Alterations in mitochondrial function as a harbinger of cardiomyopathy: Lessons from the dystrophic heart

Burelle, Yan; Khairallah, Maya; Ascah, Alexis; Allen, Bruce G.; Deschepper, Christian F.; Petrof, Basil J.; Rosiers, Christine Des

doi:10.1016/j.yjmcc.2009.09.004

Cited by 48 publications

(49 citation statements)

References 171 publications

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“…Interestingly, in the latter study, skeletal muscles, which already present a severe pathological phenotype at this age, displayed overt mitochondrial respiratory defects, suggesting that respiratory dysfunctions are detectable only when myopathy is well established. Our data thus indicate that before cardiomyopathy, an experimental stress is required to unmask abnormal mitochondrial responses in mdx hearts, as observed in other models of acquired cardiomyopathy (9).…”

Section: Discussionsupporting

confidence: 66%

“…As we suggested recently (9), the prevention of the PTP opening could constitute a mechanism by which sildenafil protects the dystrophin-deficient heart against cardiomyocyte damage in response to stress. In fact, the activation of cGMP signaling by sildenafil could potentially inhibit the PTP opening indirectly through the modulation of key cellular regulators of the PTP, such as intracellular Ca 2ϩ levels and oxidative stress (58), which are increased in DMD (53).…”

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confidence: 74%

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Stress-induced opening of the permeability transition pore in the dystrophin-deficient heart is attenuated by acute treatment with sildenafil

Ascah

Khairallah

Daussin³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Susceptibility of cardiomyocytes to stress-induced damage has been implicated in the development of cardiomyopathy in Duchenne muscular dystrophy, a disease caused by the lack of the cytoskeletal protein dystrophin in which heart failure is frequent. However, the factors underlying the disease progression are unclear and treatments are limited. Here, we tested the hypothesis of a greater susceptibility to the opening of the mitochondrial permeability transition pore (PTP) in hearts from young dystrophic (mdx) mice (before the development of overt cardiomyopathy) when subjected to a stress protocol and determined whether the prevention of a PTP opening is involved in the cardioprotective effect of sildenafil, which we have previously reported in mdx mice. Using the 2-deoxy-[(3)H]glucose method to quantify the PTP opening in ex vivo perfused hearts, we demonstrate that when compared with those of controls, the hearts from young mdx mice subjected to ischemia-reperfusion (I/R) display an excessive PTP opening as well as enhanced activation of cell death signaling, mitochondrial oxidative stress, cardiomyocyte damage, and poorer recovery of contractile function. Functional analyses in permeabilized cardiac fibers from nonischemic hearts revealed that in vitro mitochondria from mdx hearts display normal respiratory function and reactive oxygen species handling, but enhanced Ca(2+) uptake velocity and premature opening of the PTP, which may predispose to I/R-induced injury. The administration of a single dose of sildenafil to mdx mice before I/R prevented excessive PTP opening and its downstream consequences and reduced tissue Ca(2+) levels. Furthermore, mitochondrial Ca(2+) uptake velocity was reduced following sildenafil treatment. In conclusion, beyond our documentation that an increased susceptibility to the opening of the mitochondrial PTP in the mdx heart occurs well before clinical signs of overt cardiomyopathy, our results demonstrate that sildenafil, which is already administered in other pediatric populations and is reported safe and well tolerated, provides efficient protection against this deleterious event, likely by reducing cellular Ca(2+) loading and mitochondrial Ca(2+) uptake.

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Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 74%

Stress-induced opening of the permeability transition pore in the dystrophin-deficient heart is attenuated by acute treatment with sildenafil

Ascah

Khairallah

Daussin³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Superoxide anion generated by NAD(P)H-oxidase has an important role in the pathogenesis of cardiovascular diseases and scavenging superoxide anion can be considered as a reasonable therapeutic strategy [199,200]. In this review we demonstrate that scavenging superoxide anion by tempol or EUK-8 or administration of PEG-superoxide dismutase inhibits collagen production in cardiac fibroblasts.…”

Section: Perspectivesmentioning

confidence: 84%

Modulation of Reactive Oxygen Species and Collagen Synthesis by Angiotensin II in Cardiac Fibroblasts

