NADPH oxidases in cardiovascular disease: insights from in vivo models and clinical studies

Sirker, Alexander; Zhang, Min; Shah, Ajay M.

doi:10.1007/s00395-011-0190-z

Cited by 163 publications

(146 citation statements)

References 127 publications

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“…The specificity of p47 phox ASON was confirmed by observations that the treatment did not affect Nox4 in RVLM ( Supplementary Fig. S4), the expression and activation of which do not require p47 phox subunit (54). We reported previously (27) that 7 days after transfection of the adenoviral vector encoding SOD1 or SOD2 (AdSOD1 or Ad-SOD2) into RVLM, the expression of cytosol SOD1 or mitochondrial SOD2 is upregulated, alongside reduced cytosolic and mitochondrial O 2 -level.…”

Section: Innovationsupporting

confidence: 70%

Redox-Sensitive Oxidation and Phosphorylation of PTEN Contribute to Enhanced Activation of PI3K/Akt Signaling in Rostral Ventrolateral Medulla and Neurogenic Hypertension in Spontaneously Hypertensive Rats

et al. 2013

Antioxidants & Redox Signaling

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Aims: The activity of phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (Akt) is enhanced under hypertension. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of PI3K signaling, and its activity is redox-sensitive. In the rostral ventrolateral medulla (RVLM), which is responsible for the maintenance of blood pressure, oxidative stress plays a pivotal role in neurogenic hypertension. The present study evaluated the hypothesis that redox-sensitive inactivation of PTEN results in enhanced PI3K/ Akt signaling in RVLM, leading to neurogenic hypertension. Results: Compared to age-matched normotensive Wistar-Kyoto (WKY) rats, PTEN inactivation in the form of oxidation and phosphorylation were greater in RVLM of spontaneously hypertensive rats (SHR). PTEN inactivation was accompanied by augmented PI3K activity and PI3K/Akt signaling, as reflected by the increase in phosphorylation of Akt and mammalian target of rapamycin. Intracisternal infusion of tempol or microinjection into the bilateral RVLM of adenovirus encoding superoxide dismutase significantly antagonized the PTEN inactivation and blunted the enhanced PI3K/Akt signaling in SHR. Gene transfer of PTEN to RVLM in SHR also abrogated the enhanced Akt activation and promoted antihypertension. Silencing PTEN expression in RVLM with small-interfering RNA, on the other hand, augmented PI3K/Akt signaling and promoted long-term pressor response in normotensive WKY rats.Innovation: The present study demonstrated for the first time that the redox-sensitive check-and-balance process between PTEN and PI3K/Akt signaling is engaged in the pathogenesis of hypertension. Conclusion: We conclude that an aberrant interplay between the redox-sensitive PTEN and PI3k/Akt signaling in RVLM underpins neural mechanism of hypertension. Antioxid. Redox Signal. 18, 36-50.

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Section: Innovationsupporting

confidence: 70%

Redox-Sensitive Oxidation and Phosphorylation of PTEN Contribute to Enhanced Activation of PI3K/Akt Signaling in Rostral Ventrolateral Medulla and Neurogenic Hypertension in Spontaneously Hypertensive Rats

et al. 2013

Antioxidants & Redox Signaling

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“…Diabetes increases myocardial Nox4 expression, and its localization to the outer membrane of the mitochondria is significant (4,38,75). Unlike Nox1, Nox4 does not require p47 or p67 for activation, and biochemical studies suggest that it preferentially generates H 2 O 2 over superoxide (16,79,108). Block et al (4) demonstrated in mesangial cells that a siNOX4 probe abrogated glucose-induced increased superoxide generation.…”

