Different Faces of the Heme-Heme Oxygenase System in Inflammation

Wagener, Frank A. D. T. G.; Volk, Hans‐Dieter; Willis, Dean; Abraham, Nader G.; Soares, Miguel P.; Adema, Gosse J.; Figdor, Carl G.

doi:10.1124/pr.55.3.5

Cited by 489 publications

(433 citation statements)

References 256 publications

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“…The protective mechanism of CO/HO differs uniquely from those proposed for other injuries that are reported to benefit (32,33), and the administration of low dose CO for only 2 hours over a 14-day experiment establishes this protection as distinct from the transient vasodilator activity of CO. Also, to eliminate the possibility that hypoxic preconditioning played an important role in the CO protective mechanism, we compared the effects of an equivalent level of HH to that of the CO hypoxia. These data demonstrate that equivalent HH without CO is below the threshold for inducing HO-1 and does not prevent DOX-induced cardiac apoptosis or fibrosis.…”

Section: Discussionmentioning

confidence: 88%

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

Suliman¹,

Carraway²,

Ali³

et al. 2007

J. Clin. Invest.

178

243

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The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.

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Section: Discussionmentioning

confidence: 88%

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

Suliman¹,

Carraway²,

Ali³

et al. 2007

J. Clin. Invest.

178

243

View full text Add to dashboard Cite

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“…Another mechanism of heme toxicity is via heme-induced oxidative stress [123]. Heme catalyzes the formation of reactive oxygen species (ROS), and heme released from intracellular hemoproteins is an important source of redox active iron [15].…”

Section: Dysregulation Of Heme Levels Can Cause Serious Diseasesmentioning

confidence: 99%

“…Heme-mediated inflammation has been implicated in the pathogenesis of several diseases, including arteriosclerosis, renal failure and heart transplant failure [15,119,123,135]. Release of heme can bring about local inflammatory reactions that may result in renal failure [136].…”

Section: Dysregulation Of Heme Levels Can Cause Serious Diseasesmentioning

confidence: 99%

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Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

2006

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“…Increased HO-1 expression leads to degradation of heme and accumulation of iron, bilirubin, and carbon monoxide (CO) can reduce sensitivity of tissues to oxidant damage [21]. Of these metabolites, bilirubin acts as a direct antioxidant [22], whereas CO production helps to decrease vascular tone, inhibit platelet aggregation, and prevent both the production of pro-inflammatory cytokines and endothelial cell apoptosis [23]. Overexpression of HO-1 also has been demonstrated to provide potent cytoprotection against myocardial I/R injury [6].…”

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine induces heme oxygenase-1 expression and attenuates myocardial ischemia/reperfusion injury in rats

et al. 2006

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The accumulation of oxygen free radicals and activation of neutrophils are strongly implicated as pathophysiological mechanisms mediating myocardial ischemia/reperfusion injury. Heme oxygenase-1 (HO-1) has been reported to play a protective role in oxidative tissue injuries. In this study, the cardioprotective activity of tetramethylpyrazine (TMP), an active ingredient of Chinese medicinal herb Ligusticum wallichii Franchat, was evaluated in an open-chest anesthetized rat model of myocardial ischemia/reperfusion injury. Pretreatment with TMP (5 and 10 mg/kg, i.v.) before left coronary artery occlusion significantly suppressed the occurrence of ventricular fibrillation. After 45 min of ischemia and 1 h of reperfusion, TMP (5 and 10 mg/kg) caused a significant reduction in infarct size and induced HO-1 expression in ischemic myocardium. The HO inhibitor ZnPP (50 lg/rat) markedly reversed the anti-infarct action of TMP.

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Different Faces of the Heme-Heme Oxygenase System in Inflammation

Cited by 489 publications

References 256 publications

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

Tetramethylpyrazine induces heme oxygenase-1 expression and attenuates myocardial ischemia/reperfusion injury in rats

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