Lijnen¹

2011

TOHYPERJ

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Angiotensin II increases the NAD(P)H-dependent superoxide anion production and the intracellular generation of reactive oxygen species in cardiac fibroblasts and apocynin, a NAD(P)H oxidase inhibitor, abrogates this rise. The membrane associated NAD(P)H oxidase complex is the predominant source of superoxide anion and reactive oxygen species generation in angiotensin II-stimulated adult cardiac fibroblasts. Inhibition of this NAD(P)H oxidase complex with apocynin completely blocks the angiotensin II-stimulated collagen production, collagen I and III protein and mRNA expression.Superoxide anion production is also increased by the Cu,Zn-superoxide dismutase (SOD) inhibitor diethyldithiocarbamic acid (DETC) and decreased by the superoxide scavenger tempol in control and ANG II-treated fibroblasts. ANG II and DETC stimulate the collagen production and the collagen I and fibronectin content in fibroblasts. The SOD mimetics tempol and EUK-8 as well as polyethyleneglycol-SOD reduce the collagen production.ANG II also decreases the activity and mRNA and protein expression of the mitochondrial antioxidants Mn-SOD and peroxiredoxin-3. Upon phosphorylation of Akt by ANG II, P-Akt is translocated from the cytoplasm to the nucleus and nuclear phosphorylation of FOXO3a by P-Akt leads to relocalisation of FOXO3a from the nucleus to the cytosol, resulting in a decrease in its transcriptional activity and in Mn-SOD expression. These data indicate that ANG II inactivates FOXO3a by activating Akt and this leads to a reduction in the expression of the antioxidant Mn-SOD. A role of SOD and the formed reactive oxygen species in the regulation and organization of collagen in cardiac fibroblasts is suggested.

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“…However, others have not observed this effect in cardiomyocytes isolated from mice (22). Even though it is unclear which cell type is targeted by sildenafil, total heart extracts from patients with end-stage congestive heart failure have increased PDE5 expression via a mechanism involving oxidative stress (23), and a recent study has shown an increase in oxidative stress in the hearts of young mdx mice (24). Whether this increase in PDE5 expression takes place in cardiomyocytes, myofibroblasts, or vascular smooth muscle cells is still to be determined.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy

Adamo¹,

Dai²,

Percival

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

146

140

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Duchenne muscular dystrophy (DMD) is a progressive and fatal genetic disorder of muscle degeneration. Patients with DMD lack expression of the protein dystrophin as a result of mutations in the X-linked dystrophin gene. The loss of dystrophin leads to severe skeletal muscle pathologies as well as cardiomyopathy, which manifests as congestive heart failure and arrhythmias. Like humans, dystrophin-deficient mice (mdx mice) show cardiac dysfunction as evidenced by a decrease in diastolic function followed by systolic dysfunction later in life. We have investigated whether sildenafil citrate (Viagra), a phosphodiesterase 5 (PDE5) inhibitor, can be used to ameliorate the age-related cardiac dysfunction present in the mdx mice. By using echocardiography, we show that chronic sildenafil treatment reduces functional deficits in the cardiac performance of aged mdx mice, with no effect on normal cardiac function in WT controls. More importantly, when sildenafil treatment was started after cardiomyopathy had developed, the established symptoms were rapidly reversed within a few days. It is recognized that PDE5 inhibitors can have cardioprotective effects in other models of cardiac damage, but the present study reports a prevention and reversal of pathological cardiac dysfunction as measured by functional analysis in a mouse model of DMD. Overall, the data suggest that PDE5 inhibitors may be a useful treatment for the cardiomyopathy affecting patients with DMD at early and late stages of the disease.cGMP | phosphodiesterase | Viagra | echocardiography

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Alterations in mitochondrial function as a harbinger of cardiomyopathy: Lessons from the dystrophic heart

Cited by 48 publications

References 171 publications

Stress-induced opening of the permeability transition pore in the dystrophin-deficient heart is attenuated by acute treatment with sildenafil

Stress-induced opening of the permeability transition pore in the dystrophin-deficient heart is attenuated by acute treatment with sildenafil

Modulation of Reactive Oxygen Species and Collagen Synthesis by Angiotensin II in Cardiac Fibroblasts

Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy

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