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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online March 5, 2001 as doi:10.1096/fj.00-0569fje. |
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Department of Pharmacology and
* Second Department of Internal Medicine, Kagawa Medical University, Kagawa 761-0793, Japan
2Correspondence: Department of Pharmacology, Kagawa Medical University, 1750–1 Miki, Kagawa 761-0793, Japan. E-mail: kimura{at}kms.ac.jp
SPECIFIC AIMS
Myocardial mitochondrial energy metabolism in heart failure is still controversial. We focused on serial changes in the cardiac performance and adenosine triphosphate (ATP) biosynthesis in relation to the gene expression of uncoupling protein 2 (UCP-2), an inner mitochondrial membrane proton transporter, in a rat model of aortic regurgitation (AR) that gradually developed heart failure.
PRINCIPAL FINDINGS
1. AR caused eccentric cardiac hypertrophy and gradually progressed
to heart failure
The tip of a polyethylene catheter (PE-50) was introduced to the
ascending aorta from the right carotid artery of male Sprague-Dawley
rats (body weight 366 g to 415 g) and the cusp of the aortic
valve was punctured. Successful induction of AR was confirmed using
color Doppler echocardiography; rats that had a massive AR jet were
enrolled as AR rats. Serial echocardiographic measurements of left
ventricular geometry and function for the AR and sham rats were
performed. Left ventricular dimension gradually increased after AR
operation (left ventricular diastolic dimension [LVDd], baseline:
80.6 ± 2.6, 7 days; 86.3 ± 1.3, 30 days; 100.2 ± 2.0, 100 days;
108.4 ± 2.1, sham at 100 days; 81.0 ± 1.5 mm). Fractional shortening
in AR rats was not significantly different from that in sham-operated
rats until 30 days after AR operation and was significantly decreased
in AR rats at 100 days (sham: 36.2 ± 1.0, AR: 27.3 ± 0.9%).
Diastolic blood pressure significantly decreased in AR rats without any
change in body weight, heart rate, or systolic blood pressure between
the two groups until 100 days after operation.
2. Cardiac gene expression of UCP-2 was negatively related to that
of atrial natriuretic peptide (ANP) in the early developing stage
In the early developing stage (until 7 days after
AR operation), ANP mRNA expression in left ventricle with AR was
augmented in accordance with left ventricular mass enlargement (vs.
LVDd/body weight, P = 0.01). On the other hand, UCP-2 mRNA
expression was suppressed during this stage (day 1: 102%, day 3: 47%,
day 7: 78% of the sham-operated rats). Although the first day levels
of UCP-2 mRNA in the left ventricle showed no difference from that of
sham rats, 3rd and 7th day levels in AR rats were negatively related
with those of ANP mRNA (P = 0.03) and LVDd/body weight
(P = 0.01), indicating preload-dependent suppression of
cardiac UCP-2 gene expression in this stage of AR (Fig. 1
). Tumor necrosis factor 
(TNF-) mRNA expression in left ventricle
with AR showed no change during the early developing stage.
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3. The cardiac gene expression of UCP-2 was augmented in the late
stage in accompanied by an increment of TNF-
In the late stage (30 and 100 days after AR operation), ANP mRNA
expression was further increased; the level of UCP-2 mRNA in the left
ventricle was gradually increased at 30 days and reached 3.8-fold over
that of sham rats at 100 days after AR development. However, the
expression of UCP-2 mRNA in skeletal muscle was not different between
AR and sham-operated rats (Fig. 2
). Similarly, TNF- mRNA expression in the left ventricle with AR was
significantly increased in the late stage (Fig. 2)
.
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4. Cardiac contents of ATP and creatinine phosphate (CrP) in AR
rats
Although the ATP level was not different between the two groups
throughout the experiment (sham: 20.1 ± 0.5, AR: 21.0 ± 0.4
µmol/g dry tissue at 100 days), the CrP level at 100 days was
significantly reduced in AR rats compared with sham-operated rats
(sham: 14.2±1.2, AR: 10.5±1.0 µmol/g dry tissue).
