Elevated Homocysteine Levels Result in Carbonyl Formation on RyR2 and Enhanced Sensitivity of Sarcoplasmic Reticulum to Activation by Calcium

Abstract

Elevated levels in blood serum of homocysteine (>10µmol/L) is strongly correlated with the incidence of heart failure (HF) in humans. We demonstrate that the cyclic thioester, homocysteine thiolactone (HTL), a metabolic product of homocysteine, at a concentration of 100 nM, results in the formation of carbonyls on the ryanodine receptor from sheep cardiac muscle (RyR2), and an enhancement of Ca2+ dependent activation of ryanodine binding from 129.7 ± 3.4 nM to 102.0 ± 2.7 nM. 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 propose that HTL reacts with lysine residues on RyR2, generating an Ne-homocysteine-protein, which results in carbonyl formation and an enhancement in the Ca2+ sensitivity of RyR2. This is a new molecular mechanism linking elevated levels of Homocysteine, post-translational modification of RyR2, improper Ca2+ handling and heart failure. This work was supported by NIH 1 R41 HL105063-01 to J. Abramson and R. Strongin.