Apoprotein(a) is an Adhesive Protein.
Rath M and Pauling L. (1991).
Journal of Orthomolecular Medicine 6: 139-143
Apoprotein(a) [apo(a)] is a unique macromolecule that is synthesised
at a high rate in man and other species that have lost their ability
for endogenous ascorbate production (1). When associated with low-density
lipoprotein (LDL) to form lipoprotein(a) [LP(a)] it becomes a primary
risk factor for cardiovascular disease (CVD) (2). The conservation of
such a potentially detrimental genetic feature during evolution deserves
an explanation. Our discovery of the ascorbate-apo(a) connection marked
a turning point in research directions. We proposed that apo(a) must
have advantageous physiological properties that by far outweigh its disadvantages.
Subsequently we identified powerful beneficial properties of apo(a) in
the defence against the proliferation of various diseases. These properties
include the stabilisation of the extracellular matrix, the interaction
with the coagulation system, antioxidative defence, and inhibition
of plasmin-induced proteolysis. Ascorbate deficiency is the metabolic
condition where these defence mechanisms are required. Moreover, we
identified prolonged periods of ascorbate deficiency during evolution
as the life-threatening conditions that lead to the high production
of apo(a) in primates and man. The paramount importance of these discoveries
for human health is discussed in the preceding paper (3).
Based on the conclusion that the beneficial properties of apo(a) must
be greater than its role in the defence of disease proliferation, we
now propose another, perhaps the most decisive, function, of apo(a).
We propose that apo(a) can function as an adhesive protein. Moreover,
we propose that apo(a) is critically involved in differentiation, morphogenesis,
and possibly fertility and development of intelligence.
The apo(a) molecule contains the arginine-glycine-aspartate sequence
characteristic of adhesive proteins
Properties such as organ morphogenesis, differentiation, and growth have
recently been discovered to be associated with a number of proteins
present in the extracellular matrix and the blood, such as fibronectin,
collagen, laminin, vitronectin, osteopontin including also coagulation
factors such as fibrinogen and von Willebrand factor. These ‘adhesive
proteins’ contain a characteristic amino-acid sequence: arginine-glycine-aspartate
(RGD), by means of which they interact with integrins, a family of
cell surface receptors for adhesive proteins.(4,5)
Consequently we investigated the possibility that the apo(a) molecule
contains such a sequence and can function as an adhesive protein. Sequence
analysis of the apo(a) molecule revealed an arginine-glycine-aspartate
(RGD) tripeptide sequence in the kringle-35 region. This finding confirms
that apo(a) carries the decisive tripeptide sequence that characterises
the family of adhesive proteins. Via the RGD sequence apo(a) can potentially
interact with monocytes, thrombocytes, and other cells during pathophysiological
defence processes as well as under physiological conditions. We concluded
that the role of apo(a) as an adhesive protein would be further established
if we could prove its production independently of apoB and the Lp(a)
Detection of apo(a) in human sperm
When human sperm was analysed in our laboratory, both the seminal plasma
and the cellular fraction were found to contain apo(a). We could not
detect any apo B associated with this apo(a). The detection of apo(a)
in human sperm is the proof that isolated apo(a) is actually produced
and secreted into a body fluid independently of apoB and lipoprotein
particles. Two years ago Richard Lawn and co-workers screened the organs
of rhesus monkeys for their content of apo(a) mRNA. Beside in the liver,
apo(a) mRNA was also found in the testes and the brain (6). Until now
these observations have remained unexplained. The proposed function
of apo(a) as an adhesive protein offers this explanation. After our
discovery of apo(a) in the sperm it is likely that apo(a) will also
be found in the cerebrospinal fluid. Both organs are largely separated
from the bloodstream by blood-organ barriers. The detection of an autonomous
production of apo(a) I these organs leads to important conclusions.
The role of apo(a) in human metabolism is obviously so important that
virtually no organ can afford to be cut off from the apo(a) supply.
Moreover, those organs that are cut off from this apo(a) supply via
the circulatory Lp(a) have maintained the ability for autonomous apo(a)
Lp(a), the transport form of the adhesive protein apo(a)
So far much interest in Lp(a) has derived from its association with lipoprotein
metabolism, in particular its close relation to the LDL particle. On
the basis of our recent discoveries and the role of apo(a) as an adhesive
protein we conclude that this associations rather the means than the
end. The Lp(a) lipoprotein particles secreted from the liver into the
plasma are the transport form of apo(a). Via this backpacking mechanism
apo(a) can be carried to almost all sites of the body under physiological
and pathophysiological conditions. Goldstein and Brown suggested that
apo(a) may target the LDL particle to the sites of wound-healing (7).
