Divergent Cardiac Effects of Angiotensin II and Isoproterenol Following Juvenile Exposure to Doxorubicin

Kevin Agostinucci; Marianne K Grant; Davis Seelig; Dogacan Yucel; Jop van Berlo; Alessandro Bartolomucci; Jason R.B. Dyck; Beshay N. Zordoky

doi:10.3389/fcvm.2022.742193

Divergent Cardiac Effects of Angiotensin II and Isoproterenol Following Juvenile Exposure to Doxorubicin

Kevin Agostinucci, Marianne K Grant, Davis Seelig, Dogacan Yucel, Jop van Berlo, Alessandro Bartolomucci, Jason R.B. Dyck, Beshay N. Zordoky

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

6 Scopus citations

Abstract

Hypertension is the most significant risk factor for heart failure in doxorubicin (DOX)-treated childhood cancer survivors. We previously developed a two-hit mouse model of juvenile DOX-induced latent cardiotoxicity that is exacerbated by adult-onset angiotensin II (ANGII)-induced hypertension. It is still not known how juvenile DOX-induced latent cardiotoxicity would predispose the heart to pathologic stimuli that do not cause hypertension. Our main objective is to determine the cardiac effects of ANGII (a hypertensive pathologic stimulus) and isoproterenol (ISO, a non-hypertensive pathologic stimulus) in adult mice pre-exposed to DOX as juveniles. Five-week-old male C57BL/6N mice were administered DOX (4 mg/kg/week) or saline for 3 weeks and then allowed to recover for 5 weeks. Thereafter, mice were administered either ANGII (1.4 mg/kg/day) or ISO (10 mg/kg/day) for 14 days. Juvenile exposure to DOX abrogated the hypertrophic response to both ANGII and ISO, while it failed to correct ANGII- and ISO-induced upregulation in the hypertrophic markers, ANP and BNP. ANGII, but not ISO, worsened cardiac function and exacerbated cardiac fibrosis in DOX-exposed mice as measured by echocardiography and histopathology, respectively. The adverse cardiac remodeling in the DOX/ANGII group was associated with a marked upregulation in several inflammatory and fibrotic markers and altered expression of Ace, a critical enzyme in the RAAS. In conclusion, juvenile exposure to DOX causes latent cardiotoxicity that predisposes the heart to a hypertensive pathologic stimulus (ANGII) more than a non-hypertensive stimulus (ISO), mirroring the clinical scenario of worse cardiovascular outcome in hypertensive childhood cancer survivors.

Original language	English (US)
Article number	742193
Journal	Frontiers in Cardiovascular Medicine
Volume	9
DOIs	https://doi.org/10.3389/fcvm.2022.742193
State	Published - Mar 25 2022

Bibliographical note

Funding Information:
This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL151740 (BZ and AB), the St. Baldrick's Foundation for Childhood Cancer (Award ID 638335, BZ and AB); and the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494 (BZ). AB was funded by a Minnesota Partnership for Biotechnology and Medical Genomics #18.04. JD is a Canada Research Chair in Molecular Medicine and is funded by a Foundation Grant awarded by the Canadian Institutes for Health Research (CIHR) and by a Women and Children's Health Research Institute (WCHRI) grant, University of Alberta.

Funding Information:
The authors are grateful for the scientific discussions with Dr. Chetan Shenoy (Division of Cardiology, Department of Medicine, University of Minnesota Medical School). Experiments using the NanoDrop 8000 and ABI 7900 HT were done with staff support at the University of Minnesota Genomics Center. Experiments using the Vevo 2100 echocardiography system were done with staff support at the University of Minnesota Imaging Center. Processing of heart tissues for histopathological analysis was performed with staff support at the Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center. Statistical analysis of the results was performed in consultation with staff from the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota supported by NIH grant P30CA077598 and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1-TR002494.

