345
Atherosclerosis, 34 (1979) 345--347 9 Elsevier/North-Holland Scientific Publishers, Ltd.
Letter to the Editors PROSTACYCLIN SYNTHESIS IN HUMAN AND EXPERIMENTAL ATHEROSCLEROSIS
Sirs: It was recently reported in this journal [1] that prostacyclin (PGI2} generation in aortic and mesenteric arterial rings from male albino rabbits was severely depressed after 1--3 months on an atherogenic diet but reverted to normal after 5 months. Since the discovery of PGI~ [2] in 1976 and the first reports on experimental atherosclerosis [3,4] we have been especially interested in the role of this substance in atherosclerosis, because diminished PGI2 formation could be a crucial factor in early atherosclerosis, influencing platelet adhesion and platelet thrombus formation [5] in vivo. We were able to confirm Gryglewski's results [1] in studies of atherosclerotic human arteries from different locations [6,7], in which we found that despite wide variations from one specimen to another, generally much smaller amounts of PGI2 were formed than in morphologically unaltered control arteries. These observations were supported by the fact that arteries of species prone to develop atherosclerosis exhibit a lower basal PGI:-production [8]. A study of different morphological types of human atherosclerotic lesions demonstrated a significantly decreased PGI: formation by all lesion types examined [9]. In male minipigs examined 4 weeks after intraarterial balloon catheterization of the abdominal aorta we found that the ballooned segment produced 50% less PGI2 (2.0 +- 0.3 pg/mg tissue wet weight/min + SEM; P < 0.05) than the non-ballooned segment (4.2-+ 0.6 pg) [10]. In juvenile-onset diabetics [11] and in streptozotocin-treated rats [12], PGI2 formation was also shown to be significantly below normal. In contrast to Gryglewski's results in rabbits [1], we found that feeding minipigs an atherogenic diet for 4 weeks led to a significant increase in the PGI2 release by the pulmonary artery, and the abdominal and thoracic aorta, as shown in Table 1. We noted that the atherogenic diet caused an increase in the serum cholesterol content from 84 to 1147 mg/100 ml, whereas tissue cholesterol increased from 0.40 to 0.88%/dry weight in the thoracic aorta and from 0.98 to 2.83%/ dry weight in the abdominal segment. Similar data were reported by Donati, who examined prostacyclin release in aortic tissue of rats that had either been treated chronically with oestrogens or rendered hypertensive [13]. Under both conditions there appeared to be an increase in the PGI~ formation of the aortic tissue. Our own preliminary studies in rats rendered hypertensive by ligation of the aorta between the two renal arteries revealed that PGI~ formation in the mesenteric artery and the inferior vena cava was temporarily increased, while in
346 TABLE 1 PROSTACYCLIN GENERATION BY ARTERIES OF MINIATURE AND VESSEL WALL CHOLESTEROL CONTENT Parameters
SWINE. THE EFFECT OF SERUM
Group Normal diet (control)
Atherogenic diet
pa
pa
T a
A a
T a
A a
Number of animals examined
6
6
PGi2 b released
4.7 -+ 0 . 3
3.6 • 0.6
2.0 + 0.3
6.4 • 0.3
4.3 • 0.9
3.9 • 0.5
C h o l e s t e r o l c o n t e n t (% o f d r y w e i g h t )
N.D.
0.40 • 0.07
0.98 • 0.09
N.D.
0.88 + O.10
2.83 • 0.39
Serum cholesterol content (rag/100 ml)
8 4 . 4 • 5.8
1 1 4 7 • 157
a p = pulmonary artery, T = thoracic aortic segment, A = abdominal aortic segment. b P m s t a c y c l i n i n pg r e l e a s e d / r a g t i s s u e w e t w e i g h t ] r a i n • S E M . N.D. = not determined.
a later phase the values returned later to normal (Leithner et al., in preparation). A 10-fold increase in PGI: production in aortic rings o f spontaneously hypertensive rats was also observed [14]. Methodological studies with vascular rings, punching of segments with the same endothelial surface area, measurement of DNA content and others demonstrated that altered prostacyclin formation does not reflect only a change in lipid, collagen and glycosaminoglycan content o f the arterial wall. However, some methodological aspects (reference weight, basal activity, total availability, estimation methods, standards, etc.) are still open. In view of the above-mentioned findings which suggest a possible relationship between atherogenesis and PGI2 formation in the arterial wall, it seems appropriate to question whether atherogenesis can usefully be correlated with PGI2 synthesis. On the basis of our own and published observations, we should like to summarize a few facts and speculations: In many specimens of atherosclerotic human and animal tissue, PGI~ formation is diminished. Moreover, tissues of species prone to the development o f atherosclerosis release less PGI2 than those of l e s s susceptible species. Different species react differently to the same stimulus. Smooth muscle cell proliferation induces/or enhances PGI2 generation [151. We are aware of the difficulties in evaluating results of different authors obtained with not fully comparable methods, b u t we wish to make the suggestion that the generation of PGI2 in arterial tissues serve as a means of self protection, safeguarding against thrombus formation. Temporarily increased PGI2 formation can be seen as a compensatory response to damage to the vessel wall and could thus retard the progress of the disease.
