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Excitation-contraction coupling in normal and myopathic hamster hearts III: functional deficiencies in interstitial
Insights
Reduced sialyltransferase activity in heart failure leads to less surface sialic acid, impairing calcium handling and contractility in cardiomyopathic hamsters.
Area of Science:
- Biochemistry
- Cardiology
- Molecular Biology
Background:
- Extracellular calcium (Ca) is crucial for excitation-contraction (E-C) coupling in cardiac muscle.
- Congestive heart failure in cardiomyopathic hamsters shows decreased superficial Ca content and reduced contractility.
Purpose of the Study:
- To investigate the role of surface-bound Ca and sialic acid in cardiac contractility.
- To identify the molecular defect underlying impaired Ca handling in hamster cardiomyopathy.
Main Methods:
- Preparation of cardiac sarcolemmal ghosts from normal and cardiomyopathic hamsters.
- Analysis of Ca binding sites using Scatchard plots.
- Enzyme activity assays for sialyltransferase.
- Measurement of surface sialic acid content.
Main Results:
- Two Ca binding sites were identified in cardiac sarcolemmal ghosts.
- A reduction in sialyltransferase activity was observed in myopathic hearts (1.80 to 0.41 pmol/mg protein).
- Lower sialic acid content correlated with reduced Ca binding capacity and impaired contractility.
Conclusions:
- Reduced sialyltransferase activity leads to decreased surface sialic acid residues in cardiomyopathy.
- This deficiency impairs Ca handling, reduces contractility, and increases Ca influx.
- Increased Ca influx may contribute to "Ca overload" and cellular necrosis in heart failure.
Abstract:
Extracellular and surface bound Ca is essential to excitation-contraction (E-C) coupling in mammalian cardiac muscle. In intact hearts from cardiomyopathic hamster with congestive heart failure, a concomitant decrease in the Ca content of a superficial pool was associated with the reduced contractility. Ca binding to cardiac sarcolemmal ghosts prepared from these hearts revealed two binding sites by Scatchard plot. In normal hamsters, the low affinity site had a capacity of 114 nmol Ca.mg-1 protein, a KD of 1.5 mmol . litre-1 and was sensitive to neuraminidase treatment but not to 100 mmol . litre-1 Na, K, or Li, Ca binding in vitro approached a 1:1 relationship with the sialic acid content of the ghosts, 159 nmol . mg-1 protein. The activity of the enzyme responsible for glycosidically linking sialic acid to interstitial and sarcolemmal glycoproteins, sialyltransferase, was reduced from 1.80 to 0.41 pmol . mg-1 protein in the myopathic hearts. We suggest the functional defect in the hamster cardiomyopathy is a reduction in sialyltransferase activity leading to the deficiency in surface sialic acid residues. As a consequence, contractility is reduced, but Ca influx is increased. Reflex sympathetic activity increases Ca influx resulting in "Ca overload" and eventual cellular necrosis.