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Angles-Cano ; Structural
basis for the pathophysiology of lipoprotein(a) in the athero-thrombotic
process. Braz J Med Biol Res 1997 Nov;30(11):1271-80.
Lipoprotein Lp(a) is a major and independent genetic
risk factor for atherosclerosis and cardiovascular disease.
The essential difference between Lp(a) and low density lipoproteins (LDL)
is apolipoprotein apo(a), a glycoprotein structurally similar to plasminogen,
the precursor of plasmin, the fibrinolytic enzyme.
Lp(a) has the capacity to bind to fibrin and to membrane
proteins of endothelial cells and monocytes, and thereby to inhibit plasminogen
binding and plasmin generation. The inhibition of plasmin generation and
the accumulation of Lp(a) on the surface of fibrin and cell membranes
favor fibrin and cholesterol deposition at sites of vascular injury.
Moreover, insufficient activation of TGF-beta due
to low plasmin activity may result in migration and proliferation of smooth
muscle cells into the vascular intima. These mechanisms may constitute
the basis of the athero-thrombogenic mode of action of Lp(a).
Price KD; Price CS; Reynolds
RD; Hyperglycemia-induced latent scurvy and atherosclerosis: the scorbutic-metaplasia
hypothesis. Med Hypotheses 1996 Feb;46(2):119-29.
Latent scurvy
is characterized
by a reversible atherosclerosis that closely
resembles the clinical form of this disease.
Acute scurvy is
characterized by microvascular complications
such as widespread capillary hemorrhaging. Vitamin C (ascorbate) is required
for the synthesis of collagen, the protein most critical in the maintenance
of vascular integrity.
We suggest that in latent scurvy, large blood vessels
use modified LDL -- in particular lipoprotein(a) -- in addition to collagen
to maintain macrovascular integrity. By this mechanism, collagen is spared
for the maintenance of capillaries, the sites of gas and nutrient exchange.
The foam-cell phenotype of atherosclerosis is identified
as a mesenchymal genetic program, regulated by the availability of ascorbate.
When vitamin C is limited, foam cells develop and induce oxidative modification
of LDL, thereby stabilizing large blood vessels via the deposition of
LDL. The structural similarity between vitamin C and glucose suggests
that hyperglycemia will inhibit cellular uptake of ascorbate, inducing
local vitamin C deficiency.
de la Pena-Diaz A; Izaguirre-Avila
R; Angles-Cano E; Lipoprotein Lp(a) and atherothrombotic disease. Arch
Med Res 2000 Jul-Aug;31(4):353-9.
High plasma concentrations of lipoprotein (a) [Lp(a)]
are now considered a major risk factor
for atherosclerosis and cardiovascular disease. This effect
of Lp(a) may be related to its composite structure, a plasminogen-like
inactive serine-proteinase, apoprotein (a) [apo(a)].
This structure endows Lp(a) with the capacity to bind
to fibrin and to membrane proteins of endothelial cells and monocytes,
and thereby inhibits binding of plasminogen and plasmin formation. This
mechanism favors fibrin and cholesterol deposition at sites of vascular
injury and impairs activation of transforming growth factor-beta (TGF-beta)
that may result in migration and proliferation of smooth muscle cells
into the vascular intima.
Misra A; Risk factors
for atherosclerosis in young individuals. J Cardiovasc Risk 2000 Jun;7(3):215-29.
Atherosclerosis starts in childhood, and is accelerated
in some individuals. A cluster of clinical and biochemical factors constitute
the risk profile for many of them, perhaps most important being metabolic
insulin resistance syndrome.
Insulin resistance and its components for children
and adolescents, especially obesity and dyslipidemia, are generators of
hypertension, glucose intolerance and complications of atherosclerosis
in adulthood. Some individuals are genetically predisposed, particularly
those with the family history of such disorders.
For many subjects, there is 'tracking' of metabolic
and lifestyle factors from early age to adulthood. Several new risk factors
of atherosclerosis (e.g. level of lipoprotein (a), procoagulant state,
hyperhomocysteinemia, low birth weight and adverse in-utero environment,
and possibly inflammatory markers) are current and potentially future
areas of research concerning children and young individuals.
Chong PH; Bachenheimer
BS Current, new and future treatments in dyslipidaemia and atherosclerosis.
Drugs 2000 Jul;60(1):55-93.
Nicotinic acid has been made tolerable with sustained-release
formulations, and is still considered an excellent choice in elevating
HDL cholesterol and is potentially effective
in reducing lipoprotein(a) [Lp(a)] levels, an emerging risk
factor for coronary heart disease (CHD).
Although LDL cholesterol is still the major target
for therapy, it is likely that over the next several years other lipid/lipoprotein
and nonlipid parameters will become more generally accepted targets for
specific therapeutic interventions. Some important emerging lipid/lipoprotein
parameters that have been associated with CHD include elevated triglyceride,
oxidized LDL cholesterol and Lp(a) levels, and low HDL levels.
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