of Plasmin in Arteriosclerosis

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1 Significance of Plasmin in Arteriosclerosis Yuichiro GOTO Department of Medicine, School of Medicine, Keio University Introduction Arteriosclerosis is not only based on single pathological change, but also on fibrosis, atheroma and hyalinosis etc. The pathogensis of arteriosclerosis, therefore, also included various factors. Since the measurement of fibrinolysin (plasmin) has recently been performed, plasmin also has called attention as to one of pathogenic factor of arteriosclerosis. Astrupn and Mole2) considered that fibrin deposit was main cause of arteriosclerosis in relation to change of plasmin activity and Ohneda3) insisted that plasmin inhibition in plasmic state caused angionecrosis. Sarkar4) also reported that plasmin inhibitory effect in blood of arteriosclerotic patients was twenty to thirty percent higher than normal subjects. In their reports, while one stated decrease of plasmin activity accelerated degree of arteriosclerosis, and the other, elevation of plasmin activity accelerated angionecrosis. In order to analyse the correlation between plasmin activity and pathogenesis of arteriosclerosis, clinical and experimental studies were performed and reported in this paper. Method of Study 1. Materials Clinical materials were selected from patients with cerebral vascular disease and/or hypertension complicated with arteriosclerosis. Experimental studies were performed in rabbits and dogs. 2. Method of observation a. In the clinical cases, changes of fibrinolytic activity and lipid concentration in blood were followed up (periodically). In

2 Vol. 2, No. 4 SIGNIFICANCE OF PLASMIN IN ARTERIOSCLEROSIS 535 some cases, high-fat meals were given to see the correlation between them. For the determination of plasmic activity, measurements of fibrinogen concentration, Ratnoff's whole clotlysis test, S. K. activated whole plasmin value, and of Lewis' euglobulin-lysis time were performed. In the lipid determination, cholesterol was measured by modified Zak-Henly, phospholipid by Allen, and mucoprotein by Weimer-Moshin's method. b. Rabbits were grouped from Ato G according to the method of feeding or medication as shown in Table 1. In all animals, plasmin activity and lipid concentration in blood were determined Table 1. Experimental Methods in Rabbits periodically during the course of feeding. At the end of the feeding, animals were sacrificed, and the tissue plasmic activity in aorta was determined as a plasmin index. The method of determination is to calculate plasmic and anti-plasmic activities from the lysis time of the standard fibrin clot to which the aortic tissue extract and known amount of plasmin are added. Results 1. Clinical results Values of plasmic activities in cases with retinal bleeding, cerebral hemorrhage, cerebral infarction, hypertension and arteriosclerosis were as shown in Figs. 1-3.

3 536 Goto Jap. J. Med Fig. 1. Fibrinogen. Fig. 2. Whole clotlysis. Fig. 3. Whole plasmin. The higher plasmic activities are plotted in the upper part of the figures. As to fibrinogen, it was decreased in cases with retinal bleeding and cerebral hemorrhage, indicating the possible elevation of plasmic activity. Contrary to this, in cases with cerebral infarction, fibrinogen was rather increased than decreased, indicating the reduction of plasmic activity. Though in the majority of hypertensive or arteriosclerotic cases, it was ranged within normal limit, in some instances, an elevation or reduction of plasmic activity was noted. As for whole clotlysis, it was accelerated in some cases of retinal bleeding and cerebral hemorrhage, indicating the elevation of plasmic activity. But, in a few cases, reduction of plasmic activity was also noted. No cases of cerebral infarction revealed the acceleration of whole clotlysis, but in most of them, it was rather prolonged, indicating the reduction of plasmic activity. In hypertensive and arteriosclerotic cases, whole clotlysis times were variable, indicating elevation or reduction of plasmic activity. In whole plasmin value by S. K. activation, similar directions of changes were noted. Namely, plasmic activity calculated by this method was elevated in the cases with retinal bleeding or cerebral hemorrhage, whereas it was reduced in those with cerebral infarction, and, in hypertensive or arteriosclerotic cases, it was rather reduced with some exception.

