scholarly journals Disruption of COX-2 modulates gene expression and the cardiac injury response to doxorubicin

2006 ◽  
Vol 291 (2) ◽  
pp. H532-H536 ◽  
Author(s):  
Tomas G. Neilan ◽  
Glen A. Doherty ◽  
Gang Chen ◽  
Catherine Deflandre ◽  
Hester McAllister ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cardiac Dysfunction ◽  
Cell Apoptosis ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Cardiac Cell ◽  
Wild Type ◽  
Cox 2 ◽  
Prostacyclin Analog

To determine the role of cyclooxygenase (COX)-2 in anthracycline-induced cardiac toxicity, we administered doxorubicin (Dox) to mice with genetic disruption of COX-2 (COX-2−/−). After treatment with Dox, COX-2−/− mice had increased cardiac dysfunction and cardiac cell apoptosis compared with Dox-treated wild-type mice. The expression of the death-associated protein kinase-related apoptosis-inducing protein kinase-2 was also increased in Dox-treated COX-2−/− animals. The altered gene expression, cardiac injury, and dysfunction after Dox treatment in COX-2−/− mice was attenuated by a stable prostacyclin analog, iloprost. Wild-type mice treated with Dox developed cardiac fibrosis that was absent in COX-2−/− mice and unaffected by iloprost. These results suggest that genetic disruption of COX-2 increases the cardiac dysfunction after treatment with Dox by an increase in cardiac cell apoptosis. This Dox-induced cardiotoxicity in COX-2−/− mice was attenuated by a prostacyclin analog, suggesting a protective role for prostaglandins in this setting.

Overexpression of protein kinase C-alpha in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-alpha expression but not tumor promotion

1999 ◽  
Vol 112 (20) ◽  
pp. 3497-3506
Author(s):  
H.Q. Wang ◽  
R.C. Smart
Keyword(s):  
Protein Kinase ◽  
Transgenic Mice ◽  
Normal Mouse ◽  
Mouse Skin ◽  
Tumor Promotion ◽  
Epidermal Differentiation ◽  
Wild Type ◽  
Outer Root Sheath ◽  
Proinflammatory Mediators ◽  
Cox 2

Protein kinase Calpha (PKCalpha) is one of six PKC isoforms expressed in keratinocytes of mouse epidermis. To gain an understanding of the role of epidermal PKCalpha, we have localized its expression to specific cells of normal mouse skin and examined the effect of keratin 5 (K5) promoter directed expression of PKCalpha in transgenic mice. In normal mouse skin, PKCalpha was extensively expressed in the outer root sheath (ORS) keratinocytes of the anagen hair follicle and weakly expressed in keratinocytes of interfollicular epidermis. K5-targeted expression of PKCalpha to epidermal basal keratinocytes and follicular ORS keratinocytes resulted in a tenfold increase in epidermal PKCalpha. K5-PKCalpha mice exhibited no abnormalities in keratinocyte growth and differentiation in the epidermis. However, a single topical treatment with the PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in a striking inflammatory response characterized by edema and extensive epidermal infiltration of neutrophils that formed intraepidermal microabscesses in the epidermis. Compared to TPA-treated wild-type mice, the epidermis of TPA-treated K5-PKCalpha mice displayed increased expression of cyclooxygenase-2 (COX-2), the neutrophil chemotactic factor macrophage inflammatory protein-2 (MIP-2) mRNA and the proinflammatory cytokine TNFalpha mRNA but not IL-6 or IL-1alpha mRNA. To determine if K5-PKCalpha mice display an altered response to TPA-promotion, 7, 12-dimethylbenz[a]anthracene-initiated K5-PKCalpha mice and wild-type mice were promoted with TPA. No differences in papilloma incidence or multiplicity were observed between K5-PKCalpha mice and wild-type littermates. These results demonstrate that the overexpression of PKCalpha in epidermis increases the expression of specific proinflammatory mediators and induces cutaneous inflammation but has little to no effect on epidermal differentiation, proliferation or TPA tumor promotion.

