Evolution of Atherosclerosis
By- Dr.Panchadcharam Harinath MD
Director, Academia Grandisa medicinae, New Delhi.
Dr.Karishma Harbada MD
J J Hospital, Mumbai.
Abstract
Vitamin deficiency theory of atherogenesis was postulated in early 20th century but was overlooked all the time. Ascorbate is an essential vitamin which is necessary for maintaining homeostasis when organism is under stress. Ability to synthesize endogenous ascorbate was lost in the evolution before about 60million years ago. The deleterious effects caused by ascorbate deficiency were compensated by synthesis of Lipoprotein a [Lp(a)] which is accumulated in vascular wall in order to strengthen the fragile vessels. However when the extent of accumulation is too great then it produces atheroma, in the presence of other risks atherogenesis progresses faster & greater. Vitamin B12, folate & even B6 are necessary maintain the turnover & concentration of homocysteine which is an independent risk factor of atherosclerosis. Vitamin E & omega-3 fatty acids change the composition of eicosanoids towards the favorable ones & reduce triglycerides. This article gives an inside for the origin of atherosclerosis & the mechanisms operating the endothelial injury & atherogenesis.
Key words
Atherosclerosis, ascorbate, paleontology, pisces, amphibia, reptilia, L-gulonolactone oxidase, mammalia, scurvy, mutation, Prosimii, Anthropoidea, fossil, Cretaceous, Paleocene, meteor, Lipoprotein(a), Low-density lipoprotein (LDL), apoprotein B-100 , apoprotein(a), differentiation, organogenesis, extracellular matrix, fibrinolysis, thrombosis, inflammation, plasminogen, collagen, Atheroma, fetus, neonate, billiverdin, billirubin, jaundice, shear stress, Homocysteinemia, Vit B12, folate, microflora, Pseudomonas, Klebsiella, Eicosanoids, Omega-3 fatty, peroxisome, cholesterol.
Introduction
Atherosclerosis is the main aetiology for the no-1 killer Ischemic heart disease in the world. There are several theories of atherogenesis even though “theory of inflammatory response to endothelial injury” gained popularity. There are multiple causes of injury to endothelia such as hyperlipidaemia, HTN & haemodynamic factors, smoking, homocysteine, infections & toxins. Animals that posses ability to synthesis endogenous ascorbate have sufficient amount of ascorbate to maintain the strength of vessels but species lack synthetic ability have fragility of vessels; in order to counteract such condition nature replaced ascorbate with Lp(a), which in excess amount causes atherosclerosis. This article emphasizes the importance of vitamin supplement in prophylaxis of atherosclerosis
Ascorbate synthesis & evolution
Ascorbic acid is one of the very essential vitamins necessary for persistence of lives. From physiologic, structural & even paleontologic point of view its worth to say survival is not possible in organisms without this compound. Except for few species that cannot synthesize ascorbate must rely on their foods, almost all animals synthesize their own ascorbate(Stone1).
The enzymes synthesize ascorbate are located in kidneys in pisces, amphibia & reptilia. In evolution when animals became complex the inadequacy of kidneys to synthesize adequate amount of ascorabate is compensated by switching the synthesis to liver. Ascorbate maintains the homeostasis when the animal is stressed thus the amount of ascorbate synthesized in the organisms depends on the stress that is produced by complex reactions in the body.
The locus of the ascorbate synthesizing enzymes in evolution of the vertebrates from the pisces to the primates (Roy and Guha2, Chaud
huri and Chatterjee.3)
The vitamin hypothesis was postulated by Funk in 1912, which stated that deficiency of water-soluble substance, called Vitamin –C causes scurvy.
In 1959 Burns showed that the absence of enzyme in livers of some mammalian species called, L-gulonolactone oxidase, which is rate limiting enzyme in ascorbic acid synthesis; leads to development of scurvy.
The Harvard in 1966 and Yerkes Primate Research Center in 1969 discovered an interesting finding after following the suggestion of Stone1 to examine the whole order of primates for the presence of L-gulonolactone oxidase in their livers, to determine which species of order primata was mutated & lost the active L-gulonolactone oxidase.
The following diagram showing a chart of the fossil record of the primates as devised by Simons4 that is simplified by Dr.P.Harinath MD.
Results showed that active enzyme L-gulonolactone oxidase was present in species of the suborder Prosimii, but in species of the suborder Anthropoidea its absent. This data proves us the presence of not only anatomic but also physiochemical division between the Prosimii and the Anthropoidea.
