Polymorphic SERCA2a variants do not account for inter-individual differences in phospholamban-SERCA2a interactions in human heart failure

Autor: Luke Pater, Kobra Haghighi, Evangelia G. Kranias, Beate Frank, Gerald W. Dorn, Richard A. Walsh, Albrecht Schmidt
Rok vydání: 2003
Předmět:
Zdroj: Journal of molecular and cellular cardiology. 35(7)
ISSN: 0022-2828
Popis: Heart failure is a worldwide public health problem. Despite significant improvements in the management of congestive heart failure, morbidity and mortality rates remain high with a 5-year mortality rate approaching 50% [1]. The syndrome of heart failure is a common complication that ensues from a wide variety of cardiovascular pathologies, including coronary artery disease, cardiomyopathy, valvular heart disease, or congenital malformations [2]. Despite the multiplicity of inciting mechanisms, the response of the heart to these diverse events indicates that only a few molecules are critical for monitoring myocyte malfunction [2]. Among these, calcium is the most crucial ion for regulation of both cardiac excitation-contraction coupling and remodeling [3,4]. In turn, calcium itself is under the regulatory control of the sarcoplasmic reticulum (SR). Evidence from several laboratories indicates that SR-calcium cycling is depressed in heart failure, and this may have a prominent role in the progression of the disease. Specifically, decreases in SRcalcium uptake, elicited by either depressed SR-CaATPase (SERCA2a) levels or increased inhibition by phospholamban (PLN), have been suggested to contribute to SR dysfunction in failing hearts [5,6]. Moreover, recent studies indicate that inhibition of the SERCA2a-PLN interaction may prevent the progression of dilated cardiomyopathy [7,8]. The regions of SERCA2a proposed to interact with PLN [9] involve transmembrane helices M2 (AA 88–107; exon 4), M4 (AA 292–321; exon 8), M6 (AA 786–811; exon 16) [10], and M9 (AA 928–950; exon 20), and a cytoplasmic site, involving the sequence (AA 397–402) Lys-Asp-Asp-LysPro-Val (exon 11) [11] in the nucleotide-binding domain, adjacent to the phosphorylation domain. The loop between transmembrane helices M6 and M7 (AA 809–831; exon 16) has been shown to have indirect effects on the interaction between PLN and SERCA2a [12]. In addition, transmembrane helices M5 (AA 765–785; exons 15 and 16), M6 (AA 786–811; exon 16), and M8 (AA 893–918; exons 18 and 19), which form the Ca-binding and -translocation domains, may modulate the interaction between SERCA2a and PLN [13,14]. However, there are currently no reports on naturally occurring mutations in the human SERCA2a gene, which may modify this interaction and predispose to the development of heart failure, similar to mutations found in cytoskel> The peer review of this manuscript was handled by consulting editor, Stephen F. Watner, M.D. * Corresponding author. Tel.: +1-513-558-2327; fax: +1-513-558-2269. E-mail address: litsa.kranias@uc.edu (E.G. Kranias). Table 1 Clinical characteristics of patients with heart failure
Databáze: OpenAIRE
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