4 Vol. 2, No. 4 SIGNIFICANCE OF PLASMIN IN ARTERIOSCLEROSIS 537 Regarding the relationship between plasmic activity and serum lipid level, no correlation was observed between serum cholesterol level and the above mentioned three values. In arteriosclerotic patients who were given gm. of fat daily, cholesterol, phospholipid and mucoprotein were all increased, and at the same time, fibrinogen level was also increased, indicating the possible reduction of plasmic activity (Figs. 4, 5). However, those plasmic activities calculated by Lewis' method or whole clotlysis were variable, Fig. 4. Influence of high fat diet on serum lipids Fig. 5. Influence of high fat diet on plasmin activity some being elevated, others reduced. Thus, if one attaches more importance to the fibrinogen level, which might indicate an integrated plasmic activity during a period of time, it could be concluded that plasmic activities were definitely reduced in these cases except one case. Animal Experiment In an attempt to clarify the implication of plasmin in the development of arteriosclerosis, animal experiments were performed by dividing rabbits into several groups as shown in Table 1. As to the changes of serum lipid, marked lipemia was noticed after one month of the feeding in Lanolin-adrenalin, and Lanolin-antiplasmin (Ipsilon) groups. Blood plasmic activities in each group

5 538 Goto Jap. J. Med Fig. 6. Fibrinogen. Fig. 7. Whole clotlysis. Fig. 9. Lewis* unit Fig. 8. Whole plasmin. are as shown in Figs There was no significant difference of fibrinogen among each group. Plasmic activity was not so markedly elevated even in the group in which plasmin preparation was administered. However, the activity in the group changed as time went by, revealing the highest value immediately after the injection. Whole clotlysis was accelerated only in some cases of plasmin group. Although the rabbit has a low plasmic activity in general, one rabbit in control group exhibited a strong plasmic activity. Whole plasmin value tended to increase in adrenalin and adrenalin-lanolin groups. Also, it was found that there was some difference between whole plasmin values in serum and those in euglobulin fraction. While euglobulin-lysis time was normal in almost all animals in control group and Lanolin group, it was accelerated in some animals in adrenalin, adrenalin-lanolin, Plasmin, and Plasmin-Lanolin groups. In Ipsilon-Lanolin group, it was markedly prolonged. The correlation between /2-lipoprotein containing abundant serum cholesterol

6 Vol. 2, No. 4 SIGNIFICANCE OF PLASMIN IN ARTERIOSCLEROSIS 539 which is said to be related closely with plasmic activity, and whole plasmin value or fibrinogen level was not clearly demonstrated in these groups. The results of aortic tissue plasmin level in these groups of rabbits are as follows (Fig. 10). Plasmin index in the control group ranged from 0.89 to 2.44, and its mean was 1.64, whereas, in Ipsilon-Lanolin group, the mean was 2.ll, indicating a marked reduction of the activity. The mean for adrenalin group was 1.23, indicating a relatively Mgher activity than control. In plasmin group, enzymatic activity in the aorta was not always elevated. This is probably due to the fact that these Fig. 10. Plasmin index of aorta-extract. animals were sacrificed several days after the injection of tjie plasmin preparation. Therefore, in some cases sacrificed shortly.after the injection, marked elevation of the activity was noticed. Thus, tissue plasmic activity of the aorta tended to be reduced in Lanolin-Ipsilon group and to be increased in adrenalin group. There was no correlation between the tissue plasmic activity and serum cholesterol level. As to the histopathological findings, arteriosclerotic changes were hardly observed in control group except very mild one in a few cases. In Lanolin group, atherosclerosis with fat deposition was formed after 3 months of feeding. In adrenalin group, coarsening or edematous swelling of the aortic intima was noticed in some cases despite the relatively short period of administration. In Lanolin-adrenalin group, marked arteriosclerotic changes, including intimal thickening, vacuolation, and fat deposition were observed. It is interesting to note that edematous swelling and coarsening of the intima were also noticed in this group. The more severe the arteriosclerotic changes were, the longer the feeding periods were. The coarsening of the intima was, however, noticed within one month of feeding. In Dlasmin groud. the

