The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells

Sun, Zuyue; Schriewer, Jill; Tang, Mingxin; Marlin, Jerry; Taylor, Frederick R.; Shohet, Ralph V.; Konorev, Eugene

doi:10.1016/j.yjmcc.2015.12.010

Cited by 30 publications

(26 citation statements)

References 86 publications

(78 reference statements)

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“…Several mechanisms have been suggested to mediate DOXinduced toxicity to cardiomyocytes (4,25), whereas endothelial injury has received little attention (26,27). In our experiments, the apoptosis-associated DNA fragmentation was observed approximately to the same extent in cardiomyocytes and ECs.…”

Section: Discussionsupporting

confidence: 53%

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Räsänen

Degerman

Nissinen

et al. 2016

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

106

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Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumor-bearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients.

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Section: Discussionsupporting

confidence: 53%

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Räsänen

Degerman

Nissinen

et al. 2016

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

106

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“…TGF-β is associated with Dox-induced cardiotoxicity (36). In the cardiovascular system, TGF-β is involved in fibrotic cardiac remodeling, and a previous study suggested that inhibition of the TGF-β pathway alleviates left ventricular remodeling and systolic and diastolic dysfunction, thus alleviating the detrimental effects of Dox on endothelial cells (37). It has also been demonstrated that the inhibition of TGF-β attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline-induced cardiomyopathy (38).…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells attenuate doxorubicin‑induced cellular senescence through the VEGF/Notch/TGF‑β signaling pathway in H9c2 cardiomyocytes

2018

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The clinical use of doxorubicin (Dox) is limited by its cardiotoxicity. The fundamental changes it induces include interstitial myocardial fibrosis and the appearance of senescent cardiomyocytes. Mesenchymal stem cell (MSC)‑based therapies have also been reported to modulate cellular senescence, and have been used effectively to treat age‑related cardiovascular diseases. In the present study, the Transwell system was used to coculture H9c2 cells with MSCs, and their proliferation and viability were assessed. The expression of senescence‑related genes p53 and p16, and telomere length were measured using reverse transcription‑quantitative polymerase chain reaction analysis, and the Jagged‑1/Notch‑1 signaling pathway was detected using western blot analysis. The results revealed that Dox induced the senescence of H9c2 cells, characterized by a low proliferation rate, poor viability, reduced telomere length and impaired telomerase activity, and by marked increases in the expression of p53 and p16. By contrast, when cocultured with MSCs in the presence of Dox, H9c2 cell proliferation and viability increased, whereas the expression levels of p53 and p16 decreased, and telomere length and telomerase activity increased. The mechanism underlying the antisenescence function of MSCs was clarified, which involved the vascular endothelial growth factor (VEGF)/Jagged‑1/Notch‑1/transforming growth factor‑β1 (TGF‑β1) signaling pathway. It was confirmed that inhibiting VEGF, or silencing Jagged‑1 or Notch‑1 with small interfering RNA, or using recombinant TGF‑β1 eliminated the antisenescence effects of MSCs on the Dox‑treated H9c2 cells. The results revealed that MSCs rescued H9c2 cells from Dox‑induced senescence through the release of VEGF, which activated the Jagged‑1/Notch‑1 signaling pathway, leading to the inhibition of TGF‑β1 release. Therefore, treatment with MSCs may have important therapeutic implications on the attenuation of cardiotoxicity in patients with cancer treated with Dox.

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“…A potential reason for the reduction in pro-MMP 2 over time is related to the high concentration of TIMP 4 within the cardiac tissue, contributing to the regulation of its integrity and decreasing MMP-induced capillary permeability similarly to what was formerly demonstrated in clinical conditions that damage the blood-brain barrier (Rosenberg et al 1998). Besides the inhibition of MMPs enzyme activity by TIMPs, it must be emphasized that MMPs activity is a complex process that also comprises regulation of MMPs gene expression, which can be inhibited by TGF-β whose pathway is known to be involved in doxorubicin-induced cardiovascular remodeling, as well as the regulation of MMPs enzyme activity by "switch" mechanism (Papazafiropoulou & Tentolouris 2009, Sun et al 2016.…”

Section: Discussionmentioning

confidence: 59%

Matrix metalloproteinases 2 and 9 in rabbits with doxorubicin-induced cardiomyopathy

et al. 2018

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RESUMO.-[Metaloproteinases de matriz 2 e 9 em coelhos com cardiomiopatia induzida pela doxorrubicina.] Alguns estudos já demonstraram o papel exercido pelas metaloproteinases de matriz e seus inibidores na cardiotoxicidade promovida pela doxorrubicina. Assim, este estudo teve como objetivo investigar o comportamento das MMPs 2 e 9 plasmáticas e miocárdicas em coelhos com cardiomiopatia induzida pela doxorrubicina, buscando determinar se há correlação entre a atividade dessas colagenases e o remodelamento cardíaco. A cardiomiopatia foi induzida pela doxorrubicina aplicada por via intravenosa duas vezes por semana ao longo de seis semanas consecutivas. A atividade plasmática das MMPs e o ecocardiograma foram avaliados no momento basal e aos 15 e 45 dias após a primeira aplicação da doxorrubicina. A atividade miocárdica dessas enzimas foi quantificada em apenas nove coelhos aos 45 dias e os resultados comparados Some studies have shown the role played by matrix metalloproteinases and their inhibitors in doxorubicin cardiotoxicity. In this study, we sought to investigate how plasma and myocardial MMP 2 and 9 perform in rabbits with doxorubicin-induced cardiomyopathy, searching for a correlation between the activity of these collagenases and cardiac remodeling. Cardiomyopathy was induced by doxorubicin given intravenously twice a week for six consecutive weeks. Plasma MMP activity and the echocardiogram were assessed at baseline, and at 15 and 45 days after first injection of doxorubicin. The myocardial activity of these enzymes was solely evaluated in nine rabbits at 45 days, and results were compared with nine healthy controls. We only identified the full-length forms of both MMP 2 and 9 throughout the study. The plasma pro-MMP 2 reduced along the deterioration of cardiac function, while the pro-MMP 9 increased significantly at T45 as compared to baseline and T15. A negative significant correlation was found to exist between the plasma activity of pro-MMP 2 and mitral E-to-mitral septal annular early diastolic velocity ratio, which is an estimate of mean left atrial pressure and congestion. Only pro-MMP 2 was found in myocardial samples, and mean activity of such enzyme was statistically lower than that recorded for healthy controls. Although no active form was documented for either collagenase, the duration of the treatment with doxorubicin played a role in the alteration of plasma pro-forms activity. However, these changes could not be associated with most echocardiographic parameters that are supportive of cardiac remodeling. Matrix metalloproteinases 2 and 9 in rabbits with doxorubicin-induced cardiomyopathy com outros nove controles saudáveis. Foram identificadas apenas as formas inativas das MMPs 2 e 9 durante todo o estudo. A pro-MMP 2 plasmática reduziu à medida que a função cardiaca se deteriorou, enquanto a pro-MMP 9 aumentou significativamente em T45 quando comparada aos momentos basal e T15. Houve correlação negativa significativa entre a atividade plasmática da pro-MMP 2 e a relação entre E mitral e a ...

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The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells

Cited by 30 publications

References 86 publications

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Mesenchymal stem cells attenuate doxorubicin‑induced cellular senescence through the VEGF/Notch/TGF‑β signaling pathway in H9c2 cardiomyocytes

Matrix metalloproteinases 2 and 9 in rabbits with doxorubicin-induced cardiomyopathy

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