NHE-1 inhibition improves impaired mitochondrial permeability transition and respiratory function during postinfarction remodelling in the rat

Javadov, Sabzali; Huang, Cathy; Kirshenbaum, Lorrie A.; Karmazyn, Morris

doi:10.1016/j.yjmcc.2004.10.007

Cited by 76 publications

(70 citation statements)

References 35 publications

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“…Interestingly, when either NHE-1, p90 RSK , or NCX rev was inhibited during 60-min REOX, loss of ⌿ m and Ca 2ϩ m accumulation in dendrites was significantly reduced. This finding is consistent with the earlier reports on NHE-1 inhibition-induced attenuation of the mitochondrial Ca 2ϩ overload and mitochondrial permeability transition pore opening in cardiomyocytes and in ischemic/reperfused rat hearts (43)(44)(45). Taken together, these studies demonstrate a conserved role of the NHE-1 signaling mechanism in ischemic reperfusion injury among multiple cell types.…”

Section: Nhe-1-mediated Nasupporting

confidence: 93%

Excessive Na+/H+ Exchange in Disruption of Dendritic Na+ and Ca2+ Homeostasis and Mitochondrial Dysfunction following in Vitro Ischemia

Kintner

Chen

Currie

et al. 2010

Journal of Biological Chemistry

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Neuronal dendrites are vulnerable to injury under diverse pathological conditions. However, the underlying mechanisms for dendritic Na ؉ overload and the selective dendritic injury remain poorly understood. Our current study demonstrates that activation of NHE-1 (Na ؉ /H ؉ exchanger isoform 1) in dendrites presents a major pathway for Na ؉ overload. Neuronal dendrites exhibited higher pH i regulation rates than soma as a result of a larger surface area/volume ratio. Neuronal dendrites are vulnerable to injury under diverse pathological conditions, including cerebral ischemia, epilepsy, and Alzheimer disease (1, 2). The hallmark of dendritic injury is the formation of focal swelling or beads along the length of the dendritic arbor (3). However, the underlying mechanisms for this selective dendritic injury remain poorly understood. The initial NMDA or kainite-mediated swelling in dendrites of cultured neurons depends on intracellular accumulation of Na ϩ and Cl Ϫ but not Ca 2ϩ (4). On the other hand, excessive Ca 2ϩ entry plays a role in the long lasting structural damage and delayed recovery in hippocampal slices in response to NMDA (4, 5). A correlation between dendritic bead formation and ATP reduction/mitochondrial dysfunction has been demonstrated in cultured hippocampal neurons following glutamate exposure (6). However, the relationship between selective dendritic damage, loss of Na ϩ and Ca 2ϩ homeostasis, and mitochondrial dysfunction following ischemia remains to be defined.NHE-1 (Na ϩ /H ϩ exchanger isoform 1) is a plasma membrane protein present in virtually all mammalian cells and plays a central role in intracellular pH (pH i ) and cell volume regulation (7). NHE-1 activity is directly activated by intracellular acidification and/or by protein phosphorylation mediated by ERK-p90 ribosomal S6 kinase (p90 RSK ) 2 in ischemic neurons (8). Excessive NHE-1 activation results in intracellular Na ϩ accumulation, which subsequently promotes Ca 2ϩ entry via reversal of Na ϩ /Ca 2ϩ exchange (NCX rev ) and plays an important role in myocardium ischemia/reperfusion injury (9). We recently reported that NHE-1 activity in the soma of neurons and astrocytes is stimulated following ischemia, and inhibition of NHE-1 activity is neuroprotective (8, 10). In addition, inhibition of NHE-1 either pharmacologically or by genetic knockdown reduces infarction at 24 h following in vivo focal ischemia (11). However, it remains unexplored whether concurrent activation of NHE-1 and NCX rev contributes to the selective vulnerability of postsynaptic neuronal dendrites to ischemic damage.In the current study, we demonstrated that neurons exhibited robust NHE-1-dependent pH i regulation in their dendrites as a result of their large surface area/volume ratio. Further, in vitro ischemia (oxygen glucose deprivation and reoxygenation, * This work was supported, in whole or in part, by National Institutes of Health Grants RO1NS48216 (to D. S.), R01 GM071434 (to J. T.), MS RG-4054-A-8 (to S.-Y. C.), P30 HD03352 (to the Waisman Center), and...

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Section: Nhe-1-mediated Nasupporting

confidence: 93%

Excessive Na+/H+ Exchange in Disruption of Dendritic Na+ and Ca2+ Homeostasis and Mitochondrial Dysfunction following in Vitro Ischemia

Kintner

Chen

Currie

et al. 2010

Journal of Biological Chemistry

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“…Abnormalities in mitochondrial oxidative phosphorylation have been reported to occur in the rat model of coronary artery ligation-induced heart failure (22,42), the cardiomyopathic Syrian hamster model (18), the canine microembolization-induced heart failure model (44), and in the myocardium of failed explanted human hearts due to ischemic or idiopathic dilated cardiomyopathy (45). There also is evidence of ETC abnormalities.…”

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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“…Decreased cardiac PGC-1 expression was first reported in an experimental model of heart failure induced by thoracic aortic constriction (Garnier et al, 2003) and subsequently in numerous models of heart failure, such as experimental myocardial infarction (Kemi et al, 2007;Sun et al, 2007) aortic constriction (Witt et al, 2008) and in human dilated cardiomyopathy and ischemic disease (Sebastiani et al, 2007). Moreover, downregulation of NRFs and mtTFA and their downstream targets (citrate synthase and cytochrome c oxidase) was also reported (Garnier et al, 2003;Javadov et al, 2005;Jullig et al, 2008;Kemi et al, 2007;Sebastiani et al, 2007). Down-regulation of the whole mitochondrial transcription cascade occurs during heart failure.…”

Section: Mitochondrial Degeneration In Heart Failurementioning

confidence: 80%

“…It is a chronic syndrome in which the heart is not able to satisfy the metabolic and functional needs of the body.Regarding energy metabolism and mitochondrial biogenesis studies, there seems to be a consensus. Mitochondrial function is dramatically altered either in failing hearts of the dog (Marin et al, 2001;Sharov et al, 1998) rodent (De et al, 1999Garnier et al, 2003;Javadov et al, 2005;Jullig et al, 2008) and human (Mettauer et al, 2006;Sharov et al, 2000).…”

Section: Mitochondrial Degeneration In Heart Failurementioning

confidence: 99%

Mitochondrial Biogenesis in Heart: Way of Nurturing and Failure

Sharma¹,

Swarup²

2016

Int.J.Curr.Microbiol.App.Sci

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NHE-1 inhibition improves impaired mitochondrial permeability transition and respiratory function during postinfarction remodelling in the rat

Cited by 76 publications

References 35 publications

Excessive Na+/H+ Exchange in Disruption of Dendritic Na+ and Ca2+ Homeostasis and Mitochondrial Dysfunction following in Vitro Ischemia

Excessive Na+/H+ Exchange in Disruption of Dendritic Na+ and Ca2+ Homeostasis and Mitochondrial Dysfunction following in Vitro Ischemia

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

Mitochondrial Biogenesis in Heart: Way of Nurturing and Failure

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