Section: Discussionmentioning

confidence: 99%

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Hicks

Labinskyy

Piteo

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat. Am J Physiol Heart Circ Physiol 304: H903-H915, 2013. First published February 1, 2013 doi:10.1152/ajpheart.00567.2012.-Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Mitochondrial oxidant stress has been accepted as the singular cause of mitochondrial DNA (mtDNA) damage as an underlying cause of mitochondrial dysfunction. However, separate from a direct effect on mtDNA integrity, diabetic-induced increases in oxidant stress alter mitochondrial topoisomerase function to propagate mtDNA mutations as a contributor to mitochondrial dysfunction. Both glucose-challenged neonatal cardiomyocytes and the diabetic GotoKakizaki (GK) rat were studied. In both the GK left ventricle (LV) and in cardiomyocytes, chronically elevated glucose presentation induced a significant increase in mtDNA damage that was accompanied by decreased mitochondrial function. TTGE analysis revealed a number of base pair substitutions in the 3' end of COX3 from GK LV mtDNA that significantly altered the protein sequence. Mitochondrial topoisomerase DNA cleavage activity in isolated mitochondria was significantly increased in the GK LV compared with Wistar controls. Both hydroxycamptothecin, a topoisomerase type 1 inhibitor, and doxorubicin, a topoisomerase type 2 inhibitor, significantly exacerbated the DNA cleavage activity of isolated mitochondrial extracts indicating the presence of multiple functional topoisomerases in the mitochondria. Mitochondrial topoisomerase function was significantly altered in the presence of H 2O2 suggesting that separate from a direct effect on mtDNA, oxidant stress mediated type II diabetesinduced alterations of mitochondrial topoisomerase function. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mtDNA integrity and the well being of the diabetic myocardium. diabetic cardiomyopathy; type 2 diabetes; mitochondrial DNA damage; mitochondrial dysfunction CARDIOVASCULAR DISEASE is responsible for a higher incidence of mortality in diabetics than the general population. Diabetic cardiomyopathy (DCM) is characterized by the development of a myopathy that manifests initially as diastolic dysfunction, but evolves into increased cavitary dilation and mural thinning, which is reflective of decompensated eccentric hypertrophy. DCM is considered to be independent of atherosclerosis or hypertension but is exacerbated by either (94). Mitochondrial dysfunction has long been known to have a significant role in the development and complications of DCM (32,46,66,82,92). Mitochondrial dysfunction is also associated with other pathologies including cancer, skeletal muscle disorders, and neurodegenerative diseases such as Wolfram syndrome or Leber's hereditary optic neuropathy (LHON) (18,36,54,104).Separate from inborn errors, mitochondrial DNA (mtDNA) mutations are thought to accumul...

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“…In HF, it has been shown that increased amounts of superoxide are generated in mitochondria (69, 71, 103). In addition, NADPH oxidase (Nox) 2 and 4 are richly expressed in cardiomyocytes, and myocardial Nox activity has been shown to be increased in human HF (59,87,119). Stimuli relevant to the pathophysiology of HF (mechanical stretch, endothelin-1 and angiotensin II) are known to induce Nox activity (2,82).…”

Section: The Redox System Of the Heartmentioning

confidence: 99%

Redox Regulation of Sodium and Calcium Handling

Wagner

Rokita

Anderson

et al. 2013

Antioxidants & Redox Signaling

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Significance: In heart failure (HF), contractile dysfunction and arrhythmias result from disturbed intracellular Ca handling. Activated stress kinases like cAMP-dependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), which are known to influence many Ca-regulatory proteins, are mechanistically involved. Recent Advances: Beside classical activation pathways, it is becoming increasingly evident that reactive oxygen species (ROS) can directly oxidize these kinases, leading to alternative activation. Since HF is associated with increased ROS generation, ROS-activated serine/threonine kinases may play a crucial role in the disturbance of cellular Ca homeostasis. Many of the previously described ROS effects on ion channels and transporters are possibly mediated by these stress kinases. For instance, ROS have been shown to oxidize and activate CaMKII, thereby increasing Na influx through voltage-gated Na channels, which can lead to intracellular Na accumulation and action potential prolongation. Consequently, Ca entry via activated NCX is favored, which together with ROS-induced dysfunction of the sarcoplasmic reticulum can lead to dramatic intracellular Ca accumulation, diminished contractility, and arrhythmias. Critical Issues: While low amounts of ROS may regulate kinase activity, excessive uncontrolled ROS production may lead to direct redox modification of Ca handling proteins. Therefore, depending on the source and amount of ROS generated, ROS could have very different effects on Ca-handling proteins. Future Directions: The discrimination between fine-tuned ROS signaling and unspecific ROS damage may be crucial for the understanding of heart failure development and important for the investigation of targeted treatment strategies.

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NADPH oxidases in cardiovascular disease: insights from in vivo models and clinical studies

Cited by 163 publications

References 127 publications

Redox-Sensitive Oxidation and Phosphorylation of PTEN Contribute to Enhanced Activation of PI3K/Akt Signaling in Rostral Ventrolateral Medulla and Neurogenic Hypertension in Spontaneously Hypertensive Rats

Redox-Sensitive Oxidation and Phosphorylation of PTEN Contribute to Enhanced Activation of PI3K/Akt Signaling in Rostral Ventrolateral Medulla and Neurogenic Hypertension in Spontaneously Hypertensive Rats

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Redox Regulation of Sodium and Calcium Handling

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