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Multiple reaction monitoring to identify site-specific troponin I phosphorylated residues in the failing human heart.

Abstract：

BACKGROUND:Human cardiac troponin I is known to be phosphorylated at multiple amino acid residues by several kinases. Advances in mass spectrometry allow sensitive detection of known and novel phosphorylation sites and measurement of the level of phosphorylation simultaneously at each site in myocardial samples. METHODS AND RESULTS:On the basis of in silico prediction and liquid chromatography/mass spectrometry data, 14 phosphorylation sites on cardiac troponin I, including 6 novel residues (S4, S5, Y25, T50, T180, S198), were assessed in explanted hearts from end-stage heart failure transplantation patients with ischemic heart disease or idiopathic dilated cardiomyopathy and compared with samples obtained from nonfailing donor hearts (n=10 per group). Thirty mass spectrometry-based multiple reaction monitoring quantitative tryptic peptide assays were developed for each phosphorylatable and corresponding nonphosphorylated site. The results show that in heart failure there is a decrease in the extent of phosphorylation of the known protein kinase A sites (S22, S23) and other newly discovered phosphorylation sites located in the N-terminal extension of cardiac troponin I (S4, S5, Y25), an increase in phosphorylation of the protein kinase C sites (S41, S43, T142), and an increase in phosphorylation of the IT-arm domain residues (S76, T77) and C-terminal domain novel phosphorylation sites of cardiac troponin I (S165, T180, S198). In a canine dyssynchronous heart failure model, enhanced phosphorylation at 3 novel sites was found to decline toward control after resynchronization therapy. CONCLUSIONS:Selective, functionally significant phosphorylation alterations occurred on individual residues of cardiac troponin I in heart failure, likely reflecting an imbalance in kinase/phosphatase activity. Such changes can be reversed by cardiac resynchronization.

journal_name

Circulation

journal_title

Circulation

authors

Zhang P,Kirk JA,Ji W,dos Remedios CG,Kass DA,Van Eyk JE,Murphy AM

doi

10.1161/CIRCULATIONAHA.112.096388

subject

Has Abstract

pub_date

2012-10-09 00:00:00

pages

1828-37

issue

eissn

0009-7322

issn

1524-4539

pii

CIRCULATIONAHA.112.096388

journal_volume

126

pub_type

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Multiple reaction monitoring to identify site-specific troponin I phosphorylated residues in the failing human heart.