Protective effects of BiP inducer X (BIX) against diabetic cardiomyopathy in rats

2020 ◽  
Author(s):  
Gholamreza Idari ◽  
Pouran Karimi ◽  
Samad Ghaffari ◽  
Seyed Isaac Hashemy ◽  
Baratali Mashkani
Keyword(s):  
Er Stress ◽  
Diabetic Cardiomyopathy ◽  
Cell Apoptosis ◽  
Cardiac Fibrosis ◽  
Tissue Expression ◽  
Myocardial Cell ◽  
Diabetic Rats ◽  
Mrna Levels ◽  
Protective Effects ◽  
Cardiac Cell

Diabetic cardiomyopathy (DC) is associated with impaired endoplasmic reticulum (ER) function, development of ER stress, and induction of cardiac cell apoptosis. Preventive effects of BiP inducer X (BIX) were investigated against DC characteristic changes in a type 2 diabetes rat model. To establish diabetes, a high-fat diet and a single dose of streptozotocin were administered. Then, animals were assigned into following groups: control, BIX, diabetic animals monitored for one, two, and three weeks. Diabetic rats treated with BIX for one, two, and three weeks. Expressions of various ER stress and apoptotic markers were assessed by immunoblotting method. CHOP gene expression was assessed by Real-time PCR. Tissue expression of BiP was evaluated by immunohistochemistry method. Hematoxylin and eosin and Masson's trichrome staining were performed to assess histological changes in the left ventricle. Cardiac cell apoptosis was examined using TUNEL assay. BIX administration suppressed the activation of the ER stress markers and cleavage of pro-caspase 3 in the diabetic rats. Likewise, tissue expression of BiP protein was increased, while CHOP mRNA levels were decreased. These results were accompanied by reducing cardiac fibrosis and myocardial cell apoptosis suggesting protective effects of BIX against the development of DC by decreasing cardiomyocyte apoptosis and fibrosis.

scholarly journals Thyroxine Affects Lipopolysaccharide-Induced Macrophage Differentiation and Myocardial Cell Apoptosis via the NF-κB p65 Pathway Both In Vitro and In Vivo

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Shan Zhu ◽  
Yuan Wang ◽  
Hongtao Liu ◽  
Wen Wei ◽  
Yi Tu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Dysfunction ◽  
Cell Apoptosis ◽  
Cardiac Injury ◽  
Myocardial Cell ◽  
M2 Macrophage ◽  
Mrna Levels ◽  
Cytokine Mrna ◽  
M1 Macrophage

Background. Numerous studies have demonstrated that the inflammatory response is involved in the progression of lipopolysaccharide- (LPS-) induced myocardial cell apoptosis. Accumulating evidence has shown that thyroxine participates in diseases by downregulating the inflammatory response. This study aimed at investigating whether thyroxine alleviates LPS-induced myocardial cell apoptosis. Methods. Bone marrow-derived macrophages (Mø) were treated with LPS and thyroxine, and Mø differentiation and Mø-related cytokine expression were measured. The effect of Mø differentiation on mouse cardiomyocyte (MCM) apoptosis was also detected in vitro. In addition, C57BL/6 mice underwent thyroidectomy and were treated with LPS 35 days later; subsequently, Mø differentiation and myocardial cell apoptosis in hearts were analyzed. To determine whether the nuclear factor-kappa B (NF-κB) p65 pathway mediates the effect of thyroxine on Mø differentiation and myocardial cell apoptosis, the specific NF-κB p65 pathway inhibitor JSH-23 was administered to mice that underwent a thyroidectomy. Results. Levothyroxine treatment significantly reduced the activation of the NF-κB p65 pathway, decreased M1 macrophage (Mø1) differentiation and Mø1-related cytokine mRNA levels in LPS-treated Mø, and increased M2 macrophage (Mø2) differentiation and Mø2-related cytokine mRNA expression. The protective effects of levothyroxine on MCM apoptosis mediated by LPS-treated Mø were alleviated by JSH-23. In mice, thyroidectomy aggravated LPS-induced cardiac injury and cardiac dysfunction, further promoted NF-κB p65 activation, and increased cardiac Mø1 expression and myocardial cell apoptosis but decreased cardiac Mø2 expression. JSH-23 treatment significantly ameliorated the thyroidectomy-induced increases in myocardial cell apoptosis and Mø differentiation. Conclusions. Thyroxine alleviated the Mø1/Mø2 imbalance, reduced the inflammatory response, decreased myocardial cell apoptosis, and protected against cardiac injury and cardiac dysfunction in LPS-treated mice. Thyroxine may be a novel therapeutic strategy to prevent and treat LPS-induced cardiac injury.

