The inherited cardiomyopathies,
h
ypertrophic cardiomyopathy (HCM) and
dilated cardiomyopathy (DCM) are relatively common, potentially life
-
threatening and
currently untreatable.
Mutations are often in the contractile proteins of cardiac
muscle and cause abnormal Ca
2+
regulation
via
troponin.
HCM is
usually
linked to
higher myofilament Ca
2+
-
sensitivity
whilst in both HCM and DCM mutant tissue there
is often
an uncoupling of the relationship between troponin I (TnI) phosphorylation by
PKA and modulation of myofilament Ca
2+
-
sensitivity, essential for normal responses
to adrenaline.
The adrenergic response is blunted,
and this may predispose the
heart
to failu
re under stress
.
At
present
there
are
no
compounds
or
interventions
that
can
prevent
or
trea
t
sarcomeric
cardiomyopathies
.
There
is
a
need
for
novel
therapies
that
act
at
a
more
fundamental
level
to
affect
the
disease
process.
W
e
demonstrated
that
epigallocatechin
-
3
gallate
(EGCG)
was
found
to
be
capable
of
restoring
the
coupled
relationship
between
Ca
2+
-
sensitivity
and
TnI
phosphorylation
in
mutant
thin
filaments
to
normal
in
vitro
,
independent
of
the
mutation
(15
mutations
tested)
.
W
e
have
labelled
this
property
“re
-
coupling”
.
The
action
of
EGCG
in
vitro
to
reverse
the
abnormality
caused
by
myopathic
mutations
would
appear
to
be
an
ideal
pharmaceutical
profile
for
trea
tment
of
inherited
HCM
and
DCM
but
EGCG
is
known
to
be
promiscuous
i
n
vivo
and
is
thus
unsuitable
as
therapeutic
drug.
We
t
herefore
investigate
d
whether
other
structurally
related
compounds
can
r
e
-
couple
myofilaments
without
these
off
-
target
effects.
We used the quantitative
in vitro
motility assay to screen 40 compounds
,
related to
C
-
terminal Hsp90 inhibitors,
and found 23 that can re
-
couple mutant myofilaments.
There is no correlation between re
-
couplers and Hsp90 inhibitors
.
The Ca
2+
-
sensitivity shift due to
TnI
phosphorylation was restored to 2.2±0.01
–
fold (n=19)
compared to 2.0±.24 fold (n=7) in wild
-
type thin filaments.
Many of these compounds
were either pure re
-
couplers or pure desensitisers,
indicating these properties are
independent
; moreover
,
re
-
couplin
g ability could be lost with small changes of
compound structure, indicating the possibility of specificity.
Smal
l molecules that can
re
-
couple may have
therapeutic potential.