When we analyze the fossil record from Simons4, the origin of the division between Prosimii and Anthropoidea lies at a point between the late Cretaceous and late Paleocene where a defect appears to have occurred which mutated the gene of enzyme that synthesize ascorbate. This mutation occurred in the vicinity of the appearance of primate ancestor on the earth, about 58 to 63 million years ago whose descendants evolved into the suborder Anthropoidea.( Stone1)
In 1971, Russell and Tucker5 suggested that this mutation might have occurred due to the large fluxes of radiations produced by the impact of gigantic meteor on the earth in late Cretaceous period.
This mutation was compensated by ascorbate rich green & fruit supply to tree living species. However this value of compensation was lost when the decendants of these animals moved to land where the supply of ascorbate was not adequate all around the year.
Stone6 stated that humans consuming minidoses of ascorbate per day will not show the prominent & classic symptoms of frank clinical scurvy however might still suffer from severe subclinical biochemical scurvy; which I believe subclinical biochemical scurvy as a pathophysiologic component of atherosclerosis.
New approach for old problems?
Compensation fo nature for Vitamin-C deficiency
Nature compensated the vitamin C deficiency by its surrogate lipoprotein(a) to accelerate wound healing and other cell-repair mechanisms, to strengthen the extra-cellular matrix, & to scavenge the free radicals.
Lipoprotein(a) [Lp(a)] was discovered by Blumberg and Berg7. It’s a complex of low-density lipoprotein (LDL) with apoprotein B-100 and a unique glycoprotein, called apoprotein(a) which is linked to apo B by disulfide bonds. Lp(a) is detected only in the plasma of humans & other primates that have lost the active enzyme to synthesize ascorbate. This enzyme deficiency appeared to be compensated by acquiring the ability to synthesize apoprotein(a) to counteract stress.
Lipoprotein(a) [Lp(a)] is an adhesive protein which have positive roles in tissue differentiation & organogenesis, strengthening of extra-cellular matrix, repair process, wound healing & scavenging free radicals (by –SH group). Even though it’s pathologic roles are realized by blocking fibrinolysis to promote thrombosis & interacting with white cells to aggravate inflammation (Rath & Pauling8,9).
However in conditions such as scurvy where capillary fragility is present & inhibition of fibrinolysis would be beneficial, Lp(a) competitively inhibits the binding of plasminogen to fibrin thus inhibits fibrinolysis; Because of homology of Apo(a) to plasminogen.
The detection Apo(a) in non-lesioned areas of arterial wall & plasma from neonates led us a clue that Lp(a) strengthens the arterial walls & participate in organogenesis directly or indirectly by counteracting the stress which is great during this period, but atherosclerosis would occur; if this accumulation is too great.
We can draw a conclusion that a possible mechanism for Lp(a) & its adhesive properties is a compensation for decreased rate in collagen synthesis, particularly due to ascorbate deficiency.
It’s worth mentioning type I&II fibrillar collagen which is a component of extra-cellular matrix formed by post transcriptional modification with the help of ascorbate; is deficient in suclinical scurvy too. Discussion about all details of fibrillar collagen is beyond the scope of this article but it’s important to emphasize that fibrillar collagen is not only participates in the static functions of matrix but also appears to inhibit the proliferation smooth muscles in atherosclerotic plaque.
Vitamin deficiency theory of atherosclerosis initiation
Severe subclinical biochemical scurvy initiates the degenerative process in atherosclerosis. As I mentioned earlier, accumulation of Lp(a) in extra-cellular matrix is to counteract fragility of vessels but when long standing accumulation beyond the limit would switch this compensatory mechanism into a pathologic one leading to development of Atheroma.
In fetal & neonatal period that are more stressful because of tissue remodeling & organogenesis producing a lot of reactive species; the ascorbate deficiency might be the reason of high level Lip(a)in plama & would be most probably the mechanism of primary fatty streak formation.
It’s noteworthy that conversions of billiverdin to billirubin & neonatal physiologic jaundice have biologic value of survival due to the anti-oxidant property of billirubin.
The compensatory mechanism to restore the integrity of the vascular wall in severe subclinical scurvy leads to insudation of Lip(a) & produces intimal thickening throughout the vascular system. When, however other risk factors such as haemodynamic stress & homocysteine group up with the underlying vascular lesion then atherogenesis will be greater.
This theory helps to explain the reason of development of atherosclerosis mainly at sites of high shear stress Eg-Bifurcatio Aortae, a.renails & a.coronaria.
Without any doubts “Gene therapy” is an outstanding option to this no-1 killer of the world by introducing the lost gene again in body however sponsors for these researches are limited because the pharmaceuticals prefer drugs than gene therapy.
Vitamin B12 & Folate
Homocysteinemia is an independent risk factor for atherosclerosis which is proved by many researchers now. At biochemical level Vit-B12, folate & B6 are necessary to control the turn over of Homocysteine in the body.