Abstract 148: Sterol Regulatory Element-Binding Protein-1 Is Involved in the Development of Angiotensin II-Induced Cardiac Fibrosis

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Satoshi Sakai ◽  
Yoshimi Nakagawa ◽  
Nobutake Shimojo ◽  
Taizo Kimura ◽  
Kazuko Tajiri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Binding Protein ◽  
Regulatory Element ◽  
Antioxidant Genes ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Sterol Regulatory Element Binding Protein (SREBP)-1 is a transcription factor for triglyceride synthesis. SREBP-1 is shown to contribute to the organ damages such as pancreatic beta cell, liver, and kidney; however, it is unclear whether SREBP-1 also contributes to the cardiac pathogenesis. We made cardiac dysfunction and fibrosis model by 2-week infusion of angiotensin II (A-II, 1.44 mg/kg BW/day). Mice were divided into followings (n=5∼6 in each group): wild with vehicle (WC), wild with A-II (WA), SREBP-1 knockout mice (SREBP-KO) with vehicle (SC), and SREBP-KO with A-II (SA). WA clearly demonstrated cardiac dysfunction and severe perivascular fibrosis compared to WC; however, these findings were not observed in SA compared to SC. We analyzed gene expression by DNA microarray using the software DAVID and quantitative RT-PCR to find gene clusters mostly illustrative for these phenotypes. Gene expression of extracellular matrix (Col1a, 3a, periostin) was increased in WA. Highly scored annotations in WA were chemokines (CCL5, CXCL10) and their receptors (CCR5, CXCR3), and Th2 cytokines (IL-13 and TGFb), suggesting that chronic inflammatory and repairing responses occurred. These changes were normalized in SA compared to SC. Expression of NOX4, a component of NADPH oxidase, was significantly increased in WA and SA compared to each control in a similar extent, suggesting that the Ang II-induced oxidative stress to the heart did not differ. To elucidate why the cardiac fibrosis differed between WA and SA, we analyzed the expression of transcription factors. Nrf2, a transcription factor for detoxification and anti-oxidant gene against to reactive oxygen species (ROS), was significantly decreased in WA compared to WC; however, it did not differ between in SA and SC. Furthermore, expression of the Nrf2-inducible genes HO-1 and NQO1, antioxidant genes, was significantly decreased in WA compared to WC; meanwhile, there were no differences between in SA and SC. [Conclusion] SREBP-1 may positively contribute to the A-II-induced cardiac fibrosis via the involvement of chronic inflammatory responses, which is induced partly by the reduction of antioxidant activity.

scholarly journals The Human Cytomegalovirus UL97 Protein Kinase, an Antiviral Drug Target, Is Required at the Stage of Nuclear Egress

2003 ◽  
Vol 77 (2) ◽  
pp. 905-914 ◽  
Author(s):  
Paula M. Krosky ◽  
Moon-Chang Baek ◽  
Donald M. Coen
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Virus Infection ◽  
Human Cytomegalovirus ◽  
Antiviral Drug ◽  
Virus Yield ◽  
Wild Type Virus ◽  
Wild Type ◽  
Viral Dna ◽  
Nuclear Egress

