Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload

Doenst, Torsten; Pytel, Gracjan; Schrepper, Andrea; Amorim, Paulo A.; Färber, Gloria; Shingu, Yasushige; Mohr, Friedrich W.; Schwarzer, Michael

doi:10.1093/cvr/cvp414

Cited by 221 publications

(192 citation statements)

References 43 publications

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“…This is in line with what has been shown in children with right ventricular failure secondary to congenital heart disease48 and in mice with myocardial remodeling and failure postinfarction 49. It has been shown that PGC‐1α controls mitochondrial density50 and fatty acid oxidation51, 52 and its amount directly correlates with mitochondrial density, oxidative capacity,47 and the metabolic shift from fatty acid oxidation to glucose oxidation,51 which precedes cardiac decompensation 46. Previous studies assessing changes in the expression and activity of the ETC complexes in HF have shown variable results, and such changes may vary according to the HF model 45.…”

Section: Discussionsupporting

confidence: 87%

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Chaanine

Nair

Bergen

et al. 2017

JAHA

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BackgroundFollowing pressure overload, compensatory concentric left ventricular remodeling (CR) variably transitions to eccentric remodeling (ER) and systolic dysfunction. Mechanisms responsible for this transition are incompletely understood. Here we leverage phenotypic variability in pressure overload–induced cardiac remodeling to test the hypothesis that altered mitochondrial homeostasis and calcium handling occur early in the transition from CR to ER, before overt systolic dysfunction.Methods and ResultsSprague Dawley rats were subjected to ascending aortic banding, (n=68) or sham procedure (n=5). At 3 weeks post–ascending aortic banding, all rats showed CR (left ventricular volumes < sham). At 8 weeks post–ascending aortic banding, ejection fraction was increased or preserved but 3 geometric phenotypes were evident despite similar pressure overload severity: persistent CR, mild ER, and moderate ER with left ventricular volumes lower than, similar to, and higher than sham, respectively. Relative to sham, CR and mild ER phenotypes displayed increased phospholamban, S16 phosphorylation, reduced sodium‐calcium exchanger expression, and increased mitochondrial biogenesis/content and normal oxidative capacity, whereas moderate ER phenotype displayed decreased p‐phospholamban, S16, increased sodium‐calcium exchanger expression, similar degree of mitochondrial biogenesis/content, and impaired oxidative capacity with unique activation of mitochondrial autophagy and apoptosis markers (BNIP3 and Bax/Bcl‐2).ConclusionsAfter pressure overload, mitochondrial biogenesis and function and calcium handling are enhanced in compensatory CR. The transition to mild ER is associated with decrease in mitochondrial biogenesis and content; however, the progression to moderate ER is associated with enhanced mitochondrial autophagy/apoptosis and impaired mitochondrial function and calcium handling, which precede the onset of overt systolic dysfunction.

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Section: Discussionsupporting

confidence: 87%

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Chaanine

Nair

Bergen

et al. 2017

JAHA

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“…This early time point following banding was chosen due to the quick decline in the survival of Chip -/-mice following the induction of pressure overload ( Figure 1B). Following 1 week of banding, total ATP levels in extracts isolated from wild-type mice increased 1.8 fold ( Figure 2D and Supplemental Table 5), consistent with recent metabolic studies demonstrating energetic adaptation to maintain cardiac power during the initial compensation to pressure overload (20,21). In contrast, total ATP levels failed to increase in extracts isolated from Chip -/-banded hearts, supporting the theory that CHIP may be involved in ATP generation during cardiac pressure overload.…”

