Resveratrol reduces cardiac NLRP3-inflammasome activation and systemic inflammation to lessen doxorubicin-induced cardiotoxicity in juvenile mice

Zaid H. Maayah; Abrar S. Alam; Shingo Takahara; Shubham Soni; Mourad Ferdaoussi; Nobutoshi Matsumura; Beshay N. Zordoky; David D. Eisenstat; Jason R.B. Dyck

doi:10.1002/1873-3468.14091

Resveratrol reduces cardiac NLRP3-inflammasome activation and systemic inflammation to lessen doxorubicin-induced cardiotoxicity in juvenile mice

Zaid H. Maayah, Abrar S. Alam, Shingo Takahara, Shubham Soni, Mourad Ferdaoussi, Nobutoshi Matsumura, Beshay N. Zordoky, David D. Eisenstat, Jason R.B. Dyck

Experimental and Clinical Pharmacology

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Doxorubicin (DOX) is a very effective anticancer agent that is widely used in pediatric cancer patients. Nevertheless, DOX is known to have cardiotoxic effects that may progress to cardiomyopathy later in life. We have recently shown that cotreatment of resveratrol (RES) with DOX in juvenile mice attenuates late-onset hypertension-induced cardiomyopathy. However, the molecular mechanism responsible for these changes remains unknown. Herein, we show that the cardiac NLRP3 inflammasome plays a crucial role in regulating cardiac injury in a DOX -treated juvenile mouse model and the detrimental effects of hypertension in these mice later in life. We further demonstrate that RES significantly reduces systemic inflammation to contribute to the improvements observed in DOX -induced cardiac injury in young mice and late-onset hypertension-induced cardiomyopathy.

Original language	English (US)
Pages (from-to)	1681-1695
Number of pages	15
Journal	FEBS Letters
Volume	595
Issue number	12
DOIs	https://doi.org/10.1002/1873-3468.14091
State	Published - Jun 2021

Bibliographical note

Funding Information:
This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to JRBD and a grant from the Women and Children’s Health Research Institute (WCHRI) Hair Massacure Fund, University of Alberta to JRBD and DDE. JRBD is a Canada Research Chair in Molecular Medicine. ZHM is the recipient of the Alberta Innovates Health Solutions and CIHR postdoctoral fellowship awards. DDE holds the Muriel & Ada Hole Kids with Cancer Society Chair in Pediatric Oncology, University of Alberta. BNZ is supported by the National Heart, Lung, and Blood Institute grant R01HL151740 and the National Institutes of Health’s National Center for Advancing Translational Sciences grant UL1TR002494. SS is supported by Graduate Student Scholarships from WCHRI and Alberta Innovates.

Funding Information:
This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to JRBD and a grant from the Women and Children?s Health Research Institute (WCHRI) Hair Massacure Fund, University of Alberta to JRBD and DDE. JRBD is a Canada Research Chair in Molecular Medicine. ZHM is the recipient of the Alberta Innovates Health Solutions and CIHR postdoctoral fellowship awards. DDE holds the Muriel & Ada Hole Kids with Cancer Society Chair in Pediatric Oncology, University of Alberta. BNZ is supported by the National Heart, Lung, and Blood Institute grant R01HL151740 and the National Institutes of Health?s National Center for Advancing Translational Sciences grant UL1TR002494. SS is supported by Graduate Student Scholarships from WCHRI and Alberta Innovates.

Publisher Copyright:
© 2021 Federation of European Biochemical Societies.

Keywords

cancer
doxorubicin
heart
inflammation
NLRP3
resveratrol

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/1873-3468.14091

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title = "Resveratrol reduces cardiac NLRP3-inflammasome activation and systemic inflammation to lessen doxorubicin-induced cardiotoxicity in juvenile mice",

abstract = "Doxorubicin (DOX) is a very effective anticancer agent that is widely used in pediatric cancer patients. Nevertheless, DOX is known to have cardiotoxic effects that may progress to cardiomyopathy later in life. We have recently shown that cotreatment of resveratrol (RES) with DOX in juvenile mice attenuates late-onset hypertension-induced cardiomyopathy. However, the molecular mechanism responsible for these changes remains unknown. Herein, we show that the cardiac NLRP3 inflammasome plays a crucial role in regulating cardiac injury in a DOX -treated juvenile mouse model and the detrimental effects of hypertension in these mice later in life. We further demonstrate that RES significantly reduces systemic inflammation to contribute to the improvements observed in DOX -induced cardiac injury in young mice and late-onset hypertension-induced cardiomyopathy.",

keywords = "cancer, doxorubicin, heart, inflammation, NLRP3, resveratrol",

author = "Maayah, {Zaid H.} and Alam, {Abrar S.} and Shingo Takahara and Shubham Soni and Mourad Ferdaoussi and Nobutoshi Matsumura and Zordoky, {Beshay N.} and Eisenstat, {David D.} and Dyck, {Jason R.B.}",