ABSTRACT Human cytomegalovirus encodes an unusual protein kinase, UL97, that activates the established antiviral drug ganciclovir and is specifically inhibited by a new antiviral drug, maribavir. We used maribavir and a UL97 null mutant, which is severely deficient in viral replication, to determine what stage of virus infection critically requires UL97. Compared with wild-type virus, there was little or no decrease in immediate-early gene expression, viral DNA synthesis, late gene expression, or packaging of viral DNA into nuclease-resistant structures in mutant-infected or maribavir-treated cells under conditions where the virus yield was severely impaired. Electron microscopy studies revealed similar proportions of various capsid forms, including DNA-containing capsids, in the nuclei of wild-type- and mutant-infected cells. However, capsids were rare in the cytoplasm of mutant-infected or maribavir-treated cells; the magnitudes of these decreases in cytoplasmic capsids were similar to those for virus yield. Thus, genetic and pharmacological evidence indicates that UL97 is required at the stage of infection when nucleocapsids exit from the nucleus (nuclear egress), and this poorly understood stage of virus infection can be targeted by antiviral drugs. Understanding UL97 function and maribavir action should help elucidate this interesting biological process and help identify new antiviral drug targets for an important pathogen in immunocompromised patients.

scholarly journals Whole Genome Microarray Analysis of DUSP4-Deletion Reveals A Novel Role for MAP Kinase Phosphatase-2 (MKP-2) in Macrophage Gene Expression and Function

2019 ◽  
Vol 20 (14) ◽  
pp. 3434 ◽  
Author(s):  
Thikryat Neamatallah ◽  
Shilan Jabbar ◽  
Rothwelle Tate ◽  
Juliane Schroeder ◽  
Muhannad Shweash ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Whole Genome ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Macrophage Function ◽  
Mitogen Activated Protein ◽  
Whole Genome Microarray ◽  
Stimulating Factor

Background: Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP-4). It plays an important role in macrophage inflammatory responses through the negative regulation of Mitogen activated protein kinase (MAPK) signalling. However, information on the effect of MKP-2 on other aspect of macrophage function is limited. Methods: We investigated the impact of MKP-2 in the regulation of several genes that are involved in function while using comparative whole genome microarray analysis in macrophages from MKP-2 wild type (wt) and knock out (ko) mice. Results: Our data showed that the lack of MKP-2 caused a significant down-regulation of colony-stimulating factor-2 (Csf2) and monocyte to macrophage-associated differentiation (Mmd) genes, suggesting a role of MKP-2 in macrophage development. When treated with macrophage colony stimulating factor (M-CSF), Mmd and Csf2 mRNA levels increased but significantly reduced in ko cells in comparison to wt counterparts. This effect of MKP-2 deletion on macrophage function was also observed by cell counting and DNA measurements. On the signalling level, M-CSF stimulation induced extracellular signal-regulated kinases (ERK) phosphorylation, which was significantly enhanced in the absence of MKP-2. Pharmacological inhibition of ERK reduced both Csf2 and Mmd genes in both wild type and ko cultures, which suggested that enhanced ERK activation in ko cultures may not explain effects on gene expression. Interestingly other functional markers were also shown to be reduced in ko macrophages in comparison to wt mice; the expression of CD115, which is a receptor for M-CSF, and CD34, a stem/progenitor cell marker, suggesting global regulation of gene expression by MKP-2. Conclusions: Transcriptome profiling reveals that MKP-2 regulates macrophage development showing candidate targets from monocyte-to-macrophage differentiation and macrophage proliferation. However, it is unclear whether effects upon ERK signalling are able to explain the effects of DUSP-4 deletion on macrophage function.

Abstract P480: Myeloid YAP Inhibition Improves Cardiac Phenotype During Pressure Overload Stress

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Jamie J Francisco ◽  
Yu Zhang ◽  
Yasuki Nakada ◽  
Peiyong Zhai ◽  
Dominic Del Re
Keyword(s):  
Gene Expression ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Myeloid Cells ◽  
Pressure Overload ◽  
Inflammatory Gene Expression ◽  
Cardiac Inflammation ◽  
Inflammatory Gene ◽  
Raw264.7 Macrophages ◽  
Cardiac Phenotype