Funding Information:
The authors are grateful for the scientific discussions with Dr. Chetan Shenoy (Division of Cardiology, Department of Medicine, University of Minnesota Medical School). Experiments using the NanoDrop 8000 and ABI 7900 HT were done with staff support at the University of Minnesota Genomics Center. Experiments using the Vevo 2100 echocardiography system were done with staff support at the University of Minnesota Imaging Center. Processing of heart tissues for histopathological analysis was performed with staff support at the Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center. Statistical analysis of the results was performed in consultation with staff from the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota supported by NIH grant P30CA077598 and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1-TR002494.

Publisher Copyright:
Copyright © 2022 Agostinucci, Grant, Seelig, Yücel, van Berlo, Bartolomucci, Dyck and Zordoky.

Keywords

angiotensin II
anthracycline-induced cardiotoxicity
doxorubicin
hypertension
isoproterenol

PubMed: MeSH publication types

Journal Article

UN SDGs

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

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10.3389/fcvm.2022.742193

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@article{d1d6ace0fc6d4eae9c8fd12a4b5d14d0,

title = "Divergent Cardiac Effects of Angiotensin II and Isoproterenol Following Juvenile Exposure to Doxorubicin",

abstract = "Hypertension is the most significant risk factor for heart failure in doxorubicin (DOX)-treated childhood cancer survivors. We previously developed a two-hit mouse model of juvenile DOX-induced latent cardiotoxicity that is exacerbated by adult-onset angiotensin II (ANGII)-induced hypertension. It is still not known how juvenile DOX-induced latent cardiotoxicity would predispose the heart to pathologic stimuli that do not cause hypertension. Our main objective is to determine the cardiac effects of ANGII (a hypertensive pathologic stimulus) and isoproterenol (ISO, a non-hypertensive pathologic stimulus) in adult mice pre-exposed to DOX as juveniles. Five-week-old male C57BL/6N mice were administered DOX (4 mg/kg/week) or saline for 3 weeks and then allowed to recover for 5 weeks. Thereafter, mice were administered either ANGII (1.4 mg/kg/day) or ISO (10 mg/kg/day) for 14 days. Juvenile exposure to DOX abrogated the hypertrophic response to both ANGII and ISO, while it failed to correct ANGII- and ISO-induced upregulation in the hypertrophic markers, ANP and BNP. ANGII, but not ISO, worsened cardiac function and exacerbated cardiac fibrosis in DOX-exposed mice as measured by echocardiography and histopathology, respectively. The adverse cardiac remodeling in the DOX/ANGII group was associated with a marked upregulation in several inflammatory and fibrotic markers and altered expression of Ace, a critical enzyme in the RAAS. In conclusion, juvenile exposure to DOX causes latent cardiotoxicity that predisposes the heart to a hypertensive pathologic stimulus (ANGII) more than a non-hypertensive stimulus (ISO), mirroring the clinical scenario of worse cardiovascular outcome in hypertensive childhood cancer survivors.",

keywords = "angiotensin II, anthracycline-induced cardiotoxicity, doxorubicin, hypertension, isoproterenol",

author = "Kevin Agostinucci and Grant, {Marianne K} and Davis Seelig and Dogacan Yucel and {van Berlo}, Jop and Alessandro Bartolomucci and Dyck, {Jason R.B.} and Zordoky, {Beshay N.}",

