Molecular targeting of proteins by homocysteine: implications in familial and clinical hypercholesterolemia

Cardiovascular diseases (CVDs) are one of the leading causes of death and disability worldwide and one of its underlying causes is hypercholesterolemia. Hypercholesterolemia can have genetic (familial hypercholesterolemia, FH) and non-genetic causes (clinical hypercholesterolemia, CH), the first much more severe, with occurrence of premature atherosclerosis. While the pathophysiological role of homocysteine (Hcy) on CVD is still controversial, molecular targeting of protein by S and N-homocysteinylation offers a new paradigm to be considered in the vascular pathogenesis of hypercholesterolemia. On this regard, the present study aims to give new insights on protein targeting by Hcy in both CH and FH conditions. A total of 187 subjects were included: 65 normolipidemic and 122 hypercholesterolemic. Total (tHcy) and free (fHcy) fractions were quantified in serum samples after validation of an HPLCFD method, to assess S-homocysteinylation. Also, the lactonase (LACase) activity of paraoxonase-1 (PON1) was quantified by a colorimetric assay, as a surrogate of N-homocysteinylation. tHcy does not differ among groups. Nevertheless, fHcy declines in the hypercholesterolemic groups, with more evidence to the FH population. Consequently, there seems to be an increase of Shomocysteinylation, regardless of lipid lowering therapy (LLT). Also, despite of LLT use, LACase activity is lower in FH, thus the risk for protein N-homocysteinylation seems to be higher. Moreover, the decrease in LACase/ApoA1 and LACase/HDL ratios in FH, shows that HDL is dysfunctional in this population, despite its normal concentration values. Data supports that the pathophysiological role of Hcy on hypercholesterolemia may reside in its ability to post-translationally modify proteins. This role is particularly evident in FH condition. In the future, it will be interesting to identify which target proteins are modified and thus involved in vascular pathology progression.