Inflammation is a component of cardiovascular disease and is thought to contribute to cardiac dysfunction in ischemic and non-ischemic models of heart failure. While ischemia-induced inflammation has been extensively studied in the heart, relatively less is known regarding cardiac inflammation during non-ischemic stress. Recent work has implicated a role for Yes-associated protein (YAP), a transcriptional co-factor, in modulating cardiac inflammation and remodeling after myocardial infarction. We hypothesized that YAP mediates a pro-inflammatory response during pressure overload (PO)-induced non-ischemic injury, and that targeted YAP inhibition is cardioprotective. PO in mice elicits an immune response characterized by infiltration of myeloid cells that precedes cardiac dysfunction. Myeloid cells isolated from the heart after 7d PO showed evidence of increased YAP activity. Myeloid-specific YAP knockout mice (YAP F/F ;LysM Cre ) were subjected to PO stress. After 4 weeks, cardiac hypertrophy was similar between YAP KO mice and controls. However, systolic dysfunction, cardiac fibrosis, and indicators of pathological remodeling were all attenuated in YAP KO mice compared to controls. Additionally, inflammatory gene expression and macrophage infiltration to the myocardium were significantly attenuated in YAP KO mice after PO, indicating reduced inflammation compared to controls. Experiments using RAW264.7 macrophages and primary bone marrow-derived macrophages (BMDMs) from YAP KO and control mice demonstrated that increased YAP expression enhanced, while YAP suppression attenuated, inflammatory gene expression. The inflammasome is a multiprotein complex and important facilitator of cytokine processing that mediates inflammation in the PO heart. We observed attenuated inflammasome priming and function in YAP deficient BMDMs, as well as in YAP KO hearts following PO, indicating disruption of inflammasome induction. Together these data implicate YAP as an important mediator of inflammasome function and cardiac inflammation during PO stress and suggest that selective inhibition of YAP in the myeloid compartment may prove a novel therapeutic target in non-ischemic heart disease.

scholarly journals Loss of Nnt Increases Expression of Oxidative Phosphorylation Complexes in C57BL/6J Hearts

2021 ◽  
Vol 22 (11) ◽  
pp. 6101
Author(s):  
Jack L. Williams ◽  
Charlotte L. Hall ◽  
Eirini Meimaridou ◽  
Lou A. Metherell
Keyword(s):  
Gene Expression ◽  
Oxidative Phosphorylation ◽  
Cardiac Dysfunction ◽  
Mitochondrial Membrane ◽  
Oxygen Species ◽  
Wild Type ◽  
Inner Mitochondrial Membrane ◽  
Increased Risk ◽  
Differential Gene ◽  
Biallelic Mutations

Nicotinamide nucleotide transhydrogenase (NNT) is a proton pump in the inner mitochondrial membrane that generates reducing equivalents in the form of NAPDH, which can be used for anabolic pathways or to remove reactive oxygen species (ROS). A number of studies have linked NNT dysfunction to cardiomyopathies and increased risk of atherosclerosis; however, biallelic mutations in humans commonly cause a phenotype of adrenal insufficiency, with rare occurrences of cardiac dysfunction and testicular tumours. Here, we compare the transcriptomes of the hearts, adrenals and testes from three mouse models: the C57BL/6N, which expresses NNT; the C57BL/6J, which lacks NNT; and a third mouse, expressing the wild-type NNT sequence on the C57BL/6J background. We saw enrichment of oxidative phosphorylation genes in the C57BL/B6J in the heart and adrenal, possibly indicative of an evolved response in this substrain to loss of Nnt. However, differential gene expression was mainly driven by mouse background with some changes seen in all three tissues, perhaps reflecting underlying genetic differences between the C57BL/B6J and -6N substrains.

scholarly journals Thyroxine Alleviates Energy Failure, Prevents Myocardial Cell Apoptosis, and Protects against Doxorubicin-Induced Cardiac Injury and Cardiac Dysfunction via the LKB1/AMPK/mTOR Axis in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Yuan Wang ◽  
Shan Zhu ◽  
Hongtao Liu ◽  
Wen Wei ◽  
Yi Tu ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cell Apoptosis ◽  
Treatment Time ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Cardiac Injury ◽  
Energy Generation ◽  
Adenosine Diphosphate ◽  
Myocardial Cell ◽  
Energy Failure

