Inhibitory effect of the angiotensin converting enzyme inhibitors captopril and enalapril on the conversion of procollagen to collagen.

OBJECTIVE AND DESIGN: Angiotensin converting enzyme inhibitors are reported to inhibit the collagen accumulation involved in left ventricular hypertrophy. We tested the effect of captopril and enalapril on the conversion of procollagen to collagen in short-term tissue cultures in order to study the possible mechanisms by which the antifibrotic effect of this group of inhibitors takes place. METHODS: We employed short-term cartilage and tendon tissue cultures to monitor the conversion of procollagen to collagen. After pulse-labelling with [14C]-proline, the cultures were incubated further with the test compounds in different concentrations for a 180 min chase period. The reaction was stopped and radioactive collagenous peptides were analysed by gel electrophoresis. The amounts of collagenous proalpha and alpha chains were estimated, and the inhibition of procollagen to collagen conversion was calculated relative to 0 min control (100% inhibition) and 180 min control (0% inhibition) samples. RESULTS: Inhibition (50%) was obtained with 7 mmol/l captopril and 22 mmol/l enalapril in the cartilage cultures. Both compounds seemed to inhibit the conversion in clearly lower concentrations in tendon cultures, 4 mmol/l and 7 mmol/l, respectively, were sufficient for 50% inhibition. Angiotensin I, II, saralasin and bradykinin did not have any effect on conversion at 3.5, 9, 2 and 4 mmol/l concentrations, respectively. CONCLUSION: The peptidase inhibitors captopril and enalapril are able to inhibit the conversion of procollagen to collagen, which is a proteolytic process, possibly by inhibiting the specific procollagen proteases. Whether this phenomenon is involved in the antifibrotic property of angiotensin converting enzyme inhibitors warrants further study, as does the question of whether new antifibrotic agents could be developed on this basis.

Diminished arterial elasticity in diabetes: association with fluorescent advanced glycosylation end products in collagen.

OBJECTIVE: Non-enzymatic glycosylation of proteins occurs in diabetes and advanced glycosylated end products can accumulate in long lived proteins such as vascular collagen and reduce the elasticity of vessel walls. To evaluate the potential association of advanced glycosylated end products in collagen with diminished arterial elasticity in diabetes, 14 diabetic and 14 age and sex matched non-diabetic patients with coronary artery disease were studied. METHODS: Arterial elasticity was assessed in terms of carotid to femoral pulse wave velocity and by measuring the change in ascending aortic diameter induced by pulse pressure. Collagen linked fluorescence, a measure of advanced glycosylated end products, was determined from tissue specimens of the skin, ascending aorta, and right atrial appendage taken during coronary bypass surgery. RESULTS: As a sign of diminished arterial elasticity, carotid to femoral pulse wave velocity was raised (p < 0.01) and change in ascending aortic diameter tended to be diminished (p = 0.09) in the diabetic patients. Collagen linked fluorescence was increased (p < 0.05) in the myocardium of the diabetic group, but the difference in skin and aorta was not significant. Collagen linked fluorescence between the aorta, skin, and myocardium correlated with each other (r = 0.64-0.77). Collagen linked fluorescence in the aorta and myocardium correlated with carotid to femoral pulse wave velocity (r = 0.63 and r = 0.67, respectively) in the diabetic group but not in the control group. CONCLUSIONS: These data suggest that non-enzymatic glycosylation of matrix proteins, and specifically collagen, may modify arterial elasticity in diabetic patients with coronary artery disease.