Atypical G Protein β5 Promotes Cardiac Oxidative Stress, Apoptosis, and Fibrotic Remodeling in Response to Multiple Cancer Chemotherapeutics.
TL;DR: The experiments suggest that inhibition of Gβ5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.
Abstract: The clinical use of multiple classes of cancer chemotherapeutics is limited by irreversible, dose-dependent, and sometimes life-threatening cardiotoxicity. Though distinct in their mechanisms of action, doxorubicin, paclitaxel, and 5-FU all induce rapid and robust upregulation of atypical G protein Gβ5 in the myocardium correlating with oxidative stress, myocyte apoptosis, and the accumulation of proinflammatory and profibrotic cytokines. In ventricular cardiac myocytes (VCM), Gβ5 deficiency provided substantial protection against the cytotoxic actions of chemotherapeutics, including reductions in oxidative stress and simultaneous attenuation of ROS-dependent activation of the ATM and CaMKII proapoptotic signaling cascades. In addition, Gβ5 loss allowed for maintenance of Δψm, basal mitochondrial calcium uniporter expression, and mitochondrial Ca2+ levels, effects likely to preserve functional myocyte excitation-contraction coupling. The deleterious effects of Gβ5 are not restricted to VCM, however, as Gβ5 knockdown also reduces chemotherapy-induced release of proinflammatory cytokines (e.g., TNFα), hypertrophic factors (e.g., ANP), and profibrotic factors (e.g., TGFβ1) from both VCM and ventricular cardiac fibroblasts, with the most dramatic reduction occurring in cocultured cells. Our experiments suggest that Gβ5 facilitates the myofibroblast transition, the persistence of which contributes to pathologic remodeling and heart failure. The convergence of Gβ5-mediated, ROS-dependent signaling pathways in both cell types represents a critical etiological factor in the pathogenesis of chemotherapy-induced cardiotoxicity. Indeed, intracardiac injection of Gβ5-targeted shRNA allowed for heart-specific protection against the damaging impact of chronic chemotherapy. Together, our results suggest that inhibition of Gβ5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.Significance: These findings suggest that inhibiting an atypical G-protein might provide a strategy to limit the cardiotoxicity in cancer patients treated with anthracyclines, taxanes, or fluoropyrimidines. Cancer Res; 78(2); 528-41. ©2017 AACR.
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TL;DR: Current knowledge on the role of the mitochondrial calcium uniporter (MCU) complex in multiple cancer types and models is reviewed and a perspective for future research and clinical considerations is provided.
Abstract: The important role of mitochondria in cancer biology is gaining momentum. With their regulation of cell survival, metabolism, basic cell building blocks, and immunity, among other functions, mitochondria affect not only cancer progression but also the response and resistance to current treatments. Calcium ions are constantly shuttled in and out of mitochondria; thus, playing an important role in the regulation of various cellular processes. The mitochondrial calcium uniporter (MCU) channel and its associated regulators transport calcium across the inner mitochondrial membrane to the mitochondrial matrix. Due to this central role and the capacity to affect cell behavior and fate, the MCU complex is being investigated in different cancers and cancer-related conditions. Here, we review current knowledge on the role of the MCU complex in multiple cancer types and models; we also provide a perspective for future research and clinical considerations.
77 citations
Cites background from "Atypical G Protein β5 Promotes Card..."
...Cardiotoxicity in cancer patients Inhibition of Gβ5 could prevent cardiotoxicity in cancer patients treated with anthracyclines, taxanes, or fluoropyrimidines Gβ5-loss maintains membrane potential, basal MCU expression, and mCa levels, allowing functional myocyte activity [14]...
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TL;DR: It is suggested that melatonin treatment attenuated doxorubicin‐induced cardiotoxicity through preserving YAP levels, which in turn decreases oxidative stress and apoptosis.
Abstract: There are increasing concerns related to the cardiotoxicity of doxorubicin in the clinical setting. Recently, melatonin has been shown to exert a cardioprotective effect in various cardiovascular diseases, including cardiotoxic conditions. In this study, we examined the possible protective effects of melatonin on doxorubicin-induced cardiotoxicity and explored the underlying mechanisms related to this process. We found that in vitro doxorubicin treatment significantly decreased H9c2 cell viability and induced apoptosis as manifested by increased TUNEL-positive cells, down-regulation of anti-apoptotic protein Bcl-2, as well as up-regulation of pro-apoptotic protein Bax. This was associated with increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potentials (MMP). In vivo, five weeks of doxorubicin treatment significantly decreased cardiac function, as evaluated by echocardiography. TUNEL staining results confirmed the increased apoptosis caused by doxorubicin. On the other hand, combinational treatment of doxorubicin with melatonin decreased cardiomyocyte ROS and apoptosis levels, along with increasing MMP. Such doxorubicin-melatonin co-treatment alleviated in vivo doxorubicin-induced cardiac injury. Western Blots, along with in vitro immunofluorescence and in vivo immunohistochemical staining confirmed that doxorubicin treatment significantly down-regulated Yes-associated protein (YAP) expression, while YAP levels were maintained under co-treatment of doxorubicin and melatonin. YAP inhibition by siRNA abolished the protective effects of melatonin on doxorubicin-treated cardiomyocytes, with reversed ROS level and apoptosis. Our findings suggested that melatonin treatment attenuated doxorubicin-induced cardiotoxicity through preserving YAP levels, which in turn decreases oxidative stress and apoptosis.