note = "Funding Information: This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL151740 (BZ and AB), the St. Baldrick's Foundation for Childhood Cancer (Award ID 638335, BZ and AB); and the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494 (BZ). AB was funded by a Minnesota Partnership for Biotechnology and Medical Genomics #18.04. JD is a Canada Research Chair in Molecular Medicine and is funded by a Foundation Grant awarded by the Canadian Institutes for Health Research (CIHR) and by a Women and Children's Health Research Institute (WCHRI) grant, University of Alberta. Funding Information: The authors are grateful for the scientific discussions with Dr. Chetan Shenoy (Division of Cardiology, Department of Medicine, University of Minnesota Medical School). Experiments using the NanoDrop 8000 and ABI 7900 HT were done with staff support at the University of Minnesota Genomics Center. Experiments using the Vevo 2100 echocardiography system were done with staff support at the University of Minnesota Imaging Center. Processing of heart tissues for histopathological analysis was performed with staff support at the Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center. Statistical analysis of the results was performed in consultation with staff from the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota supported by NIH grant P30CA077598 and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1-TR002494. Funding Information: The authors are grateful for the scientific discussions with Dr. Chetan Shenoy (Division of Cardiology, Department of Medicine, University of Minnesota Medical School). Experiments using the NanoDrop 8000 and ABI 7900 HT were done with staff support at the University of Minnesota Genomics Center. Experiments using the Vevo 2100 echocardiography system were done with staff support at the University of Minnesota Imaging Center. Processing of heart tissues for histopathological analysis was performed with staff support at the Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center. Statistical analysis of the results was performed in consultation with staff from the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota supported by NIH grant P30CA077598 and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1-TR002494. Publisher Copyright: Copyright {\textcopyright} 2022 Agostinucci, Grant, Seelig, Y{\"u}cel, van Berlo, Bartolomucci, Dyck and Zordoky.",

year = "2022",

month = mar,

day = "25",

doi = "10.3389/fcvm.2022.742193",

language = "English (US)",

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journal = "Frontiers in Cardiovascular Medicine",

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TY - JOUR

T1 - Divergent Cardiac Effects of Angiotensin II and Isoproterenol Following Juvenile Exposure to Doxorubicin

AU - Agostinucci, Kevin

AU - Grant, Marianne K

AU - Seelig, Davis

AU - Yucel, Dogacan

AU - van Berlo, Jop

AU - Bartolomucci, Alessandro

AU - Dyck, Jason R.B.

AU - Zordoky, Beshay N.

N1 - Funding Information: This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL151740 (BZ and AB), the St. Baldrick's Foundation for Childhood Cancer (Award ID 638335, BZ and AB); and the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494 (BZ). AB was funded by a Minnesota Partnership for Biotechnology and Medical Genomics #18.04. JD is a Canada Research Chair in Molecular Medicine and is funded by a Foundation Grant awarded by the Canadian Institutes for Health Research (CIHR) and by a Women and Children's Health Research Institute (WCHRI) grant, University of Alberta. Funding Information: The authors are grateful for the scientific discussions with Dr. Chetan Shenoy (Division of Cardiology, Department of Medicine, University of Minnesota Medical School). Experiments using the NanoDrop 8000 and ABI 7900 HT were done with staff support at the University of Minnesota Genomics Center. Experiments using the Vevo 2100 echocardiography system were done with staff support at the University of Minnesota Imaging Center. Processing of heart tissues for histopathological analysis was performed with staff support at the Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center. Statistical analysis of the results was performed in consultation with staff from the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota supported by NIH grant P30CA077598 and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1-TR002494. Funding Information: The authors are grateful for the scientific discussions with Dr. Chetan Shenoy (Division of Cardiology, Department of Medicine, University of Minnesota Medical School). Experiments using the NanoDrop 8000 and ABI 7900 HT were done with staff support at the University of Minnesota Genomics Center. Experiments using the Vevo 2100 echocardiography system were done with staff support at the University of Minnesota Imaging Center. Processing of heart tissues for histopathological analysis was performed with staff support at the Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center. Statistical analysis of the results was performed in consultation with staff from the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota supported by NIH grant P30CA077598 and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1-TR002494. Publisher Copyright: Copyright © 2022 Agostinucci, Grant, Seelig, Yücel, van Berlo, Bartolomucci, Dyck and Zordoky.

