrenergic challenge.
- Altered calcium-handling protein expression suggests a compensatory mechanism to maintain diastolic function at rest.
- The study provides insights into diabetes-associated diastolic dysfunction, guiding future therapeutic development.
Background:
Diastolic dysfunction is a key factor in the development and pathology of cardiac dysfunction in diabetes, however the exact underlying mechanism remains unknown, especially in humans. We aimed to measure contraction, relaxation, expression of calcium-handling proteins and fibrosis in myocardium of diabetic patients with preserved systolic function.
Methods:
Right atrial appendages from patients with type 2 diabetes mellitus (DM, n = 20) and non-diabetic patients (non-DM, n = 36), all with preserved ejection fraction and undergoing coronary artery bypass grafting (CABG), were collected. From appendages, small cardiac muscles, trabeculae, were isolated to measure basal and β-adrenergic stimulated myocardial function. Expression levels of calcium-handling proteins, sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and phospholamban (PLB), and of β1-adrenoreceptors were determined in tissue samples by Western blot. Collagen deposition was determined by picro-sirius red staining.
Results:
In trabeculae from diabetic samples, contractile function was preserved, but relaxation was prolonged (Tau: 74 ± 13 ms vs. 93 ± 16 ms, non-DM vs. DM, p = 0.03). The expression of SERCA2a was increased in diabetic myocardial tissue (0.75 ± 0.09 vs. 1.23 ± 0.15, non-DM vs. DM, p = 0.007), whereas its endogenous inhibitor PLB was reduced (2.21 ± 0.45 vs. 0.42 ± 0.11, non-DM vs. DM, p = 0.01). Collagen deposition was increased in diabetic samples. Moreover, trabeculae from diabetic patients were unresponsive to β-adrenergic stimulation, despite no change in β1-adrenoreceptor expression levels.
Conclusions:
Human type 2 diabetic atrial myocardium showed increased fibrosis without systolic dysfunction but with impaired relaxation, especially during β-adrenergic challenge. Interestingly, changes in calcium-handling protein expression suggests accelerated active calcium re-uptake, thus improved relaxation, indicating a compensatory calcium-handling mechanism in diabetes in an attempt to maintain diastolic function at rest despite impaired relaxation in the diabetic fibrotic atrial myocardium. Our study addresses important aspects of the underlying mechanisms of diabetes-associated diastolic dysfunction, which is crucial to developing new therapeutic treatments.
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