J Am Coll Cardiol. 2013 Feb 12
Mitochondria as a therapeutic target in heart
failure.
Abstract
Heart failure is a pressing public health problem with
no curative treatment currently available. The existing
therapies provide symptomatic relief, but are unable to
reverse molecular changes that occur in cardiomyocytes.
The mechanisms of heart failure are complex and
multiple, but mitochondrial dysfunction appears to be a
critical factor in the development of this disease.
Thus, it is important to focus research efforts on
targeting mitochondrial dysfunction in the failing heart
to revive the myocardium and its contractile function.
This review highlights the 3 promising areas for the
development of heart failure therapies, including
mitochondrial biogenesis, mitochondrial oxidative
stress, and mitochondrial iron handling. Moreover, the
translational potential of compounds targeting these
pathways is discussed.
J Mol Cell Cardiol. 2013 Feb
Mitochondria in cardiac hypertrophy and heart
failure.
Abstract
Heart failure (HF) frequently is the unfavorable outcome
of pathological heart hypertrophy. In contrast to
physiological cardiac hypertrophy, which occurs in
response to exercise and leads to full adaptation of
contractility to the increased wall stress, pathological
hypertrophy occurs in response to volume or pressure
overload, ultimately leading to contractile dysfunction
and HF.
Because cardiac hypertrophy impairs the
relationship between ATP demand and production,
mitochondrial bioenergetics must keep up with the
cardiac hypertrophic phenotype. We review data regarding
the mitochondrial proteomic and energetic remodeling in
cardiac hypertrophy, as well as the temporal and causal
relationships between mitochondrial failure to match the
increased energy demand and progression to cardiac decompensation.
We suggest that the maladaptive effect
of sustained neuroendocrine signals on mitochondria
leads to bioenergetic fading which contributes to the
progression from cardiac hypertrophy to failure. This
article is part of a Special Issue entitled "Focus on
Cardiac Metabolism".
Mol Cell Biochem. 2013 Jan
Skeletal
muscle mitochondrial dysfunction precedes
right ventricular impairment in experimental pulmonary
hypertension.
Abstract
We assessed the time courses of mitochondrial biogenesis
factors and respiration in the right ventricle (RV),
gastrocnemius (GAS), and left ventricle (LV) in a model
of pulmonary-hypertensive rats. Monocrotaline (MT) rats
and controls were studied 2 and 4 weeks after injection.
Compensated and decompensated heart failure stages were
defined according to obvious congestion signs. mRNA
expression and protein level of peroxisome proliferator
activated receptor gamma co-activator 1α (PGC-1α),
citrate synthase (CS) mRNA and activity, and
mitochondrial respiration were investigated. In
addition, mRNA expression of sirtuin1, nuclear
respiratory factor 1, and mitochondrial transcription
factor A were studied.
As early as 2 weeks, the
expression of the studied genes was decreased in the MT
GAS. At 4 weeks, the MT GAS and MT RV showed decreased
mRNA levels whatever the stage of disease, but PGC-1α
protein and CS activity were significantly reduced only
at the decompensated stage. The functional result was a
significant fall in mitochondrial respiration at the
decompensated stage in the RV and GAS. The mRNA
expression and mitochondrial respiration were not
significantly modified in the MT LV. MT rats
demonstrated an early decrease in expression of genes
involved in mitochondrial biogenesis in a skeletal
muscle, whereas reduced protein expression, and the
resulting mitochondrial respiratory dysfunction appeared
only in rats with overt heart failure, in the GAS and
RV. Dissociations between mRNA and protein levels at the
compensated stage deserve to be further studied.
J Am Heart Assoc. 2012 Oct
OPA1
mutation and late-onset cardiomyopathy:
mitochondrial dysfunction and mtDNA instability.
Abstract
BACKGROUND: Mitochondrial fusion
protein mutations are a cause of inherited neuropathies
such as Charcot-Marie-Tooth disease and dominant optic
atrophy. Previously we reported that the fusion protein
optic atrophy 1 (OPA1) is decreased in heart failure.