note = "Funding Information: This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to JRBD and a grant from the Women and Children{\textquoteright}s Health Research Institute (WCHRI) Hair Massacure Fund, University of Alberta to JRBD and DDE. JRBD is a Canada Research Chair in Molecular Medicine. ZHM is the recipient of the Alberta Innovates Health Solutions and CIHR postdoctoral fellowship awards. DDE holds the Muriel & Ada Hole Kids with Cancer Society Chair in Pediatric Oncology, University of Alberta. BNZ is supported by the National Heart, Lung, and Blood Institute grant R01HL151740 and the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences grant UL1TR002494. SS is supported by Graduate Student Scholarships from WCHRI and Alberta Innovates. Funding Information: This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to JRBD and a grant from the Women and Children?s Health Research Institute (WCHRI) Hair Massacure Fund, University of Alberta to JRBD and DDE. JRBD is a Canada Research Chair in Molecular Medicine. ZHM is the recipient of the Alberta Innovates Health Solutions and CIHR postdoctoral fellowship awards. DDE holds the Muriel & Ada Hole Kids with Cancer Society Chair in Pediatric Oncology, University of Alberta. BNZ is supported by the National Heart, Lung, and Blood Institute grant R01HL151740 and the National Institutes of Health?s National Center for Advancing Translational Sciences grant UL1TR002494. SS is supported by Graduate Student Scholarships from WCHRI and Alberta Innovates. Publisher Copyright: {\textcopyright} 2021 Federation of European Biochemical Societies.",

year = "2021",

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doi = "10.1002/1873-3468.14091",

language = "English (US)",

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AU - Alam, Abrar S.

AU - Takahara, Shingo

AU - Soni, Shubham

AU - Ferdaoussi, Mourad

AU - Matsumura, Nobutoshi

AU - Zordoky, Beshay N.

AU - Eisenstat, David D.

AU - Dyck, Jason R.B.

N1 - Funding Information: This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to JRBD and a grant from the Women and Children’s Health Research Institute (WCHRI) Hair Massacure Fund, University of Alberta to JRBD and DDE. JRBD is a Canada Research Chair in Molecular Medicine. ZHM is the recipient of the Alberta Innovates Health Solutions and CIHR postdoctoral fellowship awards. DDE holds the Muriel & Ada Hole Kids with Cancer Society Chair in Pediatric Oncology, University of Alberta. BNZ is supported by the National Heart, Lung, and Blood Institute grant R01HL151740 and the National Institutes of Health’s National Center for Advancing Translational Sciences grant UL1TR002494. SS is supported by Graduate Student Scholarships from WCHRI and Alberta Innovates. Funding Information: This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to JRBD and a grant from the Women and Children?s Health Research Institute (WCHRI) Hair Massacure Fund, University of Alberta to JRBD and DDE. JRBD is a Canada Research Chair in Molecular Medicine. ZHM is the recipient of the Alberta Innovates Health Solutions and CIHR postdoctoral fellowship awards. DDE holds the Muriel & Ada Hole Kids with Cancer Society Chair in Pediatric Oncology, University of Alberta. BNZ is supported by the National Heart, Lung, and Blood Institute grant R01HL151740 and the National Institutes of Health?s National Center for Advancing Translational Sciences grant UL1TR002494. SS is supported by Graduate Student Scholarships from WCHRI and Alberta Innovates. Publisher Copyright: © 2021 Federation of European Biochemical Societies.

PY - 2021/6

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N2 - Doxorubicin (DOX) is a very effective anticancer agent that is widely used in pediatric cancer patients. Nevertheless, DOX is known to have cardiotoxic effects that may progress to cardiomyopathy later in life. We have recently shown that cotreatment of resveratrol (RES) with DOX in juvenile mice attenuates late-onset hypertension-induced cardiomyopathy. However, the molecular mechanism responsible for these changes remains unknown. Herein, we show that the cardiac NLRP3 inflammasome plays a crucial role in regulating cardiac injury in a DOX -treated juvenile mouse model and the detrimental effects of hypertension in these mice later in life. We further demonstrate that RES significantly reduces systemic inflammation to contribute to the improvements observed in DOX -induced cardiac injury in young mice and late-onset hypertension-induced cardiomyopathy.

AB - Doxorubicin (DOX) is a very effective anticancer agent that is widely used in pediatric cancer patients. Nevertheless, DOX is known to have cardiotoxic effects that may progress to cardiomyopathy later in life. We have recently shown that cotreatment of resveratrol (RES) with DOX in juvenile mice attenuates late-onset hypertension-induced cardiomyopathy. However, the molecular mechanism responsible for these changes remains unknown. Herein, we show that the cardiac NLRP3 inflammasome plays a crucial role in regulating cardiac injury in a DOX -treated juvenile mouse model and the detrimental effects of hypertension in these mice later in life. We further demonstrate that RES significantly reduces systemic inflammation to contribute to the improvements observed in DOX -induced cardiac injury in young mice and late-onset hypertension-induced cardiomyopathy.

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KW - heart

KW - inflammation

KW - NLRP3

KW - resveratrol

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SN - 0014-5793

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EP - 1695

JO - FEBS Letters

JF - FEBS Letters

IS - 12

ER -

Resveratrol reduces cardiac NLRP3-inflammasome activation and systemic inflammation to lessen doxorubicin-induced cardiotoxicity in juvenile mice

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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