DOX-induced Acute Cardiotoxicity Research Articles

α-Bisabolol: A Dietary Sesquiterpene that Attenuates Apoptotic and Nonapoptotic Cell Death Pathways by Regulating the Mitochondrial Biogenesis and Endoplasmic Reticulum Stress-Hippo Signaling Axis in Doxorubicin-Induced Acute Cardiotoxicity in Rats.

The potential for multiorgan toxicities is a significant barrier to the therapeutic use of doxorubicin (DOX) in cancer treatment. With regard to DOX-induced acute cardiotoxicity in rats, the current investigation sought to assess the cardioprotective function of α-bisabolol (BSB) as well as the underlying pharmacological and molecular processes. Acute cardiotoxicity was induced in the rats by the intraperitoneal injection of DOX (12.5 mg/kg, single dosage). Over the course of 5 days, the rats were administered 25 mg/kg of BSB orally twice a day. The DOX administration induced cardiac damage, as evidenced by altered cardiospecific diagnostic markers and macroscopic enzyme mapping assay. The occurrence of mitochondrial oxidative stress was observed by a significant decline in antioxidant defense along with an increase in lipid peroxidation. DOX also perturbed DNA damage, mitochondrial biogenesis, mitochondrial fission and dysfunction, ER stress, Hippo signaling, and caspase-dependent and independent apoptosis including necroptosis and ferroptosis in the myocardium of rats. Conversely, it has been noted that the administration of BSB preserves the myocardium and reverses all cellular, molecular, and structural disruptions in the cardiac tissues of rats exposed to DOX-induced toxicity. The results that are currently available unequivocally show the cardioprotective role of BSB in DOX-induced cardiotoxicity. This effect is attributed to BSB's strong antioxidant, antilipid peroxidative, and antiapoptotic properties, which are mediated by advantageous changes in multiple signaling pathways.

Galectin-3 contributes to acute cardiac dysfunction and toxicity by increasing oxidative stress and fibrosis in doxorubicin-treated mice

BackgroundDoxorubicin (DOX) leads to cardiovascular toxicity through direct cardiomyocyte injury and inflammation. We aimed to study the role of Galectin-3 (Gal-3), a β-galactosidase binding lectin associated with inflammation and fibrosis in DOX-induced acute cardiotoxicity in mice. MethodsMale C57 and Gal-3 knockout (KO) mice were given a single dose of DOX (15 mg/kg, i.p) or placebo. Serum creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and cardiac thiobarbituric acid-reactive substance (TBARS) were measured at 3 days to assess cardiac injury and oxidative stress. Cardiac remodeling and function were studied by echocardiography and catheterization at 7 days. Myocardial fibrosis was quantified in picrosirius red stained slices. ResultsAbsence of Gal-3 tended to reduce the mortality after DOX. DOX significantly increased CPK, LDH, AST and TBARS while treated Gal-3 KO mice showed reduced injury and oxidative stress. After 7 days, adverse remodeling, fibrosis and dysfunction in treated-C57 mice were severely affected while those effects were prevented by absence of Gal-3. ConclusionIn summary, genetic deletion of Gal-3 prevented cardiac damage, adverse remodeling and dysfunction, associated with reduced cardiac oxidative stress and fibrosis. Understanding the contribution of GAL-3 to doxorubicin-induced cardiac toxicity reinforces its potential use as a therapeutic target in patients with several cancer types.

α-Bisabolol, a Dietary Sesquiterpene, Attenuates Doxorubicin-Induced Acute Cardiotoxicity in Rats by Inhibiting Cellular Signaling Pathways, Nrf2/Keap-1/HO-1, Akt/mTOR/GSK-3β, NF-κB/p38/MAPK, and NLRP3 Inflammasomes Regulating Oxidative Stress and Inflammatory Cascades.