PY - 2022/3/25

Y1 - 2022/3/25

N2 - Hypertension is the most significant risk factor for heart failure in doxorubicin (DOX)-treated childhood cancer survivors. We previously developed a two-hit mouse model of juvenile DOX-induced latent cardiotoxicity that is exacerbated by adult-onset angiotensin II (ANGII)-induced hypertension. It is still not known how juvenile DOX-induced latent cardiotoxicity would predispose the heart to pathologic stimuli that do not cause hypertension. Our main objective is to determine the cardiac effects of ANGII (a hypertensive pathologic stimulus) and isoproterenol (ISO, a non-hypertensive pathologic stimulus) in adult mice pre-exposed to DOX as juveniles. Five-week-old male C57BL/6N mice were administered DOX (4 mg/kg/week) or saline for 3 weeks and then allowed to recover for 5 weeks. Thereafter, mice were administered either ANGII (1.4 mg/kg/day) or ISO (10 mg/kg/day) for 14 days. Juvenile exposure to DOX abrogated the hypertrophic response to both ANGII and ISO, while it failed to correct ANGII- and ISO-induced upregulation in the hypertrophic markers, ANP and BNP. ANGII, but not ISO, worsened cardiac function and exacerbated cardiac fibrosis in DOX-exposed mice as measured by echocardiography and histopathology, respectively. The adverse cardiac remodeling in the DOX/ANGII group was associated with a marked upregulation in several inflammatory and fibrotic markers and altered expression of Ace, a critical enzyme in the RAAS. In conclusion, juvenile exposure to DOX causes latent cardiotoxicity that predisposes the heart to a hypertensive pathologic stimulus (ANGII) more than a non-hypertensive stimulus (ISO), mirroring the clinical scenario of worse cardiovascular outcome in hypertensive childhood cancer survivors.

AB - Hypertension is the most significant risk factor for heart failure in doxorubicin (DOX)-treated childhood cancer survivors. We previously developed a two-hit mouse model of juvenile DOX-induced latent cardiotoxicity that is exacerbated by adult-onset angiotensin II (ANGII)-induced hypertension. It is still not known how juvenile DOX-induced latent cardiotoxicity would predispose the heart to pathologic stimuli that do not cause hypertension. Our main objective is to determine the cardiac effects of ANGII (a hypertensive pathologic stimulus) and isoproterenol (ISO, a non-hypertensive pathologic stimulus) in adult mice pre-exposed to DOX as juveniles. Five-week-old male C57BL/6N mice were administered DOX (4 mg/kg/week) or saline for 3 weeks and then allowed to recover for 5 weeks. Thereafter, mice were administered either ANGII (1.4 mg/kg/day) or ISO (10 mg/kg/day) for 14 days. Juvenile exposure to DOX abrogated the hypertrophic response to both ANGII and ISO, while it failed to correct ANGII- and ISO-induced upregulation in the hypertrophic markers, ANP and BNP. ANGII, but not ISO, worsened cardiac function and exacerbated cardiac fibrosis in DOX-exposed mice as measured by echocardiography and histopathology, respectively. The adverse cardiac remodeling in the DOX/ANGII group was associated with a marked upregulation in several inflammatory and fibrotic markers and altered expression of Ace, a critical enzyme in the RAAS. In conclusion, juvenile exposure to DOX causes latent cardiotoxicity that predisposes the heart to a hypertensive pathologic stimulus (ANGII) more than a non-hypertensive stimulus (ISO), mirroring the clinical scenario of worse cardiovascular outcome in hypertensive childhood cancer survivors.

KW - angiotensin II

KW - anthracycline-induced cardiotoxicity

KW - doxorubicin

KW - hypertension

KW - isoproterenol

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Divergent Cardiac Effects of Angiotensin II and Isoproterenol Following Juvenile Exposure to Doxorubicin

Abstract

Bibliographical note

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Divergent Cardiac Effects of Angiotensin II and Isoproterenol Following Juvenile Exposure to Doxorubicin

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Publisher link

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Fingerprint

University Assets

University Imaging Centers

Vevo 2100

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