Mini-Review :
“Endothelial Protector Drugs” and Diabetes: Is there a Role for these Drugs?
Marco Bertini
Full-Text
Diabetic vasculopathy,
including macro and micro vascular disorders, is the leading cause of morbidity
and mortality in patients with type 1 (T1) and type 2 (T2) diabetes mellitus (DM)
[1].
A lot
of researches pointed
out that endothelial
dysfunction, characterized by
an imbalance between
Endothelium-Derived Relaxing Factors
(EDRFs) and endothelium-derived contracting
factors (EDCFs) play
a central role
on the development
and progression of diabetic
vasculopathy [2-5].
Endothelial dysfunction
and inflammation, as
indicated by abnormal
flow-dependent
vasodilatation and by
increased circulating levels
of adhesion molecules
(ICAM-1 and E-selectin) are known to occur in T2DM and seems to be an
important predictor in systemic atherogenesis [6].
Both hyperglycemia
and insulin administration increasing
circulating levels of endothelin-1
(ET-1), an endothelial cell (EC)-derived potent vasoconstrictor peptide with
mitogenic, pro-oxidative and pro-inflammatory properties that have shown to be extremely
relevant to the pathophysiology of diabetic vasculopathy [7-10].
Circulating and
local levels of
ET-1 are increased
in diabetic animal
models and diabetic patients [1,11,12].
Considering the
global epidemic of diabetes,
it seems to be critical to update our understanding of
the pathogenesis of
diabetes and related
vascular complications in
order to clearly
understand if an endothelial protector
drug, able to
modulate endothelial adhesion
molecules and ET-1
could represent a
novel treatment options
for prevention and delaying the progression of diabetic complications
[6].
The mechanism
regulating endothelial cells
and vascular smooth
muscle cells function to become an important therapeutic
targets in diabetic vascular complications and especially, the modulation of
the vasoconstrictor, mitogenic, pro-oxidative and pro-inflammatory properties
of ET-1 is undoubtedly important in diabetic complications. As everybody
knows the small
vessels (microcirculation comprises
arterioles, capillaries, venules
and lymphatics, all <100 mm in diameter) are crucial for maintaining tissue metabolism
and structural and
functional changes in
the microcirculation are present in diabetes mellitus irrespective
of the organ studied (retina, kidney, CNS and skin) [6]. The pathophysiology of
diabetic microangiopathy is
complex because it involves
not only metabolic but also genetic factors [6]. For example has been shown that subjects
with diabetes heredity
have impaired microvascular
responses to both endothelium and
nonendothelium-dependent
stimuli in the
skin microcirculation in
spite of normal
body dimension, normal
glucose tolerance and
normal insulin sensitivity
[13-15]. Early on in
the course of
the disease, microvascular
perfusion
occurs in the limbs,
but most of the blood flow under normal thermal conditions passes through arteriovenous
shunts, bypassing the
nutritive capillary bed
and leading the so-called
capillary ischemia [16,17].
Endothelial
dysfunction, characterized by an imbalance between endothelium-derived vasodilatator
and vasoconstrictor substances,
plays an important
role in the pathogenesis of vascular complications in
diabetes, including microangiopathy.
Almost two
different steps seem
to be involved
in the microcirculation imbalance:
leukocyte recruitment cascade and Endothelin-1 overexpression
[16,18,19].
The recruitment of leukocytes
from circulating blood into tissues is crucial for the inflammatory response:
during this process a number of well-studied adhesion molecules on the
endothelium
sequentially interact
with their ligands expressed on the cell surface of leukocytes. The
interaction between adhesion
molecules and ligands
occurs in a
cascade-like fashion, driving
leukocytes from the circulation to
the extravascular space,
that is, through
the steps of leukocyte
rolling, firm adhesion and transmigration (Figure 1) [20].
The selectin family
of adhesion molecules mediates the capture and rolling steps
of leukocytes along
the endothelial cells.
The selectin consists
of three members
of C-type lectins
(P, E and L-selectin).
After the
selectins have initiated
leukocyte rolling along
the surface of
endothelium, a different
set of adhesion
molecules comes into play to
reduce the leukocyte rolling velocity and allow to leukocyte to
firmly adhere to the endothelial surface. This firm adhesion step is largely
mediated by molecules of immunoglobulin superfamily such
as intercellular adhesion
molecule (ICAM –
1)
and vascular cell
adhesion molecule (VCAM-1)
expressed by endothelial cells and by those expressed
constitutively by leukocyte or by many
other types of
cells. Upon achievement of
stable adhesion to
the endothelial surface,
the leukocyte extravasate
between endothelial cells
along the intercellular junctions.
PECAM-1 (Platelet
Endothelial Cell Adhesion
Molecule) and VAP (Vascular
Adhesion Protein) mediated
leukocytes transmigration [20].
Various lines of
evidence indicate that
the shedding of
selectins is enhanced
on the endothelium
during the progression
of diabetes and
that the soluble
form of selectin
proteins has the potential to be a clinically useful biomarker of the severity of
Diabetic Rethinopathy: E-Selectin,
in particular, may also
serve as a proangiogenic factor [20].
Once that the
leukocytes have transmigrated from endothelial junctions a
hyperproduction of ET-1
(Endothelin 1) have
been released by
the endotheliam. ET-1
is one of
the most potent vasoconstrictor described
and has been
suggested to be
involved in the
development of cardiovascular disease.
It possess pro-inflammatory and profibrotic effects [6].
Enhanced of endogenous ET-1 has been
demonstrated in hypertension,
coronary artery disease and heart failure [6].
In diabetic
microangiopathy one important
feature of endothelial dysfunction
is an increased
in production and biological activity
of the vasoactive
and proinflammatory peptide ET-1. Elevated
levels of ET-1
are found in
patients with type
2 diabetes. Furthermore
ET-1 may contribute
to the development
of endothelial dysfunction,
and consequently insulin
resistance, by increasing
the production of
Reactive Oxigen species,
mainly superoxide anion, in the
vasculature [6].
Taking into account
the role of endothelial adhesion molecules (specifically E-Selectin)
and ET-1 in the pathogenesis
of diabetic microangiopathy and
that mostly of the diabetic
complications such as retinopathy,
nephropathy and neuropathy have their basis in
disturbed microvascular function,
we hypnotized that
added to standard therapy an endothelial protector
drug, able to counteract hyperespression
of endothelial adhesion
molecules and ET-1 could
be a new promising idea to postpone diabetic microvascular complication.
Recent published
and not published
studies shown that
an endothelial protecting
drug, such as
aminapthone (2-hydroxy-3-methyl-1,4-napthohydroquinone-2-p-aminobenzoate),
a synthetic molecules derived
from four aminobenzoic
acid which is
currently employed for capillary disorders
could be useful
in reverse microalbuminuria and
in control nailfold
periungueal videocapillaroscopy and
retinal impairment (OCT
and fluoroangiography) in
diabetic patients [21,22].
Considering that
recently aminapthone shown
a very interesting
direct pharmacodinamic profile
on endothelial cells (improvement of
E-selectin and ET-1
hyperespression) and that other drugs
like avosentan (a new potent,
non peptidergic and selective Et-a
receptor antagonist) demonstrated to
decrease proteinuria after 3 – 6
months of treatment, it seems encouraging to
study if this
new endothelial therapeutic
approach could be useful
for diabetic patients when added to standard therapy [23-29].
Since the typical
approach with anti- ET-a selective antagonist avosertan, atrasentan
and sitaxsertan seems
to be encouraging
in term of
efficacy (proteinuria control
in diabetic patients)
but not in term of safety
(increased of morbidity and mortality associated with anti-ET-a selective
antagonists induced fluid retention) an old and
safe endothelial protector
approach with aminapthone
could represents a new/old
way to postpone diabetic microangiopathy
complications [27-29].
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Keywords
Diabetes, Diabetic vasculopathy
