TY - JOUR
T1 - Breast cancer promotes cardiac dysfunction through deregulation of cardiomyocyte ca2+-handling protein expression that is not reversed by exercise training
AU - da Costa, Tassia S.R.
AU - Urias, Ursula
AU - Negrao, Marcelo V.
AU - Jordão, Camila P.
AU - Passos, Clévia S.
AU - Gomes-Santos, Igor L.
AU - Salemi, Vera Maria C.
AU - Camargo, Anamaria A.
AU - Brum, Patricia C.
AU - Oliveira, Edilamar M.
AU - Hajjar, Ludhmila A.
AU - Chammas, Roger
AU - Filho, Roberto K.
AU - Negrao, Carlos E.
N1 - Funding Information:
This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP#2015/22814-5). Gomes-Santos and Passos received scholarship from FAPESP (#2014/13690-8 and #15/19076-2, respectively). Brum, Oliveira, Salemi and C. E. Negrao were supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ#306261/ 2016-2; #313479/2017-8; #307227/2018-9 and; #303573/2015-5).
Publisher Copyright:
© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2021
Y1 - 2021
N2 - BACKGROUND: Patients treated for breast cancer have a high incidence of cardiovascular complications. In this study, we evaluated the impact of breast cancer on cardiac function and cardiomyocyte Ca2+-handling protein expression. We also investigated whether exercise training (ET) would prevent these potential alterations. METHODS AND RESULTS: Transgenic mice with spontaneous breast cancer (mouse mammary tumor virus–polyomavirus middle T antigen [MMTV-PyMT+], n=15) and littermate mice with no cancer (MMTV-PyMT−, n=14) were studied. For the ET analysis, MMTV-PyMT+ were divided into sedentary (n=10) and exercise-trained (n=12) groups. Cardiac function was evaluated by echocardiography with speckle-tracking imaging. Exercise tolerance test was conducted on a treadmill. Both studies were performed when the tumor became palpable and when it reached 1 cm3. After euthanasia, Ca2+-handling protein expression (Western blot) was evaluated. Exercise capacity was reduced in MMTV-PyMT+ compared with MMTVPyMT− (Pinteraction =0.031). Longitudinal strain (Pgroup <0.001) and strain rate (Pgroup =0.030) were impaired. Cardiomyocyte phospholamban was increased (P=0.011), whereas phospho-phospholamban and sodium/calcium exchanger were decreased (P=0.038 and P=0.017, respectively) in MMTV-PyMT+. No significant difference in sarcoplasmic or endoplasmic reticulum calcium 2 ATPase (SERCA2a) was found. SERCA2a/phospholamban ratio was reduced (P=0.007). ET was not associated with increased exercise capacity. ET decreased left ventricular end-systolic diameter (Pgroup =0.038) and end-diastolic volume (Pgroup =0.026). Other morphological and functional cardiac parameters were not improved by ET in MMTV-PyMT+. ET did not improve cardiomyocyte Ca2+-handling protein expression. CONCLUSIONS: Breast cancer is associated with decreased exercise capacity and subclinical left ventricular dysfunction in MMTV-PyMT+, which is at least partly associated with dysregulation of cardiomyocyte Ca2+ handling. ET did not prevent or reverse these changes.
AB - BACKGROUND: Patients treated for breast cancer have a high incidence of cardiovascular complications. In this study, we evaluated the impact of breast cancer on cardiac function and cardiomyocyte Ca2+-handling protein expression. We also investigated whether exercise training (ET) would prevent these potential alterations. METHODS AND RESULTS: Transgenic mice with spontaneous breast cancer (mouse mammary tumor virus–polyomavirus middle T antigen [MMTV-PyMT+], n=15) and littermate mice with no cancer (MMTV-PyMT−, n=14) were studied. For the ET analysis, MMTV-PyMT+ were divided into sedentary (n=10) and exercise-trained (n=12) groups. Cardiac function was evaluated by echocardiography with speckle-tracking imaging. Exercise tolerance test was conducted on a treadmill. Both studies were performed when the tumor became palpable and when it reached 1 cm3. After euthanasia, Ca2+-handling protein expression (Western blot) was evaluated. Exercise capacity was reduced in MMTV-PyMT+ compared with MMTVPyMT− (Pinteraction =0.031). Longitudinal strain (Pgroup <0.001) and strain rate (Pgroup =0.030) were impaired. Cardiomyocyte phospholamban was increased (P=0.011), whereas phospho-phospholamban and sodium/calcium exchanger were decreased (P=0.038 and P=0.017, respectively) in MMTV-PyMT+. No significant difference in sarcoplasmic or endoplasmic reticulum calcium 2 ATPase (SERCA2a) was found. SERCA2a/phospholamban ratio was reduced (P=0.007). ET was not associated with increased exercise capacity. ET decreased left ventricular end-systolic diameter (Pgroup =0.038) and end-diastolic volume (Pgroup =0.026). Other morphological and functional cardiac parameters were not improved by ET in MMTV-PyMT+. ET did not improve cardiomyocyte Ca2+-handling protein expression. CONCLUSIONS: Breast cancer is associated with decreased exercise capacity and subclinical left ventricular dysfunction in MMTV-PyMT+, which is at least partly associated with dysregulation of cardiomyocyte Ca2+ handling. ET did not prevent or reverse these changes.
KW - Breast cancer
KW - Ca handling
KW - Cardiac function
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U2 - 10.1161/JAHA.120.018076
DO - 10.1161/JAHA.120.018076
M3 - Article
C2 - 33619982
AN - SCOPUS:85102537875
SN - 2047-9980
VL - 10
SP - 1
EP - 30
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 5
M1 - e018076
ER -