Background. Previous studies have demonstrated that energy failure is closely associated with cardiac injury. Doxorubicin (DOX) is a commonly used clinical chemotherapy drug that can mediate cardiac injury through a variety of mechanisms. Thyroxine is well known to play a critical role in energy generation; thus, this study is aimed at investigating whether thyroxine can attenuate DOX-induced cardiac injury by regulating energy generation. Methods. First, the effect of DOX on adenosine diphosphate (ADP) and adenosine triphosphate (ATP) ratios in mice was assessed. In addition, thyroxine was given to mice before they were treated with DOX to investigate the effects of thyroxine on DOX-induced cardiac injury. Furthermore, to determine whether the liver kinase b1 (LKB1)/adenosine 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) axis mediated the effect of thyroxine on DOX-induced cardiac injury, thyroxine was given to DOX-treated LKB1 knockout (KO) mice. Results. DOX treatment time- and dose-dependently increased the ADP/ATP ratio. Thyroxine treatment also reduced lactate dehydrogenase (LDH) and creatine kinase myocardial band (CK-MB) levels in both serum and heart tissue and alleviated cardiac dysfunction in DOX-treated mice. Furthermore, thyroxine reversed DOX-induced reductions in LKB1 and AMPK phosphorylation; mitochondrial complex I, III, and IV activity; and mitochondrial swelling and reversed DOX-induced increases in mTOR pathway phosphorylation and myocardial cell apoptosis. These effects of thyroxine on DOX-treated mice were significantly attenuated by LKB1 KO. Conclusions. Thyroxine alleviates energy failure, reduces myocardial cell apoptosis, and protects against DOX-induced cardiac injury via the LKB1/AMPK/mTOR axis in mice. Thyroxine may be a new agent for the clinical prevention of cardiac injury in tumor patients undergoing chemotherapy with DOX.

scholarly journals Early Moderate Intensity Aerobic Exercise Intervention Prevents Doxorubicin-caused Cardiac Dysfunction through Inhibition of Cardiac Fibrosis and Inflammation

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1102
Author(s):  
Hsin-Lun Yang ◽  
Pei-Ling Hsieh ◽  
Ching-Hsia Hung ◽  
Hui-Ching Cheng ◽  
Wan-Ching Chou ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Exercise Intervention ◽  
Treadmill Exercise ◽  
Cardiac Injury ◽  
Treated Group ◽  
Exercise Group ◽  
Moderate Intensity ◽  
Cardiac Damage ◽  
Creatine Kinase Mb

Doxorubicin (DOX) is known as an effective drug in the fight against various cancers. However, one of the greatest impediments is DOX-induced cardiomyopathy, which may potentially lead to heart failure. Accumulating evidence has shed light on the pathological mechanism of DOX-induced cardiotoxicity, but treatments to mitigate the cardiac damage are still required. In an attempt to address this issue, we evaluated whether exercise provides cardioprotective effects on the DOX-induced cardiotoxicity. We showed that treadmill exercise (3 times/week; 1-week of exercise acclimatization and 4-weeks of endurance exercise) during the DOX treatment successfully prevented the cardiac dysfunction. The DOX-stimulated expression of IκBα, NF-κB, COX-2, and IL-8 were all downregulated by exercise as well as the fibrosis factors (TGF-β1, phosphorylated ERK, Sp1, and CTGF). Moreover, we showed that treadmill exercise diminished the expression of several cardiac remodeling-associated factors, such as FGF2, uPA, MMP2, and MMP9. These results were in line with the finding that exercise intervention reduced cardiac fibrosis and restored cardiac function, with higher values of ejection fraction and fractional shortening compared to the DOX-treated group. Two commonly used indicators of cardiac injury, lactate dehydrogenase, and creatine kinase-MB, were also decreased in the exercise group. Collectively, our results suggested that it may be beneficial to prescribe treadmill exercise as an adjunct therapy to limit cardiac damage caused by DOX.

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