23 citations
TL;DR: In this paper, the role of ROS mediated oxidative stress mediated by oncological treatments in inducing cardiovascular disease was discussed and strategies that potentially counteract the oxidative stress in order to fight the onset and progression of cardiovascular disease.
Abstract: Reactive oxygen species (ROS) are molecules involved in signal transduction pathways with both beneficial and detrimental effects on human cells ROS are generated by many cellular processes including mitochondrial respiration, metabolism and enzymatic activities In physiological conditions, ROS levels are well-balanced by antioxidative detoxification systems In contrast, in pathological conditions such as cardiovascular, neurological and cancer diseases, ROS production exceeds the antioxidative detoxification capacity of cells, leading to cellular damages and death In this review, we will first describe the biology and mechanisms of ROS mediated oxidative stress in cardiovascular disease Second, we will review the role of oxidative stress mediated by oncological treatments in inducing cardiovascular disease Lastly, we will discuss the strategies that potentially counteract the oxidative stress in order to fight the onset and progression of cardiovascular disease, including that induced by oncological treatments
21 citations
TL;DR: In conclusion, polydatin effectively inhibited hypoxia- and AMI-induced myocardial damage by promotion of Nrf2/HO-1 signaling.
Abstract: Polydatin is a traditional Chinese medicine that provides myocardial protection after acute myocardial infarction (AMI) The study aim was to investigate the myocardial protection polydatin in H9c2 myocardial cells cultured in a hypoxic atmosphere and in a rat AMI model induced by ligating the left anterior descending coronary artery and treated with polydatin 100 mg/kg/day for 30 days The involvement of Nrf2 in mediating the effects of polydatin was investigated in H9c2 cells following Nrf2 knockdown by transfection of siRNA Polydatin suppressed hypoxia-induced H9c2 cell apoptosis and reactive oxygen species (ROS) generation by promoting Nrf2/HO-1 signaling Nrf2 knockdown reversed the protective effects of polydatin against hypoxia-induced myocardial cell injury The in vivo results were consistent with polydatin suppression of apoptosis and ROS generation in myocardial tissue by promotion of Nrf2/HO-1 signaling In conclusion, polydatin effectively inhibited hypoxia- and AMI-induced myocardial damage by promotion of Nrf2/HO-1 signaling
21 citations
TL;DR: The beneficial effects of QL on DOX-induced CHF in rats are mediated by reduction in myocardial fibrosis, promotion of TGF-β3/Smad7, and inhibition of T GF-β1/ Smad3, which may also modulate specific miRNAs.
Abstract: Context: Therapeutic doxorubicin administration is restricted as this anticancer drug may be cardiotoxic. The traditional Chinese medicine qiliqiangxin has been approved for clinical treatment of c...
17 citations
Cites background from "Atypical G Protein β5 Promotes Card..."
...Of these, cardiomyocyte inflammation and fibrosis are ordinary pathological mechanisms of myocardial remodelling in DOX-induced CHF (Liu et al. 2016; Chakraborti et al. 2018)....
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...Cardiac extracellular matrix remodelling is an important mechanism of left ventricular dysfunction and adverse outcome after DOX treatment (Liu et al. 2016; Shabalala et al. 2017; Zhang et al. 2017; Chakraborti et al. 2018)....
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...However, its clinical use is severely limited by its side effects including cardiotoxicity, cardiac remodelling, and chronic heart failure (Lipshultz et al. 2012; Liu et al. 2016; Shabalala et al. 2017; Zhang et al. 2017; Chakraborti et al. 2018)....
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References
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TL;DR: Findings implicate NOS3 as a key mediator in the development of left ventricular dysfunction after administration of doxorubicin.
Abstract: Background— Flavoprotein reductases are involved in the generation of reactive oxygen species by doxorubicin. The objective of the present study was to determine whether or not one flavoprotein reductase, endothelial nitric oxide synthase (nitric oxide synthase 3 [NOS3]), contributes to the cardiac dysfunction and injury seen after the administration of doxorubicin. Methods and Results— A single dose of doxorubicin (20 mg/kg) was administered to wild-type (WT) mice, NOS3-deficient mice (NOS3−/−), and mice with cardiomyocyte-specific overexpression of NOS3 (NOS3-TG). Cardiac function was assessed after 5 days with the use of echocardiography. Doxorubicin decreased left ventricular fractional shortening from 57±2% to 47±1% (P<0.001) in WT mice. Compared with WT mice, fractional shortening was greater in NOS3−/− and less in NOS3-TG after doxorubicin (55±1% and 35±2%; P<0.001 for both). Cardiac tissue was harvested from additional mice at 24 hours after doxorubicin administration for measurement of cell death...
