Hyperhomocysteinemia induces elastolysis in minipig arteries: Structural consequences, arterial site specificity and effect of captopril-hydrochlorothiazide

Hyperhomocysteinemia is a risk factor for arterial diseases, and the deteri oration of the arterial elastic structures is one of the possible mechanism s underlying this epidemiological association. The aim of this paper is to quantitatively characterize such structural alterations and to explore thei r causes in a previous model of dietary induced mild hyperhomocysteinemia i n minipigs. After four months, both a morphodensitometrical analysis of the elastic structure and a biochemical analysis of elastin and elastase activ ities were performed on the infrarenal abdominal aorta (IRAA) and the proxi mal left interventricular coronary artery (LIVCA) of control (C), hyperhomo cysteinemic (H) and captopril-hydrochlorothiazide (Cp-Htz, 25 + 12.5 mg/d)- treated (H+Cp) minipigs (n = 8/group). Hyperhomocysteinemia was found to induce an increase in parietal elastolyti c metalloproteinase activities. It resulted in opening and enlargement of f enestrae through the medial elastic laminae and in a decrease in medial ela stin content (p < 10(-3)), expressed as well as volume density (%) as weigh t concentration (mu g elastin/mg dry tissue). The thickness of the media an d its basic lamellar organization was unchanged. The reduction in volume de nsity was more dramatic in LIVCA (H: 4.7 +/- 0.9 vs C: 8.8 +/- 2.4), where it was evenly distributed within the media, than in IRAA (H: 6.7 +/- 1.1 vs C: 9.3 +/- 1.2), where the deep medial layers were less affected. Cp-Htz p artly prevented the hyperhomocysteinemia-induced reduction of the medial el astin content in LIVCA (5.7 +/- 1.2) and IRAA (7.9 +/- 1.4). This effect, o ccurring in the subintimal layers of the media in both arteries but not in the deeper layers, resulted in a less beneficial effect in LIVCA than in IR AA. This result parallels the moderate beneficial therapeutic effect of ACE inhibitors :against coronary atherosclerosis in humans. This paper reports for the first time a quantitative analysis of the arteri al site-dependent deterioration of the elastic structure caused by mild hyp erhomocysteinemia and the involvement of metalloproteinases in this process . These results confirm that the plaque-independent damage to elastic struc ture previously described in hyperhomocysteinemic-atherosclerotic minipigs was mainly due to homocysteine. This highlights that the metalloproteinase- related elastolysis and the subsequent structural deterioration is one of t he major events underlying the epidemiological association between mild hyp erhomocysteinemia and arterial diseases.