CONCLUSION
The present study demonstrates serial changes of UCP-2 gene expression in volume-overload left ventricle of AR rats, providing new insight for energy metabolism in the failing heart from the aspect of UCP-2 expression.
In the early stage of AR, expression of ANP mRNA in the left ventricle with AR gradually increased in accordance with left ventricular enlargement, whereas that of UCP-2 was suppressed simultaneously from 3 days after AR development. Crash of the aortic valve caused a sudden and pronounced volume overload to the left ventricle and initiated left ventricular enlargement for maintenance of cardiac output with a subsequent increase in serum natriuretic peptides, leading to circulatory homeostasis. Cardiomyocytes are forced to produce more working drive for contraction in response to increased wall tension. We therefore hypothesized that cellular energy expenditure per cardiac weight concurrently increases during the left ventricular mass enlargement and demonstrated that suppression of UCP-2 mRNA expression may be reflected by the cellular energy state. The results indicate that a decrease in UCP-2 may lead to restriction of proton leakage from mitochondria, and utilization of oxygen in the heart may thereby shift from heat production to ATP biosynthesis.
Former in vivo studies have shown dynamic changes of UCP mRNA expression in muscles according to tissue energy balance. UCP mRNA expression in rat skeletal muscle and heart was suppressed during forced exercise when cellular oxygen demand was augmented under relative hypoxic circumstance. However, a dramatic increase of UCP mRNA expression after secession of exercise has been shown in the skeletal muscle to inhibit excessive ATP production and succeeding oxygen radical formation. Our results and these results indicate that the function of UCP may regulate ATP biosynthesis by shifting cellular oxygen utilization under a variety of loading conditions.
We found that the steady-state level of UCP-2 mRNA of AR rats was increased in the late stage. Left ventricular dimension was further enlarged and fractional shortening decreased at 100 days after AR operation, which was well maintained in the early developing phase despite an enlargement of the left ventricle. The ATP content in AR heart was not different from that of sham rats throughout the experiment. A significant decrease in CrP content, however, became apparent in AR heart at 100 days. Recent NMR clinical studies have demonstrated that CrP, or the ratio of CrP to ATP, decreases in patients with chronic heart failure. It is noteworthy that replacement of the aortic valve in AR patients reduced preload mechanically and left ventricular function as well as the CrP-to-ATP ratio is normalized, indicating that disturbance of left ventricular function based on chronic AR status is not due simply to irreversible left ventricular remodeling, but rather to cell stress that is reversible and related to high-energy phosphate production. It has been clinically recognized that oxygen consumption in the failing heart is not reduced despite impairment of cardiac performance. With this in mind, alteration of cardiac UCP expression in chronic heart failure might provide a possible explanation for reversible left ventricular dysfunction as seen in AR patients.
TNF-, a proinflammatory cytokine, is produced in several types of
heart failure. Previous studies have indicated that TNF- induces
left ventricular systolic dysfunction via some mechanism such as
induction of nitric oxide synthase, inhibitions of
Ca2+ transient, and phosphorylation of the
proteins regulating muscle contraction independently of energy
metabolism. It is known that TNF- stimulates
UCP-2 expression in several organs. In the present study, the
expression of TNF- in the heart significantly increased in the late
stage of AR; this was not seen in the early stage, indicating that
production of TNF- may be a possible mechanism for an induction of
UCP-2 in the late stage of AR. TNF- may be produced in the heart in
association with macrophage and/or cardiac myocyte and may stimulate
the expression of cardiac UCP-2 via autocrine and/or paracrine fashion
in the late phase of heart failure.
Our hypothesis is summarized in Fig. 3
. Former clinical studies show that the prognosis of patients with AR is
associated with left ventricular performance, including left
ventricular remodeling and systolic function. The
present data suggest that the overexpression of UCP-2 may alter energy
efficiency in developing heart failure and that the UCPs may have an
important role in regulating cardiac function.
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FOOTNOTES
1 To read the full text of this article, go to
http://www.fasebj.org/cgi/doi/10.1096/fj.00-0569fje ; to cite this
article, use FASEB J. (March 5, 2001)
10.1096/fj.00-0569fje 
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