N-Homocysteinyl-Proteins - Homocysteine in Protein Structure/Function and Human Disease - page 72

5.3.1.5 Clinical Significance

Nε -Hcy-Lys levels are elevated under pathological conditions such as human renal

disease, peripheral artery disease, and CBS deficiency, as well as mouse Cbs or
Mthfr deficiency, suggesting increased turnover of N-Hcy-protein in these
pathologies. Plasma Nε

-Hcy-Lys comprises 0.7-1.2 and 0.7-4.4 % of plasma
tHcy or 15.5-17.5 and 8.5-35 % of plasma protein N-linked Hcy in humans
(renal disease or CBS-deficient patients) and mice, respectively. In healthy
human subjects Nε

-Hcy-Lys comprises < 1.2 % of plasma tHcy or < 12.7 % of

plasma protein N-linked Hcy. Thus, plasma Nε -Hcy-Lys levels are higher in mice

than in humans, most likely reflecting higher Hcy-thiolactone [93] and protein N-
linked Hcy [113] levels in mice compared with humans.
Nε

-Hcy-Lys is significantly elevated in acute myocardial infarction patients
compared with controls [86]. Its formation is linked with the nitric oxide synthase
inhibitor asymmetric dimethylarginine (ADMA), consistent with the origin of both
Nε -Hcy-Lys and ADMA as products of protein turnover (Fig. 5.5 ). Surprisingly, the

isopeptide Nε

-Hcy-Lys levels are not associated with plasma tHcy or vitamin B 12
and folate. Moreover, Nε -Hcy-Lys levels show no correlation with titers of anti-N-

Hcy-protein autoantibodies or with IL-6-mediated inflammation, oxidative stress,
and thrombin generation. These findings suggest that Nε -Hcy-Lys is a new marker

of acute myocardial infarction independently of Hcy-related metabolites and

cofactors [86].
Nε -Hcy-Lys isopeptide is associated with progression of peripheral artery

disease in patients treated with folic acid for 12 months [313]. Folic acid
administration decreases plasma tHcy by 70.5 %. However, despite decrease in
tHcy, serum N ɛ -Hcy-Lys is still detectable in 28 (21.4 %) of those patients on

folic acid who were current

smokers and survivors of ischemic stroke

(p < 0.001).

-Hcy-Lys is detected in 17.3 % of patients on long-term hemodialysis, but
not in control subjects [314]. Hemodialysis patients have 3.1-fold lower PON1
activity measured with

Nε

paraoxon (p < 0.0001), 20 % higher ADMA

(p < 0.0001), 30 % higher PAI-1 (p < 0.0001), and 10 % lower total cholesterol

(p ¼ 0.001) and LDL-cholesterol (p < 0.0001), together with 20 % lower

triglycerides (p < 0.0001) compared with subjects without detectable Nε -Hcy-

Lys. In hemodialysis patients Nε -Hcy-Lys levels correlate with paraoxonase 1

activity (r ¼0.62, p < 0.0001), ADMA (r ¼ 0.58, p < 0.0001), and PAI-1
(r ¼ 0.59, p < 0.0001). These findings suggest that in hemodialysis patients,

Nε -Hcy-Lys is associated with lipid profile, endothelial dysfunction, and

impaired fibrinolysis [314].