Induction of heart failure by minimally invasive aortic constriction in mice: reduced peroxisome proliferator-activated receptor γ coactivator levels and mitochondrial dysfunction.
ABSTRACT Mitochondrial dysfunction has been suggested as a potential cause for heart failure. Pressure overload is a common cause for heart failure. However, implementing pressure overload in mice is considered a model for compensated hypertrophy but not for heart failure. We assessed the suitability of minimally invasive transverse aortic constriction to induce heart failure in C57BL/6 mice and assessed mitochondrial biogenesis and function.
Minimally invasive transverse aortic constriction was performed through a ministernotomy without intubation (minimally invasive transverse aortic constriction, n = 68; sham operation, n = 43). Hypertrophy was assessed based on heart weight/body weight ratios and histologic analyses, and contractile function was assessed based on intracardiac Millar pressure measurements. Expression of selected metabolic genes was assessed with reverse transcription-polymerase chain reaction and Western blotting. Maximal respiratory capacity (state 3) of isolated mitochondria was measured with a Clark-type electrode.
Survival was 62%. Within 7 weeks, minimally invasive transverse aortic constriction induced significant hypertrophy (heart weight/body weight ratio: 10.08±0.28 mg/g for minimally invasive transverse aortic constriction vs 4.66±0.07 mg/g for sham operation; n=68; P<.01). Fifty-seven percent of mice undergoing minimally invasive transverse aortic constriction displayed signs of heart failure (pleural effusions, dyspnea, weight loss, and dp/dtmax of 3114±422 mm Hg/s, P<.05). All of them had heart weight/body weight ratios of greater than 10. Mice undergoing minimally invasive transverse aortic constriction with heart weight/body weight ratios of less than 10 had normal contractile function (dp/dtmax of 6471±292 mm Hg/s vs dp/dtmax of 6933±205 mmHg/s in sham mice) and no clinical signs of heart failure. The mitochondrial coactivator peroxisome proliferator-activated receptor γ coactivator alpha (PGC-1α) was downregulated in failing hearts only. PGC-1α and fatty acid oxidation gene expression were also decreased in failing hearts. State 3 respiration of isolated mitochondria was significantly reduced in all hearts subjected to pressure overload.
Contractile dysfunction and heart failure can be induced in wild-type mice by means of minimally invasive aortic constriction. Pressure overload-induced heart failure in mice is associated with mitochondrial dysfunction, as characterized by downregulation of PGC-1α and reduced oxidative capacity.
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ABSTRACT: The heart consumes huge amounts of energy to fulfil its function as a relentless pump. A highly sophisticated system of energy generation based on flexibility of substrate use and efficient energy production, effective energy sensing and energy transfer ensures function of the healthy heart across a range of physiological situations. In left ventricular hypertrophy and heart failure, these processes become disturbed, leading as will be discussed to impaired cardiac energetic status and to further impairment of cardiac function. These metabolic disturbances form a potential target for therapy.Heart Failure Reviews 11/2012; · 4.45 Impact Factor
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ABSTRACT: In mice, transverse aortic constriction (TAC) is variably characterized as a model of pressure overload-induced hypertrophy (left ventricular [LV] hypertrophy, or LVH) or heart failure (HF). While commonly used, variability in the TAC model is poorly defined. The objectives of this study were to characterize the variability in the TAC model and to define a simple, noninvasive method of prospectively identifying mice with HF versus compensated LVH after TAC. Eight-week-old male C57BL/6J mice underwent TAC or sham and then echocardiography at 3 weeks post-TAC. A group of sham and TAC mice were euthanized after the 3-week echocardiogram, while the remainder underwent repeat echocardiography and were euthanized at 9 weeks post-TAC. The presence of TAC was assessed with two-dimensional echocardiography, anatomic aortic m-mode and color flow, and pulsed-wave Doppler examination of the transverse aorta (TA) and by LV systolic pressure (LVP). Trans-TAC pressure gradient was assessed invasively in a subset of mice. HF was defined as lung/body weight>upper limit in sham-operated mice. As compared with sham, TAC mice had higher TA velocity, LVP and LV weight, and lower ejection fraction (EF) at 3 or 9 weeks post-TAC. Only a subset of TAC mice (28%) developed HF. As compared with compensated LVH, HF mice were characterized by similar TA velocity and higher percent TA stenosis, but lower LVP, higher LV weight, larger LV cavity, lower EF and stress-corrected midwall fiber shortening, and more fibrosis. Both EF and LV mass measured by echocardiography at 3 weeks post-TAC were predictive of the presence of HF at 3 or 9 weeks post-TAC. In wild-type mice, TAC produces a variable cardiac phenotype. Marked abnormalities in LV mass and EF at echocardiography 3 weeks post-TAC identify mice with HF at autopsy. These data are relevant to appropriate design and interpretation of murine studies.Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 07/2011; 21(3):188-98. · 1.63 Impact Factor
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ABSTRACT: 5'-adenosine monophosphate-activated protein kinase (AMPK) is considered central in regulation of energy status and substrate utilization within cells. In heart failure the energetic state is compromised and substrate metabolism is altered. We hypothesized that this could be linked to changes in AMPK activity and we therefore investigated mitochondrial oxidative phosphorylation capacity from the oxidation of long- and medium-chain fatty acids (LCFA and MCFA) in cardiomyocytes from young and old mice expressing a dominant negative AMPKα2 (AMPKα2-KD) construct and their wildtype (WT) littermates. We found a 35-45% (P < 0.05) lower mitochondrial capacity for oxidizing MCFA in AMPKα2-KD of both age-groups, compared to WT. This coincided with marked decreases in protein expression (19/29%, P < 0.05) and activity (14/21%, P < 0.05) of 3-hydroxyacyl-CoA-dehydrogenase (HAD), in young and old AMPKα2-KD mice, respectively, compared to WT. Maximal LCFA oxidation capacity was similar in AMPKα2-KD and WT mice independently of age implying that LCFA-transport into the mitochondria was unaffected by loss of AMPK activity or progressing age. Expression of regulatory proteins of glycolysis and glycogen breakdown showed equivocal effects of age and genotype. These results illustrate that AMPK is necessary for normal mitochondrial function in the heart and that decreased AMPK activity may lead to an altered energetic state as a consequence of reduced capacity to oxidize MCFA. We did not identify any clear aging effects on mitochondrial function.Frontiers in Physiology 01/2012; 3:33.