Homocysteine induces synthesis of a serine elastase in arterial smooth muscle cells from multi-organ donors.
OBJECTIVE
In heart transplant recipients with diffuse coronary arteriopathy, we have previously demonstrated the prevalence of elevated homocysteinemia, also known as an independent risk factor for myocardial infarction and stroke. In hyperhomocysteinemic mini-pigs we also observed early detectable pathologic changes in the elastic laminae. We hypothesized that homocysteine causes premature breakdown in the arterial elastic fibers by activation of the elastolytic activities.


METHODS
We examined the effect of homocysteine on elastase-like production by smooth muscle cells from sub-inguinal arteries of multi-organ donors (23.4 +/- 3.4 yr, n = 8). The freshly isolated cells were incubated for 0-72 h with homocysteine (0-250 microM), in the presence or absence of specific protease inhibitors.


RESULTS
Homocysteine was devoid of a direct effect, but after 18 h incubation the elastase-like activities increased by 5-6-fold in the extracellular medium. The enzymes were characterized as serine proteases. Incubation of cells with a nucleic acid synthesis inhibitor (actinomycin D) or a protein synthesis inhibitor (cycloheximide) suppressed the enzyme induction.


CONCLUSIONS
This is the first report of serine protease induction by homocysteine in vascular smooth muscle cells. The process may require protein synthesis and account for the early alterations of the arterial elastic structures in heart transplant recipients, and in other hyperhomocysteinemic patients, as well.
Jourdheuil-Rahmani
D
D
INSERM CJF 9401, Laboratory of Biochemistry, School of Pharmacy, Marseilles, France.
Rolland
P H
PH
Rosset
E
E
Branchereau
A
A
Garçon
D
D
D000328:Adult; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D013997:Time Factors
D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D006710:Homocysteine; D003609:Dactinomycin; D003513:Cycloheximide; D012697:Serine Endopeptidases