S-Homocysteinylated Proteins - Homocysteine in Protein Structure/Function and Human Disease - page 122

However, only creatinine is a positive determinant of S-Hcy-ApoB in CKD
patients. Lipid-lowering therapy causes a 31 % decrease in S-linked ApoB thiols,
including a 40 % decrease in S-Hcy-ApoB [422]. The decreased levels of protein
bound thiols are most likely a consequence of oxidative stress improvement as
assessed by measurements of plasma malondialdehyde levels and allantoin/uric
acid ratios during the therapy. S-Hcy-ApoB-100 and S-Cys-ApoB-100 are also
significantly elevated in acute myocardial infarction patients [423].
Lipoprotein [a] (Lp[a]) is a lipoprotein that consists of LDL and apolipoprotein
[a] (apo[a]), disulfide-linked to the apoB-100 moiety of LDL [419]. Lp[a], in
contrast to LDL, does not bind to the LDL receptor, but the reduction and removal
of apo[a] restores the affinity of the remaining LDL for the receptor to normal levels
[424]. Apo(a) shares remarkable structural homology to plasminogen and binds to
plasmin-modified fibrin surface. Its ability to compete with plasminogen for bind-
ing sites on fibrin in clots may be responsible for the association of Lp[a] with
increased risk for cardiovascular disease [425-428]. Lp[a] colocalizes with fibrin in
atherosclerotic lesions and is physically associated with fibrin in the arterial wall
[429].
The single disulfide bond between apo[a] and ApoB-100 is susceptible to
reduction by Hcy and other sulfhydryls in vitro. Incubation of Lp[a] with thiols
increases its binding to plasmin-treated fibrin, but not to other proteins [430]. DTT
is more effective than Hcy, cysteine, N-acetyl-Cys, or GSH in enhancing the
binding. The binding is specific to Lp[a], as shown by the inability of Hcy to affect
the binding of LDL or plasminogen to fibrin. Although it does not alter the
molecular weight of Lp[a] on gel filtration, Hcy partially reduces Lp[a] [430].
Thus, Hcy and other thiols alter the Lp[a] particle and increase the reactivity of
the plasminogen-like apo[a] portion of the molecule.
However, it is not known whether Lp[a] is modified by Hcy in vivo, in particular
in patients with hyperhomocysteinemia. Free apo[a] is elevated in patients with
nephrotic syndrome and in patients undergoing peritoneal dialysis, relative to
normal control subjects, but there is no relationship between apo[a] and plasma
tHcy [428].
7.2 Extracellular Matrix Proteins
7.2.1 Fibrillins
Fibrillin-1, fibrillin-2, and fibrillin-3, modular 350-kDa calcium-binding
glycoproteins, are major components of 10-12-nm microfibrils in the extracellular
matrix [431]. They serve as a scaffold for the deposition of elastin and the formation
of the elastic fibers. The structure of fibrillin-1 is dominated by two types of
disulfide-rich motifs, the calcium-binding epidermal growth factor-like (cbEGF)
and transforming growth factor beta binding protein-like (TB) domains. With its