347 References 1 Gryglewski, R.J., Dembinska-Kidd, A., Z~nuda, A. and Gx~yglewska, T., l~ostaeyelin and th~omboxane A 2 biosynthesis capacities of heart, arteries and platelets at various stages of experimental atharo* sclerosis in rabbits, Atherosclerosis, 31 (1978) 385. 2 Moncada, S., Gryglewski, R.J., Bunting, S. and Vane, J.R., A n enzyme isolated from arteries transforms prostaglandin endoparoxides to an unstable substance that inhibits platelet aggregation, Nature (Lond.), 271 (1976) 663. 3 Dembfnska-Kied, A., Gryglewska, T., Zmuda, A. and Gryglewski, R.J., The generation of prostaeyclin by arteries and by the coronary vascular bed is reduced in experimental atharosclerosis in rabbits, Prostaglandins, 14 (1977) 1025. 4 Zmuda, A., Dembfnska-Kied, A., Chytowski, A. and Gryglewski, R.J., Experimental atharosclerosis in rabbits Platelet aggregation, t h r o m b o x a n e A2 generation and anti-aggregatory potency of prostacyclin, Prostaglandins, 14 (1977) 1035. 5 Higgs, E.A., Movcada, S., Vane, J.R., Caen, J.P., Michel, H. and Tobelem, G., Effect of prostacycHn (PGI 2 ) on platelet adhesion to rabbit arterial subendoth~lium, Prostaglandins, 16 (1978) 17. 6 Sinzinger, H., Sflberbauer, K. and Winter, M., Prostacyclin-Hemmwirkung auf die Tbxombozytenanlagerung an die Gef~/sswand in vivo? Vasa, 7 (1978) 350. 7 Sinzlnger, H., Silberbauer, K., Winter, M. and Piza-Katzer, H., Is prostacyclin generation ability a main metabolic determinant for atherosclerosis? 32nd Conf. Europ. Atheroscler. Sot., Capri, September 1978 8 Sinzinger, H., Silberbauer, K., Wagner, O., Winter, M. and Auerswald, W., Prostacyclin -- Preliminary results with vascular tissue of various species and its importance for atherosclerotic involvement, Atherog~nSse, 3 (1978) 123. 9 Sinzinger, H., Winter, M., Feigl, W., Silbarbauer, K. and Auerswald, W., Postacyclin (PGI2)-generation by different types of h u m a n atheroselerotic lesions, Lancet, 2 (1979) In press. 10 Sinzinger, H., Clopath, P., Silberbauer, K. and Winter, M,, Effects of experimental atherosclerosis on prostacyclin (PGI 2 ) generation in arteries of miniature swine, Artery, (1979) In press. 11 Silberbauer, K., Schernthaner, G., Sinzinger, H., Piza-Katzer, H. and Winter, M., Decreased vascular prostacyclin in juvenile-onset diabetics, N. EngL J. Med., 300 (1979) 366. 12 Harrison, H.E., Reece, A. and Johnson, M., Decreased vascular prostacyclin in experimental diabetes, Life Sci., 23 (1978) 351. 13 Donati, M.B., Personal communication, 1978. 14 Pace-Asciak, C.R., Carrara, M.C., Rangaraj, G, and Nicolaou, K.C., Enhanced formation of PGI2, a potent hypotensive substance, b y aortic rings and homogenates of the spontaneously hypertensive rat, Prostaglandins, 15 (1978) 1005. 15 Sinzinger, H., Sflberbauer, K., Winter, M. and Auerswald, W., Is h u m a n arterial s m o o t h muscle cell proliferation regulated by prostacyclin. Exp. Pathol., (1979) In press. -
-
Atheroselerosis Research Group at the Department of Medical Physiology, A-1090 Vienna, Austria. : CIBA-Geigy Limited, 4002 Basle, Switzerland. 3 2nd Department o f Internal Medicine, University o f Vienna, Vienna, Austria. ( R e c e i v e d 24 A p r i l , 1 9 7 9 ) ( R e v i s e d , r e c e i v e d 14 J u n e , 1 9 7 9 ) ( A c c e p t e d 20 J u n e , 1 9 7 9 )
H e l m u t Sinzinger 1,3 Peter C l o p a t h 2 Karl Silberbauer 3 Wilhelm A u e r s w a l d 1
Atherosclerosis, 34 (1979) 345--347 9 Elsevier/North-Holland Scientific Publishers, Ltd.
