HOMOCYSTEINE INDUCES SYNTHESIS OF A SERINE ELASTASE IN ARTERIAL SMOOTH-MUSCLE CELLS FROM MULTIORGAN DONORS

Objectives: In heart transplant recipients with diffuse coronary arter iopathy, we have previously demonstrated the prevalence of elevated ho mocysteinemia, also known as an independent risk factor for myocardial infarction and stroke. In hyperhomocysteinemic mini-pigs we also obse rved early detectable pathologic changes in the elastic laminae. We hy pothesized that homocysteine causes premature breakdown in the arteria l 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 fo r 0-72 h with homocysteine (0-250 mu M), in the presence or absence of specific protease inhibitors. Results: Homocysteine was devoid of a d irect effect, but after 18 h incubation the elastase-like activities i ncreased by 5-6-fold in the extracellular medium. The enzymes were cha racterized as serine proteases. Incubation of cells with a nucleic aci d 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 vasc ular smooth muscle cells. The process may require protein synthesis an d account for the early alterations of the arterial elastic structures in heart transplant recipients, and in other hyperhomocysteinemic pat ients, as well.