Cancer chemotherapy with doxorubicin (DOX) may have multiorgan toxicities including cardiotoxicity, and this is one of the major limitations of its clinical use. The present study aimed to evaluate the cardioprotective role of α-Bisabolol (BSB) in DOX-induced acute cardiotoxicity in rats and the underlying pharmacological and molecular mechanisms. DOX (12.5 mg/kg, single dose) was injected intraperitoneally into the rats for induction of acute cardiotoxicity. BSB was given orally to rats (25 mg/kg, p.o. twice daily) for a duration of five days. DOX administration induced cardiac dysfunction as evidenced by altered body weight, hemodynamics, and release of cardio-specific diagnostic markers. The occurrence of oxidative stress was evidenced by a significant decline in antioxidant defense along with a rise in lipid peroxidation and hyperlipidemia. Additionally, DOX also increased the levels and expression of proinflammatory cytokines and inflammatory mediators, as well as activated NF-κB/MAPK signaling in the heart, following alterations in the Nrf2/Keap-1/HO-1 and Akt/mTOR/GSK-3β signaling. DOX also perturbed NLRP3 inflammasome activation-mediated pyroptosis in the myocardium of rats. Furthermore, histopathological studies revealed cellular alterations in the myocardium. On the contrary, treatment with BSB has been observed to preserve the myocardium and restore all the cellular, molecular, and structural perturbations in the heart tissues of DOX-induced cardiotoxicity in rats. Results of the present study clearly demonstrate the protective role of BSB against DOX-induced cardiotoxicity, which is attributed to its potent antioxidant, anti-inflammatory, and antihyperlipidemic effects resulting from favorable modulation of numerous cellular signaling regulatory pathways, viz., Nrf2/Keap-1/HO-1, Akt/mTOR/GSK-3β, NF-κB/p38/MAPK, and NLRP3 inflammasomes, in countering the cascades of oxidative stress and inflammation. The observations suggest that BSB can be a promising agent or an adjuvant to limit the cardiac injury caused by DOX. Further studies including the role in tumor-bearing animals as well as regulatory toxicology are suggested.

Anthracycline cardiotoxicity is exacerbated by global p38b genetic ablation in a sexually dimorphic manner but unaltered by cardiomyocyte-specific p38a loss.

Severe cardiotoxic effects limit the efficacy of doxorubicin (DOX) as a chemotherapeutic agent. Activation of intracellular stress signaling networks, including p38 mitogen-activated protein kinase (MAPK), have been implicated in DOX-induced cardiotoxicity (DIC). However, the roles of the individual p38 isoforms in DIC remain incompletely elucidated. We recently reported that global p38d deletion protected female but not male mice from DIC, while global p38g deletion did not significantly modulate it. Here we studied the in vivo roles of p38a and p38b in acute DIC. Male and female mice with cardiomyocyte-specific deletion of p38a or global deletion of p38b and their wild-type counterparts were injected with DOX. Survival and health were tracked for 10 days post-injection. Cardiac function was assessed by echocardiography and electrocardiography, and fibrosis by Picro Sirius Red staining. Expression and activation of signaling proteins and inflammatory markers were measured by western blot, phosphorylation array and chemokine/cytokine array, respectively. Global p38b deletion significantly aggravated DIC and worsened cardiac electrical and mechanical function deterioration in female mice. Mechanistically, DIC in p38b-null female mice correlated with increased autophagy, sustained hyperactivation of pro-apoptotic JNK signaling, as well as remodeling of myocardial inflammatory environment. In contrast, cardiomyocyte-specific deletion of p38a improved survival of DOX30-treated male mice 5 days post-treatment but did not influence cardiac function in DOX-treated male or female mice. Our data highlight the sex- and isoform-specific roles of p38a and p38b MAPKs in DOX-induced cardiac injury and suggest a novel in vivo function of p38b in protecting female mice from DIC.

Protective Effect of Omega-3 and the Potential of Toll-like Receptor Gene Expression in Rats with Doxorubicin-induced Cardiac Toxicity

Despite the clinical signs of doxorubicin (DOX)-induced cardiomyopathy, the mechanisms underlying DOX-induced cardiac damage are unknown. Toll-like receptors (TLRs) allow cardiomyocytes to respond to either endogenous or external signals, both of which have the potential to alter the pathophysiological responses to dilated cardiomyopathy. Omega-3 (OMG-3) precursors are highly active metabolites with numerous therapeutic benefits in the prevention and/or treatment of a variety of diseases. Thus, this study was aimed at evaluating the preventive effect of omega-3 on rats suffering from acute DOX-induced cardiotoxicity associated with TLR gene expression. Thirty rats were divided into five equal groups; Group 1 received no treatment, Group 2 received doxorubicin (at a toxic dose of 20 mg/kg), and Groups 3-5 received doxorubicin (20 mg/kg) after receiving OMG-3 at various doses (100, 200, and 400 mg/kg/day, respectively) for 4 weeks. At the end of the experiment, blood samples were obtained from the heart. The real time polymerase chain reaction (RT-PCR) was used to assess TLR2 and TLR4 gene expression. TLR2 had a significantly (p<0.01) elevated fold change in the DOX alone group (28.74+4.95), whereas TLR2 expression was significantly reduced in the OMG-3 pretreated groups (1.633+0.51, 0.733+0.13, and 0.709+0.16, respectively). TLR4 fold change in the DOX alone group was 8.57+1.22, whereas TLR4 expression was significantly reduced in the OMG-3 pretreated groups (100, 200, and 400 mg/kg) with values of 0.809+0.32, 0.852+0.50, and 0.272+0.16, respectively. The findings of this study revealed that OMG-3 decreased doxorubicin-induced cardiotoxicity and showed a significant cardioprotective effect by lowering TLR2 and TLR4 gene expression.

ASSESSMENT OF CARDIOPROTECTIVE EFFECT OF NECROSTATIN-1 STABLE IN A MICE MODEL OF ACUTE DOXORUBICIN-INDUCED CARDIOTOXICITY.

The aim: To evaluate the effect of Necrostatin-1s (Nec-1s), an inhibitor of necroptosis, on acute Dox-induced cardiotoxicity in a mice model. Materials and methods: Fifteen male mice were used. The animals were allocated into three groups. On the third day of the experiment, a single intraper¬itoneal dose of 20 mg/kg Dox was used to induce cardiotoxicity. Mice in the control group were given vehicle (DMSO) intraperitoneally, whereas mice in the third group were given 5 mg/kg Nec-1s two days before Dox treatment and continued for a total of five days. Animals were euthanized at the conclusion of the research. ELISA was used to assess the following parameters: cTnI, TNF-α, IL-1β, GPX-4, and Hmox-1. The expression of TNF-R1 and phosphorylated NF-κβ p65 was measured using immunohistochemistry. In addition, a histopathologic evaluation of the cardiac lesions was conducted. Results: Our results showed that Dox treatment substantially elevated serum cTnI levels, increased tissue inflammatory biomarkers (TNF-α, IL-1β, phospho NF-κβ p65 and TNF-R1), and reduced tissue antioxidant enzymes (GPX-4, Hmox-1). A histopathological analysis showed pronounced necrosis and vacuolization. These results were drastically changed by pretreatment with Nec-1s, with serum cTnI levels in this group being much lower than in the Dox group. In addition to a significant decrease in inflammatory markers, antioxidant enzymes were partially recovered. Moreover, there was preservation of the cardiac morphology to a level that was roughly normal. Conclusions: Our findings demonstrate that pretreatment with Nec-1s protected against acute Dox-induced cardiotoxicity. This cardioprotective effect was mainly due to amelioration of inflammation that reflected by inhibition of NF-κβ/TNF-α/TNF-R1 pathway, with partial restoration of antioxidant enzymes, GPX-4 and Hmox1.

Combination of Panax ginseng C. A. Mey and Febuxostat Boasted Cardioprotective Effects Against Doxorubicin-Induced Acute Cardiotoxicity in Rats.

Doxorubicin (DOX) is an anticancer agent for treating solid and soft tissue malignancies. However, the clinical use of DOX is restricted by cumulative, dose-dependent cardiotoxicity. Therefore, the present study aimed to assess the cardioprotective effects of P. ginseng C. A. Mey, febuxostat, and their combination against DOX-induced cardiotoxicity. Thirty-five Sprague Dawley male rats were used in this study. The animals were randomly divided into five groups, with seven rats per group. The control group received normal saline, the induced group received DOX only, and the treated group received P. ginseng, febuxostat, and their combination before DOX treatment. Biomarkers of acute cardiac toxicity were assessed in each group. Results showed that treatment with the combination of febuxostat and P. ginseng before DOX led to a significant improvement in the biomarkers of acute DOX-induced cardiotoxicity. In conclusion, the combination of P. ginseng and febuxostat produced more significant cardioprotective effects against DOX-induced cardiotoxicity when compared to either P. ginseng or febuxostat when used alone. The potential mechanism of this combination was mainly mediated by the anti-inflammatory and antioxidant effects of P. ginseng and febuxostat.

Underlying the Mechanisms of Doxorubicin-Induced Acute Cardiotoxicity: Oxidative Stress and Cell Death.

Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its use places survivors at risk for cardiotoxicity. Many studies have demonstrated that multiple factors are involved in DOX-induced acute cardiotoxicity. Among them, oxidative stress and cell death predominate. In this review, we provide a comprehensive overview of the mechanisms underlying the source and effect of free radicals and dependent cell death pathways induced by DOX. Hence, we attempt to explain the cellular mechanisms of oxidative stress and cell death that elicit acute cardiotoxicity and provide new insights for researchers to discover potential therapeutic strategies to prevent or reverse doxorubicin-induced cardiotoxicity.

Exercise intervention decreases acute and late doxorubicin-induced cardiotoxicity.

BackgroundDoxorubicin (Dox) is one of the most effective chemotherapy agents used to treat adolescent and young adult sarcoma patients. Unfortunately, Dox causes cardiotoxicities that compromise long‐term survival. We investigated whether exercise prevented cardiotoxicity and increased survival following myocardial infarction.MethodsJuvenile mice received Dox, Dox + exercise (Exer), Dox then exercise or were exercised during and after Dox. Mice were evaluated by echocardiography and histology immediately after therapy and 12 weeks later. Mice subjected to permanent ligation of the left anterior descending artery 90 days after therapy were assessed for survival at 45 and 100 days.ResultsMice treated with Dox, but not Dox + Exer, had decreased ejection fraction (EF) and fractional shortening (FS) immediately after Dox therapy, which continued to deteriorate over 12 weeks with the development of diastolic failure and fibrosis. Acute Dox‐induced cardiotoxicity was documented by induction of autophagy and abnormal mitochondria and vascular architecture with decreased pericytes. These abnormalities persisted 12 weeks after therapy. These acute and late changes were not seen in the Dox + Exer group. Initiating exercise after Dox therapy promoted recovery of EF and FS with no functional or histologic evidence of Dox‐induced damage 12 weeks after therapy. Survival rates at 100 days after MI were 67% for control mice, 22% for mice that received Dox alone, and 56% for mice that received Dox + Exer.ConclusionsExercise inhibited both early and late Dox‐induced cardiotoxicity and increased recovery from an ischemic event. Exercise interventions have the potential to decrease Dox‐induced cardiac morbidity.

Nerolidol Attenuates Oxidative Stress, Inflammation, and Apoptosis by Modulating Nrf2/MAPK Signaling Pathways in Doxorubicin-Induced Acute Cardiotoxicity in Rats.

The clinical usage of doxorubicin (DOX), a potent anthracycline antineoplastic drug, is often limited by its cardiotoxic effects. Thus, for improving usage of DOX, the aim of this study was to assess the cardioprotective effects of nerolidol (NERO) in a rat model of DOX-induced acute cardiotoxicity and examine underlying molecular mechanisms that contribute to these effects. To induce acute cardiotoxicity male albino Wistar rats were injected with single dose intraperitoneal DOX (12.5 mg/kg). The rats were treated with NERO (50 mg/kg, orally) for five days. DOX-injected rats showed elevated levels of cardiac marker enzymes and enhanced oxidative stress markers along with altered Nrf2/Keap1/HO-1 signaling pathways. DOX administration also induced the activation of NF-κB/MAPK signaling and increased the levels and expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) as well as expression of inflammatory mediators (iNOS and COX-2) in the heart. DOX also triggered DNA damage and apoptotic cell death in the myocardium. Additionally, histological studies revealed structural alterations of the myocardium. NERO treatment exhibited protection against the deleterious results of DOX on myocardium, as evidenced by the restoration of altered biochemical parameters, mitigated oxidative stress, inflammation, and apoptosis. The findings of the present study demonstrate that NERO provides cardioprotective effects against DOX-induced acute cardiotoxicity attributed to its potent antioxidant, anti-inflammatory, and antiapoptotic activities through modulating cellular signaling pathways.

Protection against Doxorubicin‐Related Cardiotoxicity by Jaceosidin Involves the Sirt1 Signaling Pathway

The clinical use of doxorubicin (DOX) is largely limited by its cardiotoxicity. Previous studies have shown that jaceosidin has many biological activities. However, little is known about whether jaceosidin can attenuate DOX-related acute cardiotoxicity. Here, we investigated the therapeutic effects of jaceosidin on DOX-induced acute cardiotoxicity. Mice were intraperitoneally injected with a single dose of DOX to establish an acute cardiac injury model. To explore the protective effects, mice were orally administered jaceosidin daily for 7 days, with dosing beginning 2 days before DOX injection. The results demonstrated that jaceosidin dose-dependently reduced free radical generation, inflammation accumulation, and cell loss induced by DOX in cardiomyocytes. Further studies showed that jaceosidin treatment inhibited myocardial oxidative damage and the inflammatory response and attenuated myocardial apoptotic death, thus improving cardiac function in mice injected with DOX. The inhibitory effects of jaceosidin on DOX-related acute cardiotoxicity were mediated by activation of the sirtuin1 (Sirt1) signaling pathway. Jaceosidin lost its protective effect against DOX-related injury in Sirt1-deficient cardiomyocytes and mice. In conclusion, jaceosidin has protective potential in treating DOX-related cardiac injury through activation of the Sirt1 signaling pathway.

Protective Effects of Oroxylin A against Doxorubicin-Induced Cardiotoxicity via the Activation of Sirt1 in Mice.

Doxorubicin- (DOX-) related cardiac injury impairs the life quality of patients with cancer. This largely limited the clinical use of DOX. It is of great significance to find a novel strategy to reduce DOX-related cardiac injury. Oroxylin A (OA) has been identified to exert beneficial effects against inflammatory diseases and cancers. Here, we investigated whether OA could attenuate DOX-induced acute cardiotoxicity in mice. A single dose of DOX was used to induce acute cardiac injury in mice. To explore the protective effects, OA was administered to mice for ten days beginning from five days before DOX injection. The data in our study indicated that OA inhibited DOX-induced heart weight loss, reduction in cardiac function, and the elevation in myocardial injury markers. DOX injection resulted in increased oxidative damage, inflammation accumulation, and myocardial apoptosis in vivo and in vitro, and these pathological alterations were alleviated by treatment of OA. OA activated the sirtuin 1 (Sirt1) signaling pathway via the cAMP/protein kinase A, and its protective effects were blocked by Sirt1 deficiency. OA treatment did not affect the tumor-killing action of DOX in tumor-bearing mice. In conclusion, OA protected against DOX-related acute cardiac injury via the regulation of Sirt1.

Bradykinin-Potentiating Activity of a Gamma-Irradiated Bioactive Fraction Isolated from Scorpion (Leiurus quinquestriatus) Venom in Rats with Doxorubicin-Induced Acute Cardiotoxicity: Favorable Modulation of Oxidative Stress and Inflammatory, Fibrogenic and Apoptotic Pathways.

Although doxorubicin (Dox) is a backbone of chemotherapy, the search for an effective and safe therapy to revoke Dox-induced acute cardiotoxicity remains a critical matter in cardiology and oncology. The current study was the first to explore the probable protective effects of native and gamma-irradiated fractions with bradykinin-potentiating activity (BPA) isolated from scorpion (Leiurus quinquestriatus) venom against Dox-induced acute cardiotoxicity in rats. Native or irradiated fractions (1μg/g) were administered intraperitoneally (i.p.) twice per week for 3 weeks, and Dox (15mg/kg, i.p.) was administered on day 21 at 1h after the last native or irradiated fraction treatment. Electrocardiographic (ECG) aberrations were ameliorated in the Dox-treated rats pretreated with the native fraction, and the irradiated fraction provided greater amelioration of ECG changes than that of the native fraction. The group pretreated with native protein with BPA also exhibited significant improvements in the levels of oxidative stress-related, inflammatory, angiogenic, fibrogenic, and apoptotic markers compared with those of the Dox group. Notably, the irradiated fraction restored these biomarkers to their normal levels. Additionally, the irradiated fraction ameliorated Dox-induced histological changes and alleviated the severity of cardiac injury to a greater extent than that of the native fraction. In conclusion, the gamma-irradiated detoxified fraction of scorpion venom elicited a better cardioprotective effect than that of the native fraction against Dox-induced acute cardiotoxicity in rats.

Temporary blockade of interferon-γ ameliorates doxorubicin-induced cardiotoxicity without influencing the anti-tumor effect

Doxorubicin (DOX) is commonly used as an anti-cancer agent. However, its severe cardiotoxicity often makes it life threatening even long after DOX therapy during childhood. We recently reported interferon-γ (IFN-γ) necessary for DOX-induced acute cardiotoxicity in a p38 dependent way and, asked here for the potential of IFN-γ blockade to prevent DOX-induced chronic cardiotoxicity during tumor therapy. In our model system, mice without or with growing tumors repeatedly received DOX treatment. Simultaneous injection of anti-IFN-γ antibody R46-A2 with DOX to block IFN-γ signal efficiently protected the cardiac function of DOX treated recipients. Importantly, a single late injection of R46-A2 after DOX exposure also ameliorated DOX induced cardiac dysfunction in tumor-bearing mice. The anti-IFN-γ treatment did not affect the DOX-mediated tumor suppression effect and it left the main cellular immune response intact. Therefore, temporary blockade of IFN-γ may represent a novel strategy to ameliorate established DOX induced cardiotoxicity (DIC) or prevent its development in tumor therapy.

Fucoidan from Fucus vesiculosus attenuates doxorubicin-induced acute cardiotoxicity by regulating JAK2/STAT3-mediated apoptosis and autophagy

Doxorubicin (DOX) is well-known for its potent antitumor activity but limited by its multiple and serious adverse effects. A major adverse effect is acute cardiotoxicity; yet, its mechanism has not been elucidated. Fucoidan is a multifunctional and nontoxic polysaccharide that is widely studied because of its favorable biological activities and safety. Hence, we proposed that fucoidan may play a protective role in DOX-induced acute cardiotoxicity without causing additional side effects. Sprague-Dawley rats were injected intraperitoneally with a single high dose of DOX to induce acute cardiac injury. Fucoidan was administered orally before DOX injection and AG490, a JAK2 inhibitor, was applied to verify the participation of the JAK2/STAT3 pathway. In vitro, H9C2 cells were treated with the same drugs at different concentrations and intervention times. in vivo and in vitro results demonstrated that DOX administration induced myocardial damage accompanied by acceleratory apoptosis and deficient autophagy in heart tissues or cells, which could be significantly improved by fucoidan supplement. AG490 partly abolished the cardioprotective effects of fucoidan, suggesting the involvement of JAK2 signaling. Additionally, western blotting revealed DOX-induced JAK2/STAT3 pathway activation, which was enhanced by fucoidan and weaken by AG490. Hence, fucoidan exerted a favorable effect on DOX-induced cardiotoxicity by enhancing autophagy and suppressing apoptosis in a JAK2/STAT3-dependent manner, which may provide a promising and novel therapeutic strategy against negative chemotherapy-induced effects.

Toll-like receptor 5 deficiency diminishes doxorubicin-induced acute cardiotoxicity in mice.

Rationale: Clinical application of doxorubicin (DOX) is limited by its toxic cardiovascular side effects. Our previous study found that toll-like receptor (TLR) 5 deficiency attenuated cardiac fibrosis in mice. However, the role of TLR5 in DOX-induced cardiotoxicity remains unclear.Methods: To further investigate this, TLR5-deficient mice were subjected to a single intraperitoneal injection of DOX to mimic an acute model.Results: Here, we reported that TLR5 expression was markedly increased in response to DOX injection. Moreover, TLR5 deficiency exerted potent protective effects against DOX-related cardiac injury, whereas activation of TLR5 by flagellin exacerbated DOX injection-induced cardiotoxicity. Mechanistically, the effects of TLR5 were largely attributed to direct interaction with spleen tyrosine kinase to activate NADPH oxidase (NOX) 2, increasing the production of superoxide and subsequent activation of p38. The toxic effects of TLR5 activation in DOX-related acute cardiac injury were abolished by NOX2 deficiency in mice. Our further study showed that neutralizing antibody-mediated TLR5 depletion also attenuated DOX-induced acute cardiotoxicity.Conclusion: These findings suggest that TLR5 deficiency attenuates DOX-induced cardiotoxicity in mice, and targeting TLR5 may provide feasible therapies for DOX-induced acute cardiotoxicity.

PGC1α activation by pterostilbene ameliorates acute doxorubicin cardiotoxicity by reducing oxidative stress via enhancing AMPK and SIRT1 cascades.

Doxorubicin (DOX) is a widely used and potent anticancer agent, but DOX dose-dependently induced cardiotoxicity greatly limits its use in clinic. Pterostilbene, a natural analog of resveratrol, is a known antioxidant and exerts myocardial protection. The present study explored the action and detailed mechanism of pterostilbene on DOX-treated cardiomyocytes. We investigated the effects of pterostilbene on established acute DOX-induced cardiotoxicity models in both H9c2 cells treated with 1 μM DOX and C57BL/6 mice with DOX (20 mg/kg cumulative dose) exposure. Pterostilbene markedly alleviated the DOX exposure-induced acute myocardial injury. Both in vitro and in vivo studies revealed that pterostilbene inhibited the acute DOX exposure-caused oxidative stress and mitochondrial morphological disorder via the PGC1α upregulation through activating AMPK and via PGC1α deacetylation through enhancing SIRT1. However, these effects were partially reversed by knockdown of AMPK or SIRT1 in vitro and treatment of Compound C (AMPK inhibitor) or EX527 (SIRT1 inhibitor) in vivo. Our results indicate that pterostilbene protects cardiomyocytes from acute DOX exposure-induced oxidative stress and mitochondrial damage via PGC1α upregulation and deacetylation through activating AMPK and SIRT1 cascades.

Inhibition of CACNA1H attenuates doxorubicin-induced acute cardiotoxicity by affecting endoplasmic reticulum stress

BackgroundDoxorubicin (DOX) is an anticancer drug that has been widely used in the clinic. However, recently its application has been limited due to the cardiotoxic effects it has caused. Severe cardiotoxicity of DOX causes cardiac hypertrophy that may lead to heart failure. It has previously been demonstrated that CACNA1H is re-expressed in hypertrophic cardiomyocytes. In this study, we aimed to investigate the role of CACNA1H in DOX-induced acute cardiotoxicity, and to investigate its possible underlying mechanisms of action involved. MethodsFirstly, DOX-induced cardiac injury and changes in the expression of CACNA1H were evaluated. We explored the role of endoplasmic reticulum (ER) stress and apoptosis in mice that underwent DOX-induced cardiac injury. Next, to explore the role of CACNA1H in this process, we evaluated the changes in DOX-induced cardiac injury and ER stress after treatment with the CACNA1H specific inhibitor ABT-639. Next, we used ER stress inhibitor UR906 to verify the role of ER stress in DOX induced cardiotoxicity in H9C2 cells. ResultsDOX-treatment caused acute heart injury, leading to a decrease in cardiac function in mice, an increase in apoptosis of cardiac myocytes, and a significant increase in the expression level of CACNA1H in heart tissue. Next, mice were treated with CACNA1H inhibitor ABT-639 and we demonstrated that it partly protects myocardial function and reduces myocardial cell apoptosis. In addition, our data indicated that CACNA1H may play a role in alleviating DOX-induced cardiotoxicity by reducing the severity of ER stress because the use of ABT-639 significantly changed ER stress-related proteins, including p-PERK, PERK, CHOP, GRP78, ATF6, and ATF4. Furthermore, we found that the use of ER stress inhibitor UR906 in H9C2 cells significantly alleviated the increased expression of ER stress related proteins and apoptosis related proteins caused by DOX, and meanwhile reduced the degree of intracellular oxidative stress and intracellular calcium ion concentration. ConclusionCACNA1H inhibitors significantly alleviated DOX-induced cardiotoxicity and apoptosis induced by ER stress.

Abstract 304: Pgc1a Activation by Pterostilbene Ameliorates Acute Doxorubicin Cardiotoxicity via Reducing Mitochondrial Oxidative Stress Through Enhancing Ampk and Sirt1 Cascades

Background: Doxorubicin (DOX) is a widely used and potent anticancer agent, but DOX dose-dependently induced cardiotoxicity greatly limits its use in clinic. Pterostilbene, a natural analog of resveratrol, is a known antioxidant and exerts myocardial protection. The present study explored the actions and detailed mechanisms of pterostilbene on DOX-treated cardiomyocytes. Experimental Approach: We investigated the effects of pterostilbene on established acute DOX-induced cardiotoxicity models in both H9c2 cells treated with 1 μM DOX and C57BL/6 mice with DOX (20 mg/kg cumulative dose) exposure. Cell viability, ATP content, oxidative parameters, transmission electron microscopy, western blot analyses were respective performed. AMPK and SIRT1 siRNA, Compound C and EX527 treatment were further conducted to elucidate the underlying mechanism about the involvement of AMPK, SIRT1 and PGC1α cascades. Key Results: Pterostilbene markedly upregulated the cell viability and ATP content in DOX-treated H9c2 cells. Both in vitro and in vivo studies revealed that pterostilbene inhibited the acute DOX exposure-caused oxidative stress and mitochondrial morphological disorder via the PGC1α upregulation through activating AMPK and via PGC1α deacetylation through enhancing SIRT1. However, these effects were partially reversed by knockdown of AMPK or SIRT1 in vitro and treatment of Compound C or EX527 in vivo . Conclusion and Implications: Our results indicate that pterostilbene protects cardiomyocytes from acute DOX exposure-induced oxidative stress and mitochondrial damage via PGC1α upregulation and deacetylation through activating AMPK and SIRT1 cascades.

Loss of Rubicon ameliorates doxorubicin-induced cardiotoxicity through enhancement of mitochondrial quality

BackgroundThe therapeutic potential of doxorubicin (DOX) is limited by cardiotoxicity. Rubicon is an inhibitory interacting partner of autophagy protein UVRAG. Currently, the role of Rubicon in DOX-induced cardiotoxicity is unknown. In this study, we test the hypothesis that loss of Rubicon attenuates DOX-induced cardiotoxicity. MethodsA mouse model of acute DOX-induced cardiotoxicity was established by a single intraperitoneal injection of DOX at a dose of 20 mg/kg. Rubicon expression was detected by Western blot. Cardiac damage was determined by measuring activities of lactate dehydrogenase and myocardial muscle creatine kinase in the serum, cytoplasmic vacuolization, collagen deposition, ROS levels, ATP content and mitochondrial damage in the heart. Cardiac morphometry and function were assessed by echocardiography. Markers for autophagy, mitophagy and mitochondrial dynamics were evaluated by Western blot and real time reverse transcription polymerase chain reaction. ResultsRubicon expression was reduced in the heart 16 h after DOX treatment. DOX induced accumulation of cytoplasmic vacuolization and collagen, increased serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, enhanced ROS levels, reduced ATP content, pronounced mitochondrial damage and greater left ventricular wall thickness in wild type mice, which were mitigated by Rubicon deficiency. Mechanistically, loss of Rubicon improved DOX-induced impairment of autophagic flux, Parkin-mediated mitophagy and mitochondrial fission and fusion in the heart. ConclusionsLoss of Rubicon ameliorates DOX-induced cardiotoxicity through enhancement of mitochondrial quality by improving autophagic flux, mitophagy and mitochondrial dynamics. Rubicon is a potential molecular target for prevention and therapy of DOX cardiotoxicity.