METHODS AND RESULTS: We investigated
cardiac function, mitochondrial function, and mtDNA
stability in a mouse model of the disease with OPA1
mutation. The homozygous mutation is embryonic lethal.
Heterozygous OPA(+/-) mice exhibit reduced mtDNA copy
number and decreased expression of nuclear antioxidant
genes at 3 to 4 months. Although initial cardiac
function was normal, at 12 months the OPA1(+/-) mouse
hearts had decreased fractional shortening, cardiac
output, and myocyte contraction. This coincided with the
onset of blindness. In addition to small fragmented
mitochondria, aged OPA1(+/-) mice had impaired cardiac
mitochondrial function compared with wild-type
littermates.
CONCLUSIONS: OPA1 mutation leads to
deficiency in antioxidant transcripts, increased
reactive oxygen species, mitochondrial dysfunction, and
late-onset cardiomyopathy.
Circ Res. 2012 Oct 12
Mitochondria as a drug target in ischemic heart
disease and cardiomyopathy.
Abstract
Ischemic heart disease is a significant cause of
morbidity and mortality in Western society. Although
interventions, such as thrombolysis and percutaneous
coronary intervention, have proven efficacious in
ischemia and reperfusion injury, the underlying
pathological process of ischemic heart disease,
laboratory studies suggest further protection is
possible, and an expansive research effort is aimed at
bringing new therapeutic options to the clinic.
Mitochondrial dysfunction plays a key role in the
pathogenesis of ischemia and reperfusion injury and
cardiomyopathy. However, despite promising
mitochondria-targeted drugs emerging from the
laboratory, very few have successfully completed
clinical trials. As such, the mitochondrion is a
potential untapped target for new ischemic heart disease
and cardiomyopathy therapies.
Notably, there are a number of overlapping therapies for
both these diseases, and as such novel therapeutic
options for one condition may find use in the other.
This review summarizes efforts to date in targeting
mitochondria for ischemic heart disease and
cardiomyopathy therapy and outlines emerging drug
targets in this field.
Int J Mol Sci. 2012 Nov 30
Alterations in glutathione redox
metabolism, oxidative stress, and
mitochondrial function in the left ventricle of elderly
zucker diabetic Fatty rat heart.
Abstract
The Zucker diabetic fatty (ZDF) rat is a genetic model
in which the homozygous (FA/FA) male animals develop
obesity and type 2 diabetes. Morbidity and mortality
from cardiovascular complications, due to increased
oxidative stress and inflammatory signals, are the
hallmarks of type 2 diabetes.
The precise molecular
mechanism of contractile dysfunction and disease
progression remains to be clarified. Therefore, we have
investigated molecular and metabolic targets in male ZDF
(30–34 weeks old) rat heart compared to age
matched Zucker lean (ZL) controls. Hyperglycemia was
confirmed by a 4-fold elevation in non-fasting blood
glucose (478.43 ± 29.22 mg/dL in ZDF vs. 108.22
± 2.52 mg/dL in ZL rats). An increase in reactive
oxygen species production, lipid peroxidation and
oxidative protein carbonylation was observed in ZDF
rats. A significant increase in CYP4502E1 activity
accompanied by increased protein expression was also
observed in diabetic rat heart. Increased expression of
other oxidative stress marker proteins, HO-1 and iNOS
was also observed. GSH concentration and activities of
GSH-dependent enzymes, glutathione S-transferase and GSH
reductase, were, however, significantly increased in ZDF
heart tissue suggesting a compensatory defense
mechanism.
The activities of mitochondrial respiratory
enzymes, Complex I and Complex IV were significantly
reduced in the heart ventricle of ZDF rats in comparison
to ZL rats. Western blot analysis has also suggested a
decreased expression of IκB-α and phosphorylated-JNK in diabetic heart tissue. Our results
have suggested that mitochondrial dysfunction and
increased oxidative stress in ZDF rats might be
associated, at least in part, with altered
NF-κB/JNK dependent redox cell signaling. These
results might have implications in the elucidation of
the mechanism of disease progression and designing
strategies for diabetes prevention.
