Anthracycline-Induced Cardiotoxicity: The Role of Endothelial Dysfunction

Гракова, Е. В.; Шилов, С. Н.; Kopeva, K. V.; Березикова, Е. Н.; Попова, А. А.; Неупокоева, М. Н.; Ratushnyak, Elena T.; Teplyakov, A. T.

doi:10.1159/000512771

Cited by 22 publications

(11 citation statements)

References 27 publications

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“…Though doxorubicin can drive ROS generation via several mechanisms, superoxide produced by NOX complexes represents one key source 10,11 and polymorphisms in the genes encoding NOX subunits have been linked to susceptibility to anthracycline-induced cardiotoxicity. 60 Indeed, our data show that TGFβ1 production from VCM requires NOX activation. As in the heart, activation of TGFβ1 receptors in the liver leads to differentiation of HSCs into myofibroblasts, hepatocyte cell death, and fibrosis.…”

Section: Discussionmentioning

confidence: 62%

“…Our results suggest that, following chronic chemotherapy exposure, the relative content of RGS7 versus RGS11 increases in VCM leading to ROS‐dependent TGFβ1 production and release into the peripheral circulation. Though doxorubicin can drive ROS generation via several mechanisms, superoxide produced by NOX complexes represents one key source 10,11 and polymorphisms in the genes encoding NOX subunits have been linked to susceptibility to anthracycline‐induced cardiotoxicity 60 . Indeed, our data show that TGFβ1 production from VCM requires NOX activation.…”

Section: Discussionmentioning

confidence: 70%

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Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

et al. 2023

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Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin‐induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin‐treated cardiomyocytes secrete the endocrine factors transforming growth factor β1 (TGFβ1) and TGFβ superfamily binding protein follistatin‐related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFβ1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFβ1 from the heart and the profibrotic and pro‐oxidant actions of TGFβ1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 70%

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

et al. 2023

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“…The arising cardiovascular toxicity can trigger the development of heart failure. In particular, endothelial cells undergo an environmental insult with the dysregulation of inflammatory and vascular reparative functions, leading to endothelial cell death and the progression of cardiomyopathy [ 10 ]. Despite this, DOX is widely used to treat cancer, which is the most prominent cause of death globally, even if, as a side effect, it is the cause of cardiovascular diseases, which have among the highest mortality rates in the world.…”

Section: Discussionmentioning

confidence: 99%

“…DOX can be conjugated with Top IIβ and intercalated with both nuclear DNA and mitochondrial DNA, activating the DNA damage response and apoptosis [ 8 , 9 ]. DOX-induced endothelial dysfunction is critical in the progression of cardiovascular disease in patients treated with this anthracycline [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

The Impairment of Cell Metabolism by Cardiovascular Toxicity of Doxorubicin Is Reversed by Bergamot Polyphenolic Fraction Treatment in Endothelial Cells

Algieri

Bernardini²,

Oppedisano³

et al. 2022

IJMS

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The beneficial effects of bergamot polyphenolic fraction (BPF) on the mitochondrial bioenergetics of porcine aortic endothelial cells (pAECs) were verified under the cardiotoxic action of doxorubicin (DOX). The cell viability of pAECs treated for 24 h with different concentrations of DOX was reduced by 50%, but the negative effect of DOX was reversed in the presence of increasing doses of BPF (100 µg/mL and 200 µg/mL BPF). An analysis of the protective effect of BPF on the toxic action of DOX was also carried out on cell respiration. We observed the inhibition of the mitochondrial activity at 10 µM DOX, which was not restored by 200 µg/mL BPF. Conversely, the decrease in basal respiration and ATP production caused by 0.5 or 1.0 µM DOX were improved in the presence of 100 or 200 µg/mL BPF, respectively. After 24 h of cell recovery with 100 µg/mL or 200 µg/mL BPF on pAECs treated with 0.5 µM or 1.0 µM DOX, respectively, the mitochondrial parameters of oxidative metabolism impaired by DOX were re-boosted.

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“…And the in vivo results might be affected by other cells in myocardial tissue. Numerous studies implied a central role for increased ROS production in the mechanism of doxorubicin-mediated ECs injury [ 35 ]. In addition to the traditional TGF-β-Smads pathway, oxidative stress is another factor that promoted EndMT.…”

Section: Discussionmentioning

confidence: 99%

Irisin ameliorates doxorubicin-induced cardiac perivascular fibrosis through inhibiting endothelial-to-mesenchymal transition by regulating ROS accumulation and autophagy disorder in endothelial cells

et al. 2021

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The dose-dependent toxicity to cardiomyocytes has been well recognized as a central characteristic of doxorubicin (DOX)-induced cardiotoxicity (DIC), however, the pathogenesis of DIC in the cardiac microenvironment remains elusive. Irisin is a new hormone-like myokine released into the circulation in response to exercise with distinct functions in regulating apoptosis, inflammation, and oxidative stress. Recent advances revealed the role of irisin as a novel therapeutic method and an important mediator of the beneficial effects of exercise in cardioprotection. Here, by using a low-dose long-term mouse DIC model, we found that the perivascular fibrosis was involved in its myocardial toxicity with the underlying mechanism of endothelial-to-mesenchymal transition (EndMT). Irisin treatment could partially reverse DOX-induced perivascular fibrosis and cardiotoxicity compared to endurance exercise. Mechanistically, DOX stimulation led to excessive accumulation of ROS, which activated the NF-κB-Snail pathway and resulted in EndMT. Besides, dysregulation of autophagy was also found in DOX-treated endothelial cells. Restoring autophagy flux could ameliorate EndMT and eliminate ROS. Irisin treatment significantly alleviated ROS accumulation, autophagy disorder, NF-κB-Snail pathway activation as well as the phenotype of EndMT by targeting uncoupling protein 2 (UCP2). Our results also initially found that irisin was mainly secreted by cardiomyocytes in the cardiac microenvironment, which was significantly reduced by DOX intervention, and had a protective effect on endothelial cells in a paracrine manner. In summary, our study indicated that DOX-induced ROS accumulation and autophagy disorders caused an EndMT in CMECs, which played a role in the perivascular fibrosis of DIC. Irisin treatment could partially reverse this phenomenon by regulating UCP2. Cardiomyocytes were the main source of irisin in the cardiac microenvironment. The current study provides a novel perspective elucidating the pathogenesis and the potential treatment of DIC.

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Anthracycline-Induced Cardiotoxicity: The Role of Endothelial Dysfunction

Cited by 22 publications

References 27 publications

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

The Impairment of Cell Metabolism by Cardiovascular Toxicity of Doxorubicin Is Reversed by Bergamot Polyphenolic Fraction Treatment in Endothelial Cells

Irisin ameliorates doxorubicin-induced cardiac perivascular fibrosis through inhibiting endothelial-to-mesenchymal transition by regulating ROS accumulation and autophagy disorder in endothelial cells

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