Mitochondrial abnormalities in myocardium of dogs with chronic heart failure

Sabbah, Hani N.; Sharov, Victor G.; Riddle, Jeanne M.; Kono, Tatsuji; Lesch, Michael; Goldstein, Sidney

doi:10.1016/0022-2828(92)93098-5

Cited by 133 publications

(98 citation statements)

References 30 publications

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“…There also is evidence of ETC abnormalities. For example, abnormalities in mitochondrial morphology (31,41) and in complexes I, III, IV, and V of the ETC have been reported to occur in animal models of heart failure (20,33) and human patients with heart failure (2, 21). However, defects in mitochondrial function may be dependent on the method by which heart failure is induced.…”

Section: Discussionmentioning

confidence: 99%

High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction

Rennison¹,

McElfresh²,

Okere³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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November 17, 2006; doi:10.1152/ajpheart.01021.2006.-Lipid accumulation in nonadipose tissue due to enhanced circulating fatty acids may play a role in the pathophysiology of heart failure, obesity, and diabetes. Accumulation of myocardial lipids and related intermediates, e.g., ceramide, is associated with decreased contractile function, mitochondrial oxidative phosphorylation, and electron transport chain (ETC) complex activities. We tested the hypothesis that the progression of heart failure would be exacerbated by elevated myocardial lipids and an associated ceramide-induced inhibition of mitochondrial oxidative phosphorylation and ETC complex activities. Heart failure (HF) was induced by coronary artery ligation. Rats were then randomly assigned to either a normal (10% kcal from fat; HF, n ϭ 8) or high saturated fat diet (60% kcal from saturated fat; HF ϩ Sat, n ϭ 7). Sham-operated animals (sham; n ϭ 8) were fed a normal diet. Eight weeks postligation, left ventricular (LV) function was assessed by echocardiography and catheterization. Subsarcolemmal and interfibrillar mitochondria were isolated from the LV. Heart failure resulted in impaired LV contractile function [decreased percent fractional shortening and peak rate of LV pressure rise and fall (ϮdP/dt)] and remodeling (increased end-diastolic and end-systolic dimensions) in HF compared with sham. No further progression of LV dysfunction was evident in HF ϩ Sat. Mitochondrial state 3 respiration was increased in HF ϩ Sat compared with HF despite elevated myocardial ceramide. Activities of ETC complexes II and IV were elevated in HF ϩ Sat compared with HF and sham. High saturated fat feeding following coronary artery ligation was associated with increased oxidative phosphorylation and ETC complex activities and did not adversely affect LV contractile function or remodeling, despite elevations in myocardial ceramide. oxidative phosphorylation; electron transport chain; ceramide; lipotoxicity FATTY ACIDS (FA) are the dominant energy source for the adult mammalian heart and also are utilized for membrane biosynthesis, generation of lipid signaling molecules, posttranslational protein modification, and transcriptional regulation (43). Chronic exposure to FA can result in an imbalance between FA uptake and utilization that potentially can trigger cytotoxic mechanisms, leading to cell dysfunction or death, a phenomenon known as lipotoxicity. Extensive clinical and animal studies have shown that excess lipid accumulation in nonadipose tissue due to enhanced circulating FA may play an important role in pathophysiological conditions such as heart failure, obesity, insulin resistance, and diabetes (15,43,58).A loss of synchronization between FA availability and utilization in cardiomyocytes, despite otherwise normal or upregulated ␤-oxidation capacity, can lead to an increase in the accumulation of tissue ceramide (24). Ceramide, a lipid signaling molecule, has been implicated in the formation of reactive oxygen species and peroxidation of membrane lipids (11), a...

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Section: Discussionmentioning

confidence: 99%

High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction

Rennison¹,

McElfresh²,

Okere³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…23 The progressive deterioration of LV function in heart failure is reportedly due to an ongoing loss of viable myocytes. 24,25 Active myocardial necrosis is uncommon in DCM and an ongoing process of myocyte dropout or apoptosis may lead to a progressive deterioration in myocardial function. 26 Thus, our observation of a correlation between the percentage of in situ TdT stained myocytes and the severity of cardiac dysfunction suggests that myocardial damage by apoptosis may contribute to the cardiac dysfunction in patients with DCM.…”

Section: Discussionmentioning

confidence: 99%

Fas Expression and Apoptosis Correlate With Cardiac Dysfunction in Patients With Dilated Cardiomyopathy

et al. 1999

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“…We previously showed that cardiomyocytes in failing heart exhibit ultrastructural abnormalities of mitochondria including matrix swelling, unfolding of cristae and damage of inner membrane [1]. These morphological abnormatities in mitochondria of the failing heart occur with decreased state-3 respiration in human cardiomyopathy [2] and in experimental canine ischemic cardiomyopathy [3].…”

Section: Introductionmentioning

confidence: 98%

“…MPTP inhibitor cyclosporine A (CsA) completely blocks MPTP and prevents swelling of brain mitochondria induced by calcium insult [5] or by transient ischemia [6]. The role of MPTP in mitochondrial abnormalities described in viable cardiomyocytes of failing heart [1] is not clear. The data about the effect of of CsA in cardiomyocytes with intact sarcolemma are also very limited.…”

Section: Introductionmentioning

confidence: 99%

Cyclosporine A attenuates mitochondrial permeability transition and improves mitochondrial respiratory function in cardiomyocytes isolated from dogs with heart failure

Sharov

Todor

Khanal

et al. 2007

Journal of Molecular and Cellular Cardiology

101

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Objective-We used isolated cardiomyocytes to investigate a possible role of mitochondrial permeability transition pore in mitochondrial abnormalities associated with heart failure.Methods-Cardiomyocytes were isolated from LV myocardium of normal control dogs and dogs with heart failure produced by intracoronary microembolizations. Mitochondrial permeability transition was measured in isolated cardiomyocytes with intact sarcolemma with and without 0.2 μM Cyclosporin A using calcein AM and the fluorometer. State-3 mitochondrial respiration was also measured with the Clark electrode. Mitochondrial membrane potential was measured with JC-1 probe using the fluorometer. Propidium iodide was used to ensure sarcolemma integrity.Results-200 minutes after loading with calcein AM, mitochondria of failing cardiomyocytes showed only 50% of maximal level of calcein fluorescence while it remained unchanged in normal cells. The mitochondrial membrane potential in failing cardiomyocytes was significantly decreased by 38% compared to normal cardiomyocytes. Cyclosporine A significantly slowed the exit of calcein from mitochondria of failing cardiomyocytes and increased mitochondrial membrane potential by 29%. State-3 respiration was not affected with Cyclosporine A in normal cardiomyocytes while it was significantly increased in failing cardiomyocytes by 20%.Conclusions-Exit of calcein (m.w. 1.0 kDa) from mitochondria of viable failing cardiomyocytes with intact sarcolemma suggests an existence of a reversible transitory permeability transition opening in high conductance mode. Attenuation of calcein exit, ΔΨ m and improvement of state-3 respiration achieved with CsA (0.2 μM) show that permeability transition opening could be a cause of mitochondrial dysfunction described in the failing heart.

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Mitochondrial abnormalities in myocardium of dogs with chronic heart failure

Cited by 133 publications

References 30 publications

High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction

High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction

Fas Expression and Apoptosis Correlate With Cardiac Dysfunction in Patients With Dilated Cardiomyopathy

Cyclosporine A attenuates mitochondrial permeability transition and improves mitochondrial respiratory function in cardiomyocytes isolated from dogs with heart failure

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