Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo

Dowd, N.; Scully, Michael; Adderley, Sharon R.; Cunningham, Anthony J.; Fitzgerald, Desmond J.

doi:10.1172/jci200111334

Cited by 164 publications

(67 citation statements)

References 31 publications

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“…Both COX-2 and its PGI 2 and PGE 2 products have been implicated in cardioprotection: prevention against oxidative injury via activation of the IP or the EP3 (21, 33) and ischemic preconditioning via COX-2 (22). Here, as previously observed in other species (21,22), the dominant prostaglandin (PG) formed by the heart is PGI 2 , and the second most abundant PG is PGF 2␣ (Fig. S2).…”

Section: Discussionsupporting

confidence: 63%

“…One such example was an overview-trial analysis interpreted to suggest that arrhythmia, cardiac arrest, and sudden cardiac death might result from off target effects of rofecoxib (18). However, the dominant products of cardiomyocyte (CM) COX-2 are PGI 2 and PGE 2 , and deletion of the IP exacerbates ischemia reperfusion injury in mice (19) and inhibition of COX-2 exacerbates doxorubicininduced cardiotoxicity in vitro (20) and in vivo (21), an effect attenuated by PGI 2 analogues. COX-2-derived PGI 2 and PGE 2 have both been implicated as mediators of cardioprotection in late-phase ischemic preconditioning (22,23).…”

mentioning

confidence: 99%

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Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Wang

Patel

Ricciotti

et al. 2009

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

108

105

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Nonsteroidal anti-inflammatory drugs selective for inhibition of COX-2 increase heart failure and elevate blood pressure. The COX-2 gene was floxed and crossed into merCremer mice under the ␣-myosin heavy-chain promoter. Tamoxifen induced selective deletion of COX-2 in cardiomyocytes depressed cardiac output, and resulted in weight loss, diminished exercise tolerance, and enhanced susceptibility to induced arrhythmogenesis. The cardiac dysfunction subsequent to pressure overload recovered progressively in the knockouts coincident with increasing cardiomyocyte hypertrophy and interstitial and perivascular fibrosis. Inhibition of COX-2 in cardiomyocytes may contribute to heart failure in patients receiving nonsteroidal anti-inflammatory drugs specific for inhibition of COX-2.arrhythmia ͉ heart failure ͉ knockout ͉ NSAIDs ͉ fibrosis R andomized, placebo-controlled trials indicate that nonsteroidal antinflammatory drugs (NSAIDs) specific for inhibition of cyclooxygense (COX)-2 confer an increased risk of myocardial infarction and stroke (1-5), effects explicable by suppression of COX-2-derived products, such as prostacyclin (PGI 2 ) and prostaglandia E 2 (PGE 2 ) (6). While, the clinical spectrum of hazard is dominated by a predisposition to thrombosis, an additional feature has been congestive heart failure (1-4). NSAIDs may variably increase blood pressure (7): studies in rodents (8, 9) and a meta-analysis of clinical studies (10) suggest that this reflects inhibition of COX-2 and the specificity with which this is attained (11). Elevation of blood pressure by manipulation of the prostaglandin pathway is conditioned by genetic background in rodents (12). However, given this caveat, deletion or inhibition of COX-2 (8, 13) and deletion of the E prostanoid (EP)-2 receptor (14, 15) or the I-prostanoid receptor (IP) (16) for the COX-2 products, PGE 2 and PGI 2 respectively, may each result in hypertension. Indeed, deletion of the IP in these mice also results in cardiac hypertrophy and fibrosis, effects ameliorated by coincident deletion of the receptor for thromboxane A 2 , the TP, a maneuver that does not, alone, affect blood pressure (16). By contrast, inhibition or deletion of COX-1 attenuates the hypertensive response to infusion of angiotensin II (8) or treatment with a COX-2 inhibitor (13). Although placebo-controlled trials provide unequivocal evidence that COX-2-specific NSAIDs confer a cardiovascular hazard, the number of events within each trial are insufficient to permit analysis of covariates. Thus, it is unknown whether congestive heart failure on NSAIDs results solely from or is exacerbated by hypertension.Although suppression of COX-2-derived prostanoids is sufficient to explain the cardiovascular hazard conferred by purposedesigned and older NSAIDs specific for inhibition of COX-2 (17), there has been interest in the possibility that some or all of these effects might reflect ''off target'' effects. One such example was an overview-trial analysis interpreted to suggest that arrhythmia, cardiac arrest, ...

