Basic Research Unit (DLIF Lab)
The major emphasis of our Basic Research Unit is work related
to characterizing the mammalian cardenolides, digoxin-like
immunoreactive factors (DLIFs) and ouabain-like
factors (OLFs), and establishing their physiologic
role. Present thinking is that these endogenous mammalian
compounds regulate the activity of the sodium pump and as
such may constitute a novel hormone regulatory-axis linked
to controlling ion-transport in cells. Regulation and fine
control of ion-transport is centrally important to many diseases
including cardiovascular, psychiatric, and kidney disease,
to mention only a few.
Our laboratory and others have identified what now constitutes
a family of the DLIF and OLF compounds and we believe these
are produced and secreted by the adrenal glands. Several very
important questions remain to be answered and they form the
basis for hypotheses driving our research:
- How are the DLIFs and OLFs produced
in the adrenal cells? What enzymes are involved and how
are these regulated?
- How are the structural forms of
DLIF and OLF linked to control of the individual sodium
pump isoforms?
- What is the transport binding
protein(s) in blood that carries DLIF and OLF to their target
cells?
- How is the amount of DLIF and
OLF in blood related to disease processes involving dysregulation
of sodium pump activity?
The mammalian cardenolides often referred to as endogenous
"cardiotonic steroids" or as "digitalis- or ouabain-like factors"
are molecules that mimic the actions of digitalis or ouabain.
Digitalis and ouabain are plant-derived compounds used as
medicines (digoxin) or as poisons (ouabain). The mammalian
DLIF and OLF compounds were originally discovered because
of their cross-reactivity with antibodies raised against the
plant-derived compounds digoxin and ouabain and by their ability
to inhibit the activity of the sodium pump. Hence, a structural
similarity between DLIFs and digoxin was proposed.
In our laboratory, the interest in characterizing DLIF originated
with the detection of an anomalously high value of digoxin
in the serum of a hospitalized patient who, as it turned out,
had not been given digoxin in many days.
Because this patient was in renal failure, we then measured
the blood of other patients with renal insufficiency but not
taking digoxin and found that most immunoassays used at that
time to measure digoxin in blood detected what appeared to
be a digoxin-like immunoreactive substance.
Subsequently, we and other found that humans with several
other normal physiological and clinical conditions also contained
such substances.
 
In preliminary studies, we also showed that these compound
were tightly bound to a protein in blood and that the DLIF
concentrations changed in conditions such as pregnancy and
during cardiovascular stress.
 
Subsequent analysis revealed that DLIFs were, in fact, similar
in structure but sufficiently different from digoxin to be
separated by chromatography and that they also contained 3
sugars and a lactone-ring much like digoxin.
 
Recent work has revealed that DLIF is secreted by the adrenal
glands and also by cultured adrenal cell lines.
Presently, a family of structurally-related DLIF and OLF
compounds is known to exist all with structural similarities
to digoxin and ouabian but produced in humans and other mammals.
What is fascinating about this work is that these DLIFs and
OLFs are now believed to regulate the activity of the sodium
pump (a critically important protein in controlling ion-transport
in cells) and, by that mechanism, exert their physiological
effects. We are actively studying the role of DLIF and OLF
in normal physiology and in pathophysiology (diseases such
as heart failure, psychiatric conditions, vision, etc). |
