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

Although primary genetic defects have been identified for some forms of inh erited cardiomyopathy, it is not well understood how secondary abnormalitie s actually lead to muscle cell destruction. Since cardiomyopathies signific antly influence morbidity and mortality rates worldwide, it is important to improve the differential diagnosis of these disorders and develop potentia l treatments for inherited diseases of the heart. Elucidation of the second ary molecular mechanisms underlying cardiac cell necrosis might help linkin g a specific mutation in a cardiac gene to acute heart failure. As disturbe d Ca2+-homeostasis may contribute to heart failure, we have investigated th e relative abundance and oligomeric status of the sarcoplasmic reticulum Ca 2+-ATPase and phospholamban in various cardiomyopathies. These two proteins represent important factors in cardiac relaxation. The SERCA2 isoform of t he Ca2+-ATPase represents a major Ca2+-removal system in cardiac muscle fib res and phospholamban is a regulator of Ca2+-pump activity. Although Ca2+-A TPase expression did not seem to be markedly altered, the comparative immun oblot analysis presented here clearly shows that phospholamban expression i s increased in dilated cardiomyopathy, possibly explaining the decreased Ca 2+-uptake in the disease. In contrast to the normal enzyme, the Ca2+-pump w as demonstrated to exhibit an impairment of crosslinker-stabilized oligomer ization in dilated cardiomyopathy. Since Ca2+-ATPase oligomerization is imp ortant for co-operative kinetics and protection against proteolytic degrada tion, the monomeric Ca2+-ATPase may trigger an abnormal contraction-relaxat ion cycle in dilated cardiomyopathy leading to heart failure.