We, however, propose in the light of the concept presented here that
the apo(a) molecule rather than the LDL molecule is the more important
partner in this metabolic co-operation. Thus the LDL particle is rather
the means, i.e. a convenient transport vehicle, than the end, lipid
substrate supply for tissue repair. A closer look on the amount of
LDL and Lp(a) and their relation as part of the individual plasma confirms
this concept: apo(a), not LDL, is the limiting partner. We do not,
of course, exclude that the availability of lipid substrates at the
site of tissue growth or repair may be an additional advantage for
the combination of apo(a) with LDL.
The role of the adhesive protein apo(a) under physiological conditions
Elevated plasma Lp(a) concentrations have been detected in new-borns
as well as during periods of increased growth.8 It is thus conceivable
that the primary role of the adhesive protein apo(a) is during development
and differentiation of the human body and its organs. Those organs
unable to synthesize apo(a) are supplied via Lp(a) from the circulation.
Those organs separated from the circulation by a blood-organ barrier
would depend on their own production.
In this respect the ability of the brain to produce apo(a) deserves particular
attention. It has been shown by in vitro studies with other adhesive
proteins that the RGD tripeptide is critically involved in the differentiation
and morphogenesis of the central and peripheral nervous system as well
as the binding of oligodendrocytes to various components of the glial-derived
matrix (9). It is therefore conceivable that the adhesive protein apo(a)
is involved in the development and differentiation of the brain.
Similarly the presence of apo(a) in the seminal fluid suggests a specific
role for apo(a). The RGD sequences have been shown to be essential for
the formation of Sertoli cell cords. Moreover, during conception the RGD
sequence is involved in sperm-oolemmal adhesion and egg penetration. Both
the formation of Sertoli cell cords and the fertilisation itself have
been successfully inhibited by synthetic peptides containing the RGD sequence.10
The detection of apo(a) in human sperm suggests a role of apo(a) in fertility
The role of the adhesive protein apo(a) under pathological conditions
The importance of apo(a) as an adhesive protein increases under pathological
conditions and ascorbate deficiency. Apo(a) co-ordinates the interaction
between cellular systems and the extracellular matrix during repair
processes. Apo(a) is involved in tissue reformation during acute repair
processes such as wound-healing and Lp(a) plasma levels are known to
be elevated during the post operative phase.
Chronic repair processes are characteristic for all pathological states
and they are sustained by chronic ascorbate deficiency. In this situation
adhesive proteins play a particular role. They interact specifically
with cellular systems such as monocytes, T cells as well as thrombocytes
and thereby play a critical role in inflammatory, infectious, hemostatic
and many other processes (4,5).
The adhesive protein apo(a), on the basis of its physiological properties,
may play an important role in disease containment, tissue reorganisation
and chronic repair processes in general. The elevation of Lp(a) plasma
levels as established for cancer, cardiovascular, inflammatory and
many other diseases is additional confirmation for this concept.
In this context it is noteworthy that apo(a) can interact with a variety
of other adhesive proteins, such as fibrinogen, collagen, and fibronectin.
The interaction of apo(a) with fibronectin is of particular interest.
Apo(a) and fibronectin
Fibronectin is one of the best-characterised adhesive proteins. It is
present in plasma and other body fluids, with a particularly high concentration
in the seminal fluid. Fibronectin is involved in cellular migration
during embryogenesis, morphogenesis, differentiation, and growth of
many systems. In particular it has been shown to be involved in development
and differentiation of the brain and the peripheral nervous system.
Other functions comprise platelet aggregation, thrombus formation,
and wound healing (5).
Apo(a) and fibronectin share common structural and functional properties.
Both molecules consist of numerous repeated segments, including kringle
structures, and possibly share common ancestral genes. Both apo(a)
and fibronectin can bind to fibrin and collagen. A particularly well-characterised
region is the cell-binding region of fibronectin, which contains an
RGD sequence and is critically involved in the interaction of fibronectin
with integrins and different cell systems.
It has been reported that apo(a) not only can bind to fibronectin but
also cleaves this molecule. This observation has been interpreted as
an indication for the pathogenic role of apo(a) (11). An alternative
interpretation is presented here: the coexistence of apo(a) and fibronectin
e.g. in plasma, the seminal fluid, and other body fluids in relatively
high concentrations largely excludes a genuine hostile interaction
of these two proteins.
