Impaired Ca2+-ATPase oligomerization and increased phospholamban expression in dilated cardiomyopathy.

Abstract

Although primary genetic defects have been identified for some forms of inherited cardiomyopathy, it is not well understood how secondary abnormalities actually lead to muscle cell destruction. Since cardiomyopathies significantly influence morbidity and mortality rates world-wide, it is important to improve the differential diagnosis of these disorders and develop potential treatments for inherited diseases of the heart. Elucidation of the secondary molecular mechanisms underlying cardiac cell necrosis might help linking a specific mutation in a cardiac gene to acute heart failure. As disturbed Ca2+-homeostasis may contribute to heart failure, we have investigated the relative abundance and oligomeric status of the sarcoplasmic reticulum Ca2+-ATPase and phospholamban in various cardiomyopathies. These two proteins represent important factors in cardiac relaxation. The SERCA2 isoform of the Ca2+-ATPase represents a major Ca2+-removal system in cardiac muscle fibres and phospholamban is a regulator of Ca2+-pump activity. Although Ca2+-ATPase expression did not seem to be markedly altered, the comparative immunoblot analysis presented here clearly shows that phospholamban expression is increased in dilated cardiomyopathy, possibly explaining the decreased Ca2+-uptake in the disease. In contrast to the normal enzyme, the Ca2+-pump was demonstrated to exhibit an impairment of crosslinker-stabilized oligomerization in dilated cardiomyopathy. Since Ca2+-ATPase oligomerization is important for co-operative kinetics and protection against proteolytic degradation, the monomeric Ca2+-ATPase may trigger an abnormal contraction-relaxation cycle in dilated cardiomyopathy leading to heart failure.