bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: April 26, 2024
Abstract
Right
heart
failure
(RHF)
is
a
leading
cause
of
mortality
in
multiple
cardiovascular
diseases
and
preclinical
human
data
suggest
impaired
metabolism
significant
contributor
to
right-sided
cardiac
dysfunction.
Ferroptosis
nonapopotic
form
cell
death
driven
by
metabolism.
Rodent
suggests
ferroptosis
inhibition
can
restore
mitochondrial
electron
transport
chain
function
enhance
contractility
left
models,
but
the
effects
translational
large
animal
models
RHF
are
unknown.
Here,
we
showed
ferrostatin-1
mediated
antagonism
improve
right
structure
pulmonary
artery
banded
pigs.
Molecularly,
restored
cristae
combatted
downregulation
proteins.
Metabolomics
lipidomics
analyses
revealed
improved
fatty
acid
Thus,
these
may
be
therapeutic
target
for
RHF.
Graphical
Circulation Research,
Journal Year:
2024,
Volume and Issue:
136(2)
Published: Dec. 10, 2024
BACKGROUND:
Pulmonary
hypertension
(PH)
is
associated
with
endothelial
dysfunction.
However,
the
cause
of
dysfunction
and
its
impact
on
PH
remain
incompletely
understood.
We
aimed
to
investigate
whether
hypoxia-inducible
FUNDC1
(FUN14
domain-containing
1)-dependent
mitophagy
pathway
underlies
pathogenesis
progression.
METHODS:
first
analyzed
protein
levels
in
lung
samples
from
patients
animal
models.
Using
rodent
models
induced
by
HySu
(hypoxia+SU5416)
or
chronic
hypoxia,
we
further
investigated
development
response
global
cell-type-specific
Fundc1
loss/gain-of-function.
also
spontaneous
mice
inducible
loss
.
In
addition,
histological,
metabolic,
transcriptomic
studies
were
performed
delineate
molecular
mechanisms.
Finally,
findings
validated
vivo
compound
deficiency
HIF2α
(hypoxia-inducible
factor
2α;
Epas1
)
pharmacological
intervention.
RESULTS:
reduced
vessels
clinical
subjects
Global
exacerbated
PH,
while
overexpression
was
protective.
The
effect
mediated
cells
rather
than
smooth
muscle
cells.
Further,
postnatal
sufficient
spontaneously,
whereas
augmenting
protected
against
before
after
onset
disease.
Mechanistically,
impaired
basal
cells,
leading
accumulation
dysfunctional
mitochondria,
metabolic
reprogramming
toward
aerobic
glycolysis,
pseudohypoxia,
senescence,
likely
via
a
mtROS-HIF2α
signaling
pathway.
Subsequently,
-deficient
increased
IGFBP2
(insulin-like
growth
factor-binding
2)
secretion
that
drove
pulmonary
arterial
remodeling
instigate
PH.
proof-of-principle
showed
significant
efficacy
amelioration
targeting
mitophagy,
IGFBP2.
CONCLUSIONS:
Collectively,
show
FUNDC1-mediated
critical
for
homeostasis,
disruption
instigates
pathogenesis.
Given
similar
changes
observed
patients,
our
are
relevance
provide
novel
therapeutic
strategies
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 28, 2025
Abstract
Background
Pulmonary
arterial
hypertension
(PAH)
is
a
rare
but
debilitating
condition
that
causes
exercise
intolerance
and
ultimately
death.
Skeletal
muscle
derangements
contribute
to
depressed
capacity
in
PAH,
the
mechanisms
underlying
dysfunction
including
changes
biology
based
on
fiber
type
are
understudied.
Methods
We
evaluated
capacity,
histopathology,
mitochondrial
density,
proteomics,
metabolomics/lipidomics
of
quadriceps
(
predominately
fast
fibers
)
soleus
slow
fibers)
muscles
monocrotaline
(MCT)
rat
model
PAH.
Results
MCT
rats
exhibited
impaired
capacity.
Surprisingly,
there
were
divergent
atrophic
metabolic
remodeling
rats.
In
,
was
mild
response
only
II
fibers.
contrast,
both
I
atrophied
.
Both
fibrotic
infiltration,
density
reduced
only.
Mitochondrial
proteomics
tissue
profiling
demonstrated
two
distinct
responses
as
had
impairments
oxidative
phosphorylation/fat
metabolism
storage
triacylglycerides.
However,
showed
signs
proteasome
deficiencies
alterations
phosphatidylcholine/phosphatidylethanolamine
homeostasis.
Finally,
metabolites/lipids
serum
identified
potential
novel
biomarkers
PAH
dimethylarginine
pathway,
cysteine,
Conclusion
Our
data
suggests
differential
cachectic
occur
PAH-induced
myopathy.
nominate
biogenesis
activation
druggable
targets
for
PAH-myopathy.
Expert Opinion on Therapeutic Targets,
Journal Year:
2025,
Volume and Issue:
unknown
Published: May 14, 2025
Pulmonary
arterial
hypertension
(PAH)
is
a
progressive,
life-threatening
disease
driven
by
vascular
remodeling,
right
ventricular
(RV)
dysfunction,
and
metabolic
inflammatory
dysregulation.
Current
therapies
primarily
target
vasodilation
to
relieve
symptoms
but
do
not
reverse
progression.
The
recent
approval
of
sotatercept,
which
modulates
BMP/TGF-β
signaling,
marks
shift
toward
anti-remodeling
therapies.
Building
on
this,
preclinical
advances
have
identified
promising
therapeutic
targets
potentially
disease-modifying
treatments.
This
review
synthesizes
the
evolving
landscape
emerging
PAH
drugs,
highlighting
innovative
approaches
aimed
at
addressing
underlying
mechanisms
Additionally,
we
discuss
novel
strategies
under
development.
Recent
in
research
beyond
vasodilators,
including
modulation
programs,
epigenetics,
cancer-related
extracellular
matrix,
immune
pathways,
among
others.
Sotatercept
represents
significant
advance
that
go
vasodilation,
long-term
safety,
efficacy,
durability
are
being
assessed.
Future
treatment
will
focus
precision
approaches,
noninvasive
technologies,
regenerative
biology
improve
outcomes
remodeling.