It is rather likely that apo(a) and fibronectin share several common
functions. This conclusion is supported by the fact that an increase
in plasma fibronectin is found almost immediately at sites of wound
healing and cell repair (12). Lp(a), however, in trauma patients reaches
its maximum in plasma only after one week. Thus a replacement of the
short-term adhesive protein fibronectin by apo(a), a long-term adhesive
molecule with superior functions, is conceivable.
The adhesive protein apo(a) and its possible role in the evolution
The role of adhesive proteins in morphogenesis and organ differentiation
is well established, yet little is known about the potential role of
adhesive proteins in the differentiation of species during evolution.
This in part reflects the fact that the adhesive proteins discovered
so far, including fibronectin, are highly conserved throughout the
animal word. Therefore it is difficult to study their role in relation
to the differentiation between species. This is not the case for the
adhesive protein apo(a). Apo(a) has become a major constituent of the
metabolism mainly in primates and man.
Thus, apo(a), on the basis of other evolutionary advantages achieved
during primate evolution, may have become an additional important metabolic
element towards the evolution of man. The production of apo(a) in testes
and the brain could be interpreted as additional evidence. These organs
have determined critical evolutionary advantages: Fertility and intelligence.
We propose that apo(a) is an adhesive protein. We provide several lines
of evidence. The apo(a) molecule contains an RGD tripeptide sequence,
a characteristic peptide sequence of adhesive proteins. Consequently,
apo(a) is proposed to interact with integrin receptor systems on the
surface of thrombocytes, monocytes, and other cells under physiological
and pathophysiological conditions. Corroborating the role of apo(a)
is the detection of apo(a) in human organs that do not have access
to apo(a) supply via the Lp(a) particle in the circulation is a remarkable
fact. It suggests that virtually all organs of the human body are critically
dependent on apo(a) supply.
With our discovery of the ascorbate-apo(a) connection it became immediately
evident that apo(a) exerts powerful beneficial properties in health
and disease. With the recognition of apo(a) as an adhesive protein
we continue to elucidate these properties. With confirmatory evidence
for the role of apo(a) as an adhesive protein, the implications of
this discovery may be far-reaching. We propose that apo(a) participates
in a comprehensive coordinative way in the morphogenesis and differentiation
of organs as well as in body growth. Moreover, the preferential production
of apo(a) in primates and man and its autonomous production in those
organs critical for intelligence and reproduction provide yet another
clue: apo(a) may turn out to be an important piece of the metabolic
mosaic towards evolution of man during the remarkably short time in
which he became the dominant species on earth.
1. Rath M, Pauling L (1990): Hypothesis: Lipoprotein(a) is a surrogate
for ascorbate. Proceedings of the National Academy of Sciences USA. 87:
2. Rath M, Pauling L (1991): Solution to the puzzle of
human cardiovascular disease: Its primary cause is ascorbate deficiency
leading to the deposition
of lipoprotein(a) and fibrinogen/fibrin in the vascular wall. Journal
of Orthomolecular Medicine 6: 125-134.
3. Rath M, Pauling L (1991): An orthomolecular theory
of human health and disease. Journal of Orthomolecular Medicine 6.
4. Ruoslahti E, Pierschbacher MD (1987): New perspectives
in cell adhesion: RGD and integrins. Science 238: 491-497.
5. Hynes RO (1990): Fibronectins, (Rich, A., ed.) Springer-Verlag
Series in Molecular Biology, Springer-Verlag, New York.
6. Tomlinson JE, McLean JW, Lawn RM (1989): Rhesus monkey
apolipoprotein(a). Sequence, evolution and sites of synthesis. Journal
Chemistry 264: 5957-5965.
7. Brown MS, Goldstein JL (1987): Teaching old dogmas
new tricks. Nature 330: 113-114.
8. Van Biervliet JP, Labeur C, Michiels G, Usher DC,
Rosseneu M (1991): Lipoprotein(a) profiles and evolution in new-borns.
9. Cardwell MC, Rome LH (1988): Evidence that an RGD-dependent
receptor mediates the binding of oligodendrocytes to
a novel ligand in a glial-derived
matrix. Journal of Cell Biology 107: 1541-1549.
10. Bronson RA, Fusi F (1990): Evidence that an Arg-Gly-Asp
adhesion sequence plays a role in mammalian fertilisation.
11. Salonen E-M, Jauhiainen M, Zardi L, Vaheri A,
Ehnholm C (1989): Lipoprotein(a) binds to fibronectin
activity capable of cleaving it. EMBO Journal:
12. Stenman S, von Smitten K, Vaheri A (1980): Fibronectin
and atherosclerosis. Acta Medica Scandinavica 642: 165-170.