Letter to the Editors PROSTACYCLIN SYNTHESIS IN HUMAN AND EXPERIMENTAL ATHEROSCLEROSIS
Sirs: It was recently reported in this journal [1] that prostacyclin (PGI2} generation in aortic and mesenteric arterial rings from male albino rabbits was severely depressed after 1--3 months on an atherogenic diet but reverted to normal after 5 months. Since the discovery of PGI~ [2] in 1976 and the first reports on experimental atherosclerosis [3,4] we have been especially interested in the role of this substance in atherosclerosis, because diminished PGI2 formation could be a crucial factor in early atherosclerosis, influencing platelet adhesion and platelet thrombus formation [5] in vivo. We were able to confirm Gryglewski's results [1] in studies of atherosclerotic human arteries from different locations [6,7], in which we found that despite wide variations from one specimen to another, generally much smaller amounts of PGI2 were formed than in morphologically unaltered control arteries. These observations were supported by the fact that arteries of species prone to develop atherosclerosis exhibit a lower basal PGI:-production [8]. A study of different morphological types of human atherosclerotic lesions demonstrated a significantly decreased PGI: formation by all lesion types examined [9]. In male minipigs examined 4 weeks after intraarterial balloon catheterization of the abdominal aorta we found that the ballooned segment produced 50% less PGI2 (2.0 +- 0.3 pg/mg tissue wet weight/min + SEM; P < 0.05) than the non-ballooned segment (4.2-+ 0.6 pg) [10]. In juvenile-onset diabetics [11] and in streptozotocin-treated rats [12], PGI2 formation was also shown to be significantly below normal. In contrast to Gryglewski's results in rabbits [1], we found that feeding minipigs an atherogenic diet for 4 weeks led to a significant increase in the PGI2 release by the pulmonary artery, and the abdominal and thoracic aorta, as shown in Table 1. We noted that the atherogenic diet caused an increase in the serum cholesterol content from 84 to 1147 mg/100 ml, whereas tissue cholesterol increased from 0.40 to 0.88%/dry weight in the thoracic aorta and from 0.98 to 2.83%/ dry weight in the abdominal segment. Similar data were reported by Donati, who examined prostacyclin release in aortic tissue of rats that had either been treated chronically with oestrogens or rendered hypertensive [13]. Under both conditions there appeared to be an increase in the PGI~ formation of the aortic tissue. Our own preliminary studies in rats rendered hypertensive by ligation of the aorta between the two renal arteries revealed that PGI~ formation in the mesenteric artery and the inferior vena cava was temporarily increased, while in
346 TABLE 1 PROSTACYCLIN GENERATION BY ARTERIES OF MINIATURE AND VESSEL WALL CHOLESTEROL CONTENT Parameters
SWINE. THE EFFECT OF SERUM
Group Normal diet (control)
Atherogenic diet
pa
pa
T a
A a
T a
A a
Number of animals examined
6
6
PGi2 b released
4.7 -+ 0 . 3
3.6 • 0.6
2.0 + 0.3
6.4 • 0.3
4.3 • 0.9
3.9 • 0.5
C h o l e s t e r o l c o n t e n t (% o f d r y w e i g h t )
N.D.
0.40 • 0.07
0.98 • 0.09
N.D.
0.88 + O.10
2.83 • 0.39
Serum cholesterol content (rag/100 ml)
8 4 . 4 • 5.8
1 1 4 7 • 157
a p = pulmonary artery, T = thoracic aortic segment, A = abdominal aortic segment. b P m s t a c y c l i n i n pg r e l e a s e d / r a g t i s s u e w e t w e i g h t ] r a i n • S E M . N.D. = not determined.
a later phase the values returned later to normal (Leithner et al., in preparation). A 10-fold increase in PGI: production in aortic rings o f spontaneously hypertensive rats was also observed [14]. Methodological studies with vascular rings, punching of segments with the same endothelial surface area, measurement of DNA content and others demonstrated that altered prostacyclin formation does not reflect only a change in lipid, collagen and glycosaminoglycan content o f the arterial wall. However, some methodological aspects (reference weight, basal activity, total availability, estimation methods, standards, etc.) are still open. In view of the above-mentioned findings which suggest a possible relationship between atherogenesis and PGI2 formation in the arterial wall, it seems appropriate to question whether atherogenesis can usefully be correlated with PGI2 synthesis. On the basis of our own and published observations, we should like to summarize a few facts and speculations: In many specimens of atherosclerotic human and animal tissue, PGI~ formation is diminished. Moreover, tissues of species prone to the development o f atherosclerosis release less PGI2 than those of l e s s susceptible species. Different species react differently to the same stimulus. Smooth muscle cell proliferation induces/or enhances PGI2 generation [151. We are aware of the difficulties in evaluating results of different authors obtained with not fully comparable methods, b u t we wish to make the suggestion that the generation of PGI2 in arterial tissues serve as a means of self protection, safeguarding against thrombus formation. Temporarily increased PGI2 formation can be seen as a compensatory response to damage to the vessel wall and could thus retard the progress of the disease.