7 540 Goto Jap. J. Med coarsening of the intima was severe and the edematous swelling of the media was also noticed in some cases. Not only in rabbits but also in dogs, the coarsening of subendothelial tissue was noticed. In plasmin-lanolin group, the effects of both plasmin and Lanolin were exhibited histopathologically. In Lanolin-Ipsilon group, although serum cholesterol was markedly elevated, there were several cases in which atherosclerotic changes were not observed. On the other hand, in these cases, intimal thickening and severe medial changes were paradoxically observed. Furthermore, while vascular changes in other groups were relatively diffuse and generalized, some of vascular changes in this group were fairly localized, being felt as a hard nodule of the vascular wall on palpation. Discussion In the clinical data, while plasmin activity elevated in cases of retinal bleeding and cerebral hemorrhage, it decreased in cerebral infarction. In hypertensive and arteriosclerotic patients it ranged within normal limit, but in some instances, an elevation or reduction of plasmic activity was observed.5) In the group with high fat meals, cholesterol, phospholipid and mucoprotein increased after administration, and at the same time, it caused an increase of fibrinogen indicating reduced plasmin activity. In the animal experiment, adrenalin and plasmin group demonstrated high value of plasmic activity in blood and tissue. Administration of lipid and antiplasmic preparation was found to cause a antiplasmic state. In the group with fat meal, atherosclerosis developed as well as elevation of lipid, and adrenalin and plasmin group showed arteriosclerotic changes which were characterized by edematous swelling of intima and media as an initiating pathological change. In the group with antiplasmic preparation (Ipsilon), it produced marked increase of hardening of arterial wall and arteriosclerotic change which consisted of various histopathological changes within different adjacent location. These findings suggested occurrence of plasma inhibition due to increased permeability of intima in case with elevated plasmic activity, and possible process to

8 Vol. 2, No. 4 SIGNIFICANCE OF PLASMIN IN ARTERIOSCLEROSIS 541 arteriosclerosis through plasma inhibition was assumed. On the other hand, in antiplasmic case, metabolism between blood and blood vessel has not smoothly carried out as a result of reduced permeability of blood vessel, causing disordered metabolism in the blood vessels. It resulted in arteriosclerosis via retention of metabolic end-product. Therefore, in order to maintain normal construction of blood vessel, it is necessary to make a balance of plasmin and antiplasmin in both blood and tissue. The disturbance of this equilibrium suggested that both plasmic and antiplasmic states seemed to accelerate the process toward arteriosclerosis, although each one resulted in different histopathological change. However,, in antiplasmic case the increase of fibrin in blood could be considered of possibility of thrombus formation6^ Summary With clinical and animal experiments, the significance of fibrinolytic enzyme, plasmin, in arteriosclerosis was investigated. The elevation of plasmic activity in blood related to pathogenesis of arteriosclerosis with increase of permeability of blood vessel and the reduction of plasmic activity could be one of factor of thrombus through the increase of plasma fibrinogen. Furthermore, the change of blood and tissue plasmic activity was assumed to disturb the metabolism of blood vessel and the unbalance of plasmin enzymatic system with antiplasmic substance was considered to influence directly and indirectly on pathogenesis and development of arteriosclerosis. 1) Astrup, T.: Lancet 2: 565, References 2) Mole, B.: J. Path. Bacteriol. 60: 413, ) Ohneda, G.: Nihon-Rinsho 17: 711, ) Sarkar, N.: Proc. VIII Internat. Congr. Hematology, Tokyo, ) Goto,Y. et al.: Keio J.Med. 8: 293, ) Duguid, J.B.: Brit. Med. Bull. ll: 36, ) Greig, H.B.W.: Lancet 2: 16, ) Greig, H.B.W. and Rund, LA.: Lancet 2: 461, ) Ungar, G.: Acta Inc. Montreal 151, ) Matsuoka, M. et al.: Geriatrics 9: 711, 1960.

Citation Acta Medica Nagasakiensia. 1987, 32

NAOSITE: Nagasaki University's Ac Title Author(s) The Effect of Glomerulonephritis on -A Special Reference to the Glomeru Aortic Intima- Ohi, Junji Citation Acta Medica Nagasakiensia. 1987, 32 Issue Date