Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases

Ajith, Thekkuttuparambil Ananthanarayanan; Jayakumar, T.G.

doi:10.4330/wjc.v6.i10.1091

Cited by 58 publications

(43 citation statements)

References 65 publications

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“…In Germany injected ALA is a prescription medicine to treat type II diabetes [16] [17]. On the other hand, clinical trials with ALA have failed to produce data that are consistent with the results reported by Xiong et al, although specific endpoints consistent with this report have not explored [18] [19] [20] [21].…”

Section: Medical Implicationssupporting

confidence: 74%

Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence

Mendelsohn

Larrick

2015

Rejuvenation Research

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Reduced telomere length with increasing age in dividing cells has been implicated in contributing to the pathologies of human aging, which include cardiovascular and metabolic disorders, through induction of cellular senescence. Telomere shortening results from the absence of telomerase, an enzyme required to maintain telomere length. Telomerase reverse transcriptase (TERT), the protein subunit of telomerase, is expressed only transiently in a subset of adult somatic cells, which include stem cells and smooth muscle cells. A recent report from Xiong and colleagues demonstrates a pivotal role for the transcription co-factor peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) in maintaining TERT expression and preventing vascular senescence and atherosclerosis in mice. Ablation of PGC-1α reduced TERT expression and increased DNA damage and reactive oxygen species (ROS), resulting in shortened telomeres and vascular senescence. In the ApoE(-/-) mouse model of atherosclerosis, forced expression of PGC-1α increased expression of TERT, extended telomeres, and reversed genomic DNA damage, vascular senescence, and the development of atherosclerotic plaques. Alpha lipoic acid (ALA) stimulated expression of PGC-1α and TERT and reversed DNA damage, vascular senescence, and atherosclerosis, similarly to ectopic expression of PGC-1α. ALA stimulated cyclic adenosine monophosphate (cAMP) signaling, which in turn activated the cAMP response element-binding protein (CREB), a co-factor for PGC-1α expression. The possibility that ALA might induce TERT to extend telomeres in human cells suggests that ALA may be useful in treating atherosclerosis and other aging-related diseases. However, further investigation is needed to identify whether ALA induces TERT in human cells, which cell types are susceptible, and whether such changes have clinical significance.

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Section: Medical Implicationssupporting

confidence: 74%

Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence

Mendelsohn

Larrick

2015

Rejuvenation Research

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“…Both compounds have been extensively used as tools to probe the role of ROS in physiological and pathophysiological processes (Zafarullah et al . ; Ajith & Jayakumar, ). Our previous studies demonstrated that N ‐acetylcysteine at 1 m m effectively ablated hypoxia‐ and noradrenaline‐stimulated ROS generation in H9c2 cells and intact fetal hearts (Patterson et al .…”

Section: Methodsmentioning

confidence: 99%

Direct effect of chronic hypoxia in suppressing large conductance Ca²⁺‐activated K⁺ channel activity in ovine uterine arteries via increasing oxidative stress

Huang

Xiao

et al. 2015

The Journal of Physiology

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Key pointsr Chronic hypoxia has a direct effect in down-regulating the BK Ca channel β1 subunit and inhibiting the BK Ca channel activity in uterine arteries of pregnant sheep.r Oxidative stress plays a causal role in hypoxia-mediated suppression of BK Ca channel function. r The steroid hormone-induced effect on BK Ca channels is a target of hypoxia-mediated oxidative stress.r Inhibition of oxidative stress ameliorates the adverse effect of hypoxia both ex vivo and in vivo in pregnant sheep exposed to long-term high-altitude hypoxia.r Our findings provide novel evidence of a causative role of oxidative stress in hypoxia-mediated inhibition of the BK Ca channel activity in uterine arteries and new insights in understanding and alleviating pregnancy complications associated with gestational hypoxia such as pre-eclampsia and fetal growth restriction.Abstract Uterine arteries of pregnant sheep acclimatized to long-term high-altitude hypoxia were associated with a decrease in large-conductance Ca 2+ -activated K + (BK Ca ) channel activity. The present study tested the hypothesis that prolonged hypoxia has a direct effect in suppressing BK Ca channel activity by increasing oxidative stress. Uterine arteries were isolated from non-pregnant and near-term (ß142 days) pregnant sheep, and were treated ex vivo with 21.0 or 10.5% O 2 for 48 h. The hypoxia treatment significantly increased the production of reactive oxygen species in uterine arteries, which was blocked by N-acetylcysteine. In uterine arteries of pregnant sheep, hypoxia significantly inhibited BK Ca channel current density, decreased NS1619-induced relaxations and increased pressure-dependent tone, which were annulled by N-acetylcysteine. In accordance, hypoxia resulted in down-regulation of BK Ca channel β1 subunit, which was restored in the presence of N-acetylcysteine. In addition, the N-acetylcysteine treatment significantly increased BK Ca channel β1 subunit abundance and BK Ca channel current density in uterine arteries from pregnant sheep exposed to high-altitude hypoxia (3801 m, P aO 2 : 60 mmHg) for 110 days. In uterine arteries of non-pregnant animals, hypoxia inhibited steroid hormone-induced up-regulation of BK Ca channel current density and NS1619-mediated relaxations, which were reversed by N-acetylcysteine. Furthermore, the synthetic superoxide dismutase and catalase mimetic EUK-134 also ablated the effects of hypoxia on BK Ca channel currents in uterine arteries. The results demonstrate a direct effect of hypoxia in inhibiting the BK Ca channel activity in uterine arteries via increased oxidative stress.

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“…Earlier studies conducted by Ajith et al (2014) in our laboratory demonstrated the TCA cycle stimulating activity of G.lucidum 2010). DOX form complexes with metals like Fe 3+ and Cu 2+ .…”

Section: Discussion:-mentioning

confidence: 81%

Ganoderma Lucidum (Fr.) P. Karst Ameliorate Mitochondrial Dysfunction in Doxorubicin-Induced Cardiotoxicity in Rats.

Veena¹,

Janardhanan²

2017

IJAR

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Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases

Cited by 58 publications

References 65 publications

Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence

Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence

Direct effect of chronic hypoxia in suppressing large conductance Ca²⁺‐activated K⁺ channel activity in ovine uterine arteries via increasing oxidative stress

Ganoderma Lucidum (Fr.) P. Karst Ameliorate Mitochondrial Dysfunction in Doxorubicin-Induced Cardiotoxicity in Rats.

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Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases

Cited by 58 publications

References 65 publications

Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence

Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence

Direct effect of chronic hypoxia in suppressing large conductance Ca2+‐activated K+ channel activity in ovine uterine arteries via increasing oxidative stress

Ganoderma Lucidum (Fr.) P. Karst Ameliorate Mitochondrial Dysfunction in Doxorubicin-Induced Cardiotoxicity in Rats.

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Direct effect of chronic hypoxia in suppressing large conductance Ca²⁺‐activated K⁺ channel activity in ovine uterine arteries via increasing oxidative stress