Body depends on external sources for Vit B12 & folate, however, the human small intestine also harbours microflora (at least two groups of organisms -Pseudomonas and Klebsiella sp ) that may synthesize significant amounts of the vitamin B12.( Albert, Mathan & Baker10 )
I believe that the food we consume may have sufficient amount of B12 & folate to run processes such as DNA synthesis but these amounts may not be sufficient enough to carry our minute processes such as regulation of homocysteine turnover. Compare to other species, Human’s foods became too artificial which is low in vitamins, also the intestinal normal flora may be less productive than other species in synthetic point of view (use of antibiotics destroys normal flora too).This minute deficiency may run a subclinical phase of Homocysteinemia which build up deleterious effects on atherosclerosis. Many animal studies shows B12 & B6 supplementation decreases atherosclerosis but this has to be determined in humans.
Vit E
They act as antioxidant decrease oxidation of LDL, decreases Eicosanoids synthesis, decrease adhesion molecules expression. Vitamin E was reported to inhibit serum-induced smooth muscle cell proliferation (Chan11). As vitamins mentioned above minute deficiency subclinically affects atherosclerosis progression.
Omega-3 fatty acids
Omega-3 fatty acids increase 3 series eicosanoids which is hundred times less potent th
an the 2 series eicosanoids & decrease triglyceride synthesis in liver (HARRIS12).
Human liver cannot make double bonds beyond omega 3 position in fatty acids, because the peroxisomal enzyme which is responsible for this process is lost in evolution too where it’s still present in sum fishes.
This could be also a contributing factor in atherosclerosis in humans
Cholesterol excretion
Last but not least excretion of cholesterol is not as efficient as other species in humans which increases the availability of cholesterol to circulate can also be a contributing factor in atherosclerosis in humans.
Conclusion
Ascorbate deficiency is the main factor that makes the vessels susceptible to atheroma by raising the level of Lp(a); which is a protective action of turned out to de deleterious as all other chronic inflammatory diseases. Other vitamins such as Vit-B12, folate, B6, Vit-E are important controlling the turnover of injurious agents like Homocysteine & oxygen radicals; when deficiencies of such factors occur can lead to the accumulation of these injurious agents. When we substitute Arachidonate with Omega-3 fatty acids it obviously reduces the inflammatory process by synthesizing less potent mediators like PG3s. 
Such deficiencies appeared to have occurred in our ancestors long time ago however as evolution progresses defects caused by mutations, behavior & environment accumulated through species & showing maximum impacts on humans.
This review emphasizes the necessity of the above mentioned vitamin supplements for prophylaxis of atherosclerosis, but “Gene therapy” is the only scope of permanent prophylaxis in future.
References
1-Stone, I.: Studies of a mammalian enzyme system for producing evolutionary evidence in Man. Amer. J. Phys. Anthrop. 1965; 3:83-85.
2-Roy, R. N. and Guha, B. C.: Species difference in regard to the biosynthesis of ascorbic acid. Nature, 1958; 182:319-320.
3- Chaudhuri, C. R. and Chatterjee, I. B.: Ascorbic acid synthesis in birds: Phylogenetic trend. Science, 1969; 164:435-436.
4-Simons, E. L.: The early relatives of man. Sc. Amer. 1964;1:55.
5- Russell, D. and Tucker, V. V.: Supernovae and the extinction of the dinosaurs. Nature.1971; 229:553-554.
6- Stone, I.: The genetic disease, Hypoascorbemia. A fresh approach to an ancient disease and some of its medical implications. Acta Genet. Med. et Gemel. 1967; 16:52-62.
7-Berg K: A new serum type system in man – The Lp system. Acta Pathologica
1963; 59: 369-382.
8-Rath M, Pauling L : Hypothesis: Lipoprotein(a) is a surrogate for
ascorbate. Proceedings of the National Academy of Sciences USA. 1990; 87: 6204-
6207.
9-Rath M. Apoprotein(a) Is an Adhesive Protein
Proceedings of the National Academy of Sciences, 1991; 87: 6204-6207.
10- Albert M. J. ,Mathan V. I. & Baker S. J.; Vitamin B12 synthesis by human small intestinal bacteria, Nature, 1980; 283, 781 - 782 (21 February).
11-Alvin C. Chan ; Vitamin E and Atherosclerosis, The Journal of Nutrition, 1998;128,1593-1596.
12-Harris William S. & Bulchandani Diepti; Why do omega-3 fatty acids lower serum triqlycerides?, Current opinion in lipidology ,2006, 17, 387-393.
No comments:
Post a Comment