Section: Figuresupporting

confidence: 86%

CHIP protects against cardiac pressure overload through regulation of AMPK

Schisler

Rubel²,

Zhang³

et al. 2013

J. Clin. Invest.

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Protein quality control and metabolic homeostasis are integral to maintaining cardiac function during stress; however, little is known about if or how these systems interact. Here we demonstrate that C terminus of HSC70-interacting protein (CHIP), a regulator of protein quality control, influences the metabolic response to pressure overload by direct regulation of the catalytic α subunit of AMPK. Induction of cardiac pressure overload in Chip -/-mice resulted in robust hypertrophy and decreased cardiac function and energy generation stemming from a failure to activate AMPK. Mechanistically, CHIP promoted LKB1-mediated phosphorylation of AMPK, increased the specific activity of AMPK, and was necessary and sufficient for stress-dependent activation of AMPK. CHIP-dependent effects on AMPK activity were accompanied by conformational changes specific to the α subunit, both in vitro and in vivo, identifying AMPK as the first physiological substrate for CHIP chaperone activity and establishing a link between cardiac proteolytic and metabolic pathways. IntroductionPathological cardiac hypertrophy (subsequently referred to as cardiac hypertrophy) is an adaptive response to increased afterload brought about by hypertension, decreased arterial compliance, and other cardiac stressors (1). During the development of cardiac hypertrophy, numerous cellular processes come into play, including protein synthesis and proteolysis to account for the structural changes that accompany hypertrophy, as well as changes in cardiac metabolism to cope with increased energy demands. Despite the well-known fact that protein turnover and metabolic changes accompany cardiac hypertrophy, surprisingly little is known about how stress-dependent protein quality control mechanisms and metabolic regulation are coordinated, if at all, in the heart. C terminus of HSC70-interacting protein (CHIP, also known as STUB1) is a 35-kDa cytosolic protein initially identified in a screen for proteins that interact with the mammalian chaperones HSC70, HSP70 (2), and HSP90 (3). CHIP is ubiquitously expressed in mammalian tissues but is expressed at highest levels in the adult heart (2). CHIP plays an important dual role as both a cochaperone and a ubiquitin ligase (2-5). More recently, however, an additional role for CHIP in protein quality control has been suggested. Evidence that CHIP can act as an autonomous chaperone, independent of its association with HSPs, has been reported (6). However, these observations were made with a nonphysiological substrate (luciferase), and, to date, verification of CHIP's chaperone activity and identification of a physiological substrate have not been made.Changes in cardiac metabolism, such as oxidative substrate preference, mitochondrial function, and biogenesis, play a key role in the adaptive response to cardiac stress (7). As cardiomyocyte hypertrophy progresses, energy demand increases and cellu-

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“…In a model of aortic arch constriction, Doenst et al 60 investigated cardiac function and fatty acid and glucose metabolism during the development of hypertrophy and heart failure. Diastolic and systolic dysfunction were observed at 6 weeks and 10 weeks, respectively, following aortic constriction.…”

Section: Cardiac Metabolism In Left Heart Failurementioning

confidence: 99%

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

Sankaralingam

Lopaschuk

2015

Pulm. circ.

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Pressure overload of the heart, such as seen with pulmonary hypertension and/or systemic hypertension, can result in cardiac hypertrophy and the eventual development of heart failure. The development of hypertrophy and heart failure is accompanied by numerous molecular changes in the heart, including alterations in cardiac energy metabolism. Under normal conditions, the high energy (adenosine triphosphate [ATP]) demands of the heart are primarily provided by the mitochondrial oxidation of fatty acids, carbohydrates (glucose and lactate), and ketones. In contrast, the hypertrophied failing heart is energy deficient because of its inability to produce adequate amounts of ATP. This can be attributed to a reduction in mitochondrial oxidative metabolism, with the heart becoming more reliant on glycolysis as a source of ATP production. If glycolysis is uncoupled from glucose oxidation, a decrease in cardiac efficiency can occur, which can contribute to the severity of heart failure due to pressure-overload hypertrophy. These metabolic changes are accompanied by alterations in the enzymes that are involved in the regulation of fatty acid and carbohydrate metabolism. It is now becoming clear that optimizing both energy production and the source of energy production are potential targets for pharmacological intervention aimed at improving cardiac function in the hypertrophied failing heart. In this review, we will focus on what alterations in energy metabolism occur in pressure overload induced left and right heart failure. We will also discuss potential targets and pharmacological approaches that can be used to treat heart failure occurring secondary to pulmonary hypertension and/or systemic hypertension.

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Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload

Cited by 221 publications

References 43 publications

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

CHIP protects against cardiac pressure overload through regulation of AMPK

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

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