2011
DOI: 10.1016/j.atherosclerosis.2011.06.042
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Measuring oxidative burden and predicting pharmacological response in coronary artery disease patients with a novel direct activator of haem-free/oxidised sGC

Abstract: We describe platelet-based assays that allow the determination of patients' oxidative status and thus allow the prediction of pharmacological response to direct sGC activators.

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Cited by 23 publications
(21 citation statements)
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“…It was proposed initially that these drugs activate sGC if either the heme iron is oxidized or the heme group is missing (Stasch et al, 2002), but recent data suggest that oxidation results in dissociation of the ferric heme group, with heme-free sGC being the sole target for this class of sGC activators (Roy et al, 2008). Based on their unique mechanism of action, BAY 58-2667 and analogs are useful tools to determine the fraction of heme-free sGC in cells and tissues under various physiological or pathophysiological conditions (Stasch et al, 2006;Roy et al, 2008;Ahrens et al, 2011;Hoffmann et al, 2011).…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…It was proposed initially that these drugs activate sGC if either the heme iron is oxidized or the heme group is missing (Stasch et al, 2002), but recent data suggest that oxidation results in dissociation of the ferric heme group, with heme-free sGC being the sole target for this class of sGC activators (Roy et al, 2008). Based on their unique mechanism of action, BAY 58-2667 and analogs are useful tools to determine the fraction of heme-free sGC in cells and tissues under various physiological or pathophysiological conditions (Stasch et al, 2006;Roy et al, 2008;Ahrens et al, 2011;Hoffmann et al, 2011).…”
Section: Discussionmentioning
confidence: 99%
“…Preclinical and clinical data obtained with BAY 58-2667 suggest that the relative amount of heme-free vascular sGC is increased in cardiovascular disorders such as coronary artery disease, pulmonary hypertension, and chronic heart failure (Boerrigter et al, 2007;Lapp et al, 2009;Ahrens et al, 2011). In view of the essential role of oxidative stress in most cardiovascular diseases (Strobel et al, 2011), this is probably due to oxidation by reactive oxygen species and subsequent dissociation of sGC-bound heme.…”
Section: Discussionmentioning
confidence: 99%
“…Particularly, in hypercholesterolemic rabbits sGC expression was found to be reduced [21]. Additionally, CAD patients display an elevated oxidative status and impaired function of sGC compared to healthy controls and might, therefore, benefit from pharmacological treatment with a sGC activator [3]. As mentioned previously, impairment of sGC activity and reduced cGMP formation can also facilitate atherothrombotic events [7].…”
Section: Discussionmentioning
confidence: 83%
“…Since cardiac sGC expression was not altered by doxorubicin treatment, the observed decrease in activity likely results from post-translational modification of sGC. Oxidative modification of sGC, leading to loss of its prosthetic heme group and generation of NOinsensitive sGC, was previously reported in cardiovascular diseases associated with increased oxidative stress (2,4,26,42,48). In vivo administration of the radical scavenger, tempol, or targeting oxidized and heme-free sGC by adding the sGC activator, BAY 58-2667, ex vivo rescued the doxorubicinassociated decrease in cardiac sGC activity, suggesting that doxorubicin-induced oxidative modification of sGC represents an underlying mechanism for the reduction in activity.…”
Section: Discussionmentioning
confidence: 90%
“…It is conceivable that the oxidative stress associated with doxorubicin administration results in direct oxidative modification of sGC, potentially leading to loss of its prosthetic heme moiety (2,4,26,42,48) and decreased enzyme activity. To explore this possibility, we administered the radical scavenger tempol to WT mice before treatment with doxorubicin (20 mg/ kg, IP) or saline and evaluated cardiac sGC activity in the presence of DETA-NO.…”
Section: Doxorubicin Administration Reduces Cardiac Sgc Activitymentioning
confidence: 99%