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Section: Discussionsupporting

confidence: 63%

mentioning

confidence: 99%

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Wang

Patel

Ricciotti

et al. 2009

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

108

105

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“…Among doxorubicin alone treated group, the significant increase in LDH levels were revealed in all tested periods of time only at highest dose of this drug. These results are consistent with the previously reported results which had shown an elevation in LDH activity in rats receiving single and repeated doses of doxorubicin [2,9,10]. Significant increase in total LDH activity and cardiac isoform activity was also described by Al-Shabanah et al [3] even at 3 h after treatment with 15 mg doxorubicin/kg, what implies that source of the enzyme can be cardiomyocytes.…”

Section: Discussionsupporting

confidence: 92%

Effect of iodothyronine hormone status on doxorubicin related cardiotoxicity

Dudka¹,

Mańdziuk²,

Madej-Czerwonka³

et al. 2013

Folia Morphol

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“…However, chronic inhibition of COX2 results in undesirable cardiovascular and gastrointestinal side effects that are due, in part, to reduced levels of prostacyclin PGI 2 and thromboxane A 2 (30,31). Thus, based on the obtained results, it is reasonable to suggest that selective targeting PGE 2 -forming enzyme mPGES1 or targeted genetic overexpression of PGE 2 -degrading enzyme 15-PGDH could provide more effective and safe way to combat cancer.…”

Section: Resultsmentioning

confidence: 97%

COX2/mPGES1/PGE ₂ pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

Prima

Kaliberova

Kaliberov

et al. 2017

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

385

311

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In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)-mediated inhibition of activated PD-1 + T lymphocytes plays a major role in tumor escape from immune system during cancer progression. Lately, the anti-PD-L1 and -PD-1 immune therapies have become an important tool for treatment of advanced human cancers, including bladder cancer. However, the underlying mechanisms of PD-L1 expression in cancer are not fully understood. We found that coculture of murine bone marrow cells with bladder tumor cells promoted strong expression of PD-L1 in bone marrowderived myeloid cells. Tumor-induced expression of PD-L1 was limited to F4/80 + macrophages and Ly-6C + myeloid-derived suppressor cells. These PD-L1-expressing cells were immunosuppressive and were capable of eliminating CD8 T cells in vitro. Tumor-infiltrating PD-L1 + cells isolated from tumor-bearing mice also exerted morphology of tumorassociated macrophages and expressed high levels of prostaglandin E 2 (PGE 2 )-forming enzymes microsomal PGE 2 synthase 1 (mPGES1) and COX2. Inhibition of PGE 2 formation, using pharmacologic mPGES1 and COX2 inhibitors or genetic overexpression of PGE 2 -degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulted in reduced PD-L1 expression. Together, our study demonstrates that the COX2/mPGES1/PGE 2 pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE 2 metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host.PD-L1 | tumor-associated macrophages | PGE 2 metabolism | myeloid cells | bone marrow

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Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo

Cited by 164 publications

References 31 publications

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Effect of iodothyronine hormone status on doxorubicin related cardiotoxicity

COX2/mPGES1/PGE ₂ pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

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Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo

Cited by 164 publications

References 31 publications

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Effect of iodothyronine hormone status on doxorubicin related cardiotoxicity

COX2/mPGES1/PGE 2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

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COX2/mPGES1/PGE ₂ pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells