PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy

Johnson, Taylor A.; Singla, Dinender K.

doi:10.1152/ajpheart.00121.2018

Cited by 38 publications

(34 citation statements)

References 59 publications

(90 reference statements)

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“…Chemotherapy has been shown to mitigate the in ammatory response with exercise (53,64), induce leukopenia/cytopenia (19), and disrupt cardiacmacrophage in ltration (65). To the best of our knowledge, this is the rst study to demonstrate that chemotherapeutic 5FU has deleterious effects on immune cell abundance in otherwise healthy uninjured skeletal muscle.…”

Section: Discussionmentioning

confidence: 82%

The Acute Effects of 5 Fluorouracil on Skeletal Muscle Resident and Infiltrating Immune Cells in Mice

VanderVeen

Sougiannis

Velázquez

et al. 2020

Preprint

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Abstract Background: 5 fluorouracil (5FU) has been a first-choice chemotherapy drug for several cancer types (e.g. colon, breast, head & neck); however, its efficacy is diminished by patient acquired resistance and pervasive side effects. Leukopenia is a hallmark of 5FU; however, the impact of 5FU-induced leukopenia on healthy tissue is only becoming unearthed. Recently, skeletal muscle has been shown to be impacted by 5FU in clinical and preclinical setting and weakness and fatigue remain among the most consistent complaints in cancer patients undergoing chemotherapy. Monocytes, or more specifically macrophages, are the predominate immune cell in skeletal muscle which regulate turnover and homeostasis through both the removal of damaged or old materials and coordinate repair and remodeling. Whether 5FU-induced leukopenia extends beyond circulation toimpact resident and infiltrating skeletal muscle immune cells had not been examined. The purpose of the study was to examine the acute effects of 5FU on resident and infiltrating skeletal muscle monocytes and inflammatory mediators. Methods: Male C57BL/6 mice were given a physiologically translatable dose (35mg/kg) of 5FU, or PBS, i.p. once daily for 5 days to recapitulate 1 dosing cycle. Results: Our results demonstrate that 5FU reduced circulating leukocytes, erythrocytes, and thrombocytes while inducing significant body weight loss (>5%). Flow cytometry analysis of the skeletal muscle indicated a reduction in total CD45+ immune cells with a corresponding decrease in total CD45+CD11b+ monocytes. There was a strong relationship between circulating leukocytes and skeletal muscle CD45+ immune cells. Skeletal muscle Ly6cHigh activated monocytes and M1-like macrophageswere reduced with 5FU treatment while total M2-like CD206+CD11c-macrophageswere not changed with 5FU. Interestingly, 5FU reduced bone marrow CD45+ immune cells and CD45+CD11b+ monocytes.Conclusions: Our results demonstrate that 5FU induced body weight loss and decreased skeletal muscle CD45+ immune cells in associated with a reduction in infiltrating Ly6cHigh monocytes. Interestingly, the loss of skeletal muscle immune cells occurred with bone marrow cell cycle arrest.Together our results highlight that skeletal muscle is sensitive to the cytotoxic effects of 5FU which disrupts both circulating and skeletal muscle immune cells.

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Section: Discussionmentioning

confidence: 82%

The Acute Effects of 5 Fluorouracil on Skeletal Muscle Resident and Infiltrating Immune Cells in Mice

VanderVeen

Sougiannis

Velázquez

et al. 2020

Preprint

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show abstract

“…In another study, Hadi et al reported that treatment with vitamin E and telmisartan significantly reduces infiltration of monocytes into the heart, thereby reducing the cardiac inflammatory response, relieving DOX-induced cardiac injury and improving cardiac dysfunction [ 37 ]. We and other researchers have reported that DOX treatment promotes imbalance between M1 macrophages and M2 macrophages in mice, and aggravation of this imbalance further aggravates cardiac injury and cardiomyocyte apoptosis [ 7 , 38 ]. These results suggest that DOX-induced immune cell activation plays an important role in myocardial injury.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

Wang

et al. 2020

Redox Biology

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Several interleukin (IL) family members have been demonstrated to be involved in doxorubicin (DOX)-induced cardiac injury. This study aimed to investigate the role of IL-22 in DOX-induced cardiac injury and explore its possible mechanisms. In this study, mice were given DOX, and the cardiac expression and sources of IL-22 were determined. Then, IL-22 was knocked out to observe the effects on DOX-induced cardiac injury in mice. In addition, the p38 mitogen-activated protein kinase (MAPK) pathway was inhibited, macrophages were depleted and adoptively transferred, and Fizz3 was up-regulated in mice to explore the mechanisms. The results showed that cardiac IL-22 expression was significantly increased by DOX treatment and was mostly derived from cardiac macrophages. IL-22 knockout significantly reduced cardiac vacuolization and the expression of cardiomyocyte injury markers in both serum and left ventricular tissue and improved cardiac function in DOX-treated mice. In addition, IL-22 knockout reversed DOX-induced cardiac M1 macrophage/M2 macrophage imbalance, reduced oxidative stress and protected against cardiomyocyte apoptosis. p38 MAPK pathway inhibition with SB203580 and macrophage depletion further alleviated the above effects in DOX-treated IL-22-knockout mice. The effects were stronger IL-22-knockout mice with adoptive transfer of WT macrophages than in those with adoptive transfer of IL-22-knockout macrophages. Furthermore, increasing the expression of Fizz3 reduced cardiomyocyte apoptosis and alleviated cardiac dysfunction. Our results may suggest that IL-22 knockout alleviate DOX-induced oxidative stress and cardiac injury by inhibiting macrophage differentiation and thereby increasing the expression of Fizz3. Reductions in IL-22 expression may be beneficial for clinical chemotherapy in tumor patients.

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“…Further evidences demonstrate that a potent inhibitor of PTEN, VO-OHpic, inhibits adverse cardiac remodeling due to the macrophages polarization. Pro-inflammatory M1 macrophages are reduced while anti-inflammatory M2 macrophages are increased in animal models treated with doxorubicin which unfortunately can stimulate cardiomyopathy [94].…”

Section: Role Of Pten In Macrophages Functionmentioning

confidence: 99%

The Tumor Suppressor PTEN as Molecular Switch Node Regulating Cell Metabolism and Autophagy: Implications in Immune System and Tumor Microenvironment

Aquila

Santoro

Caputo

et al. 2020

Cells

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Recent studies conducted over the past 10 years evidence the intriguing role of the tumor suppressor gene Phosphatase and Tensin Homolog deleted on Chromosome 10 PTEN in the regulation of cellular energy expenditure, together with its capability to modulate proliferation and survival, thus expanding our knowledge of its physiological functions. Transgenic PTEN mice models are resistant to oncogenic transformation, present decreased adiposity and reduced cellular glucose and glutamine uptake, together with increased mitochondrial oxidative phosphorylation. These acquisitions led to a novel understanding regarding the role of PTEN to counteract cancer cell metabolic reprogramming. Particularly, PTEN drives an “anti-Warburg state” in which less glucose is taken up, but it is more efficiently directed to the mitochondrial Krebs cycle. The maintenance of cellular homeostasis together with reduction of metabolic stress are controlled by specific pathways among which autophagy, a catabolic process strictly governed by mTOR and PTEN. Besides, a role of PTEN in metabolic reprogramming and tumor/stroma interactions in cancer models, has recently been established. The genetic inactivation of PTEN in stromal fibroblasts of mouse mammary glands, accelerates breast cancer initiation and progression. This review will discuss our novel understanding in the molecular connection between cell metabolism and autophagy by PTEN, highlighting novel implications regarding tumor/stroma/immune system interplay. The newly discovered action of PTEN opens innovative avenues for investigations relevant to counteract cancer development and progression.

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PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy

Cited by 38 publications

References 59 publications

The Acute Effects of 5 Fluorouracil on Skeletal Muscle Resident and Infiltrating Immune Cells in Mice

The Acute Effects of 5 Fluorouracil on Skeletal Muscle Resident and Infiltrating Immune Cells in Mice

Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

The Tumor Suppressor PTEN as Molecular Switch Node Regulating Cell Metabolism and Autophagy: Implications in Immune System and Tumor Microenvironment

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