347 References 1 Gryglewski, R.J., Dembinska-Kidd, A., Z~nuda, A. and Gx~yglewska, T., l~ostaeyelin and th~omboxane A 2 biosynthesis capacities of heart, arteries and platelets at various stages of experimental atharo* sclerosis in rabbits, Atherosclerosis, 31 (1978) 385. 2 Moncada, S., Gryglewski, R.J., Bunting, S. and Vane, J.R., A n enzyme isolated from arteries transforms prostaglandin endoparoxides to an unstable substance that inhibits platelet aggregation, Nature (Lond.), 271 (1976) 663. 3 Dembfnska-Kied, A., Gryglewska, T., Zmuda, A. and Gryglewski, R.J., The generation of prostaeyclin by arteries and by the coronary vascular bed is reduced in experimental atharosclerosis in rabbits, Prostaglandins, 14 (1977) 1025. 4 Zmuda, A., Dembfnska-Kied, A., Chytowski, A. and Gryglewski, R.J., Experimental atharosclerosis in rabbits Platelet aggregation, t h r o m b o x a n e A2 generation and anti-aggregatory potency of prostacyclin, Prostaglandins, 14 (1977) 1035. 5 Higgs, E.A., Movcada, S., Vane, J.R., Caen, J.P., Michel, H. and Tobelem, G., Effect of prostacycHn (PGI 2 ) on platelet adhesion to rabbit arterial subendoth~lium, Prostaglandins, 16 (1978) 17. 6 Sinzinger, H., Sflberbauer, K. and Winter, M., Prostacyclin-Hemmwirkung auf die Tbxombozytenanlagerung an die Gef~/sswand in vivo? Vasa, 7 (1978) 350. 7 Sinzlnger, H., Silberbauer, K., Winter, M. and Piza-Katzer, H., Is prostacyclin generation ability a main metabolic determinant for atherosclerosis? 32nd Conf. Europ. Atheroscler. Sot., Capri, September 1978 8 Sinzinger, H., Silberbauer, K., Wagner, O., Winter, M. and Auerswald, W., Prostacyclin -- Preliminary results with vascular tissue of various species and its importance for atherosclerotic involvement, Atherog~nSse, 3 (1978) 123. 9 Sinzinger, H., Winter, M., Feigl, W., Silbarbauer, K. and Auerswald, W., Postacyclin (PGI2)-generation by different types of h u m a n atheroselerotic lesions, Lancet, 2 (1979) In press. 10 Sinzinger, H., Clopath, P., Silberbauer, K. and Winter, M,, Effects of experimental atherosclerosis on prostacyclin (PGI 2 ) generation in arteries of miniature swine, Artery, (1979) In press. 11 Silberbauer, K., Schernthaner, G., Sinzinger, H., Piza-Katzer, H. and Winter, M., Decreased vascular prostacyclin in juvenile-onset diabetics, N. EngL J. Med., 300 (1979) 366. 12 Harrison, H.E., Reece, A. and Johnson, M., Decreased vascular prostacyclin in experimental diabetes, Life Sci., 23 (1978) 351. 13 Donati, M.B., Personal communication, 1978. 14 Pace-Asciak, C.R., Carrara, M.C., Rangaraj, G, and Nicolaou, K.C., Enhanced formation of PGI2, a potent hypotensive substance, b y aortic rings and homogenates of the spontaneously hypertensive rat, Prostaglandins, 15 (1978) 1005. 15 Sinzinger, H., Sflberbauer, K., Winter, M. and Auerswald, W., Is h u m a n arterial s m o o t h muscle cell proliferation regulated by prostacyclin. Exp. Pathol., (1979) In press. -
-
Atheroselerosis Research Group at the Department of Medical Physiology, A-1090 Vienna, Austria. : CIBA-Geigy Limited, 4002 Basle, Switzerland. 3 2nd Department o f Internal Medicine, University o f Vienna, Vienna, Austria. ( R e c e i v e d 24 A p r i l , 1 9 7 9 ) ( R e v i s e d , r e c e i v e d 14 J u n e , 1 9 7 9 ) ( A c c e p t e d 20 J u n e , 1 9 7 9 )
H e l m u t Sinzinger 1,3 Peter C l o p a t h 2 Karl Silberbauer 3 Wilhelm A u e r s w a l d 1
