First Advisor

Jonathan Abramson

Date of Publication

Fall 11-14-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Physics

Department

Physics

Language

English

Subjects

Homocysteine, Ryanodine -- Receptors, Sarcoplasmic reticulum

DOI

10.15760/etd.2070

Physical Description

1 online resource (vii, 57 pages)

Abstract

Elevated levels in blood serum (≥10μmol/L) of the amino acid homocysteine is strongly correlated with the incidence of heart failure (HF). We present evidence that the cyclic thioester, homocysteine thiolactone (HTL), a metabolic product of homocysteine, irreversibly modifies proteins that regulate the contractile process in cardiac muscle. Two proteins found in the sarcoplasmic reticulum (SR), the Ca2+ pump (SERCA2), and the ryanodine receptor (RyR2), are responsible for controlling the cytosolic Ca2+ concentration and hence the contractile state of the heart. While both improper Ca2+ handling and elevated homocysteine levels have been considered bio-markers in HF, a direct connection between the two has not previously been made. We show that HTL reacts with lysine residues on RyR2, generating a Nε-homocysteine-protein, which results in carbonyl formation and a change in the Ca2+ sensitivity of RyR2. This is a new molecular mechanism linking elevated levels of Homocysteine, improper Ca2+ handling and heart failure. This work was supported by NIH 1 R41 HL105063-01 to J. Abramson and R. Strongin.

Rights

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Persistent Identifier

http://archives.pdx.edu/ds/psu/13164

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