150 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...following doxorubicin exposure through dysregulation of the mitochondrial electron transport chain(8,9), direct interaction with endothelial nitric oxide synthase (eNOS)(10), and activation of NADPH oxidase (Nox) complexes(11,12)....
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TL;DR: It is demonstrated that cardiac overexpression of ACE2 exerts protective influence on the heart during myocardial infarction by preserving cardiac functions, LV wall motion and contractility, and by attenuating LV wall thinning.
Abstract: Angiotensin converting enzyme 2 (ACE2) has been linked to cardiac dysfunction and hypertension-induced cardiac pathophysiology. In this study, we used a gene overexpression approach to investigate the role of ACE2 in cardiac function and remodeling after myocardial infarction. Rats received an intracardiac injection of 4.5x10(8) lentivirus containing ACE2 cDNA, followed by permanent coronary artery ligation (CAL) of the left anterior descending artery. At 24 hours and 6 weeks after surgery, cardiac functions, viability, and pathophysiology were assessed by MRI) and by histological analysis. At 24 hours post-CAL, left ventricular (LV) anterior wall motion was stunted to the same extent in control CAL and lenti-ACE2-treated CAL rats. However lenti-ACE2-treated CAL rats showed a 60% reduction in delayed contrast-enhanced LV volume after gadodiamide injection, indicating early ischemic protection of myocardium by ACE2. At 6 weeks after CAL, lenti-ACE2 rats demonstrated a complete rescue of cardiac output, a 41% rescue of ejection fraction, a 44% rescue in contractility, a 37% rescue in motion, and a 53% rescue in LV anterior (infracted) wall thinning compared with control CAL rats. No changes were observed in the LV posterior (noninfarcted) wall other than an 81% rescue in motion produced by ACE2 in CAL rats. Finally, infarct size measured by 2,3,5-triphenyl-tetrazolium chloride staining was not significantly different between the ligated groups. These observations demonstrate that cardiac overexpression of ACE2 exerts protective influence on the heart during myocardial infarction by preserving cardiac functions, LV wall motion and contractility, and by attenuating LV wall thinning.
140 citations
"Atypical G Protein β5 Promotes Card..." refers methods in this paper
...5 X 10(8) lentiviral vectors containing control or Gβ5 targeted shRNA according to a previously published protocol(27) before being returned to their mothers until weaning....
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...TUNELand H&E staining were performed as described previously(27)....
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TL;DR: RGS/β5 complexes may contribute to the selectivity of signal transduction initiated by receptors coupled to Gi and Go by binding to phospholipase C and stimulating the GTPase activity of Gαo.
137 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...Instead, Gβ5 forms co-stabilizing complexes with R7 family RGS proteins(20-22)....
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...The atypical G protein Gβ5 forms co-stabilizing complexes with R7 subfamily regulators of G protein signaling (RGS) proteins(20-22)....
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TL;DR: Experimental studies revealed potential mechanisms of cardiotoxicity ranging from direct toxic effects on vascular endothelium involving endothelial NO synthase leading to coronary spasms and endothelial independent vasoconstriction via protein kinase C to verapamil type calcium antagonists as well as nitrates seem to be useful for treatment of 5-FU induced coronary spasm.
Abstract: Cardiac side effects of the cytostatic agent 5-fluorouracil (5-FU) have an incidence of 1.2-7.6%. Potentially, arrhythmias, myocardial infarction and sudden cardiac death could occur. Life-threatening cardiotoxicity is rarely observed with a frequency <1%. Cardiotoxicity of 5-FU seems to differ from well known effects of other cytostatics, e.g., anthracyclines. Myocardial ischemia was suggested as potential mechanism due to occasionally observed ECG alterations during 5-FU administration. Experimental studies revealed potential mechanisms of cardiotoxicity ranging from direct toxic effects on vascular endothelium involving endothelial NO synthase leading to coronary spasms and endothelium independent vasoconstriction via protein kinase C. In addition, rheological side effects have to be considered. Coronary artery disease is judged to increase the risk of cardiac side effects. Despite lack of prospective trials, verapamil type calcium antagonists as well as nitrates seem to be useful for treatment of 5-FU induced coronary spasms. In addition, modification of the cytostatic regimen has to be considered in patients who had been symptomatic. It could be assumed that 5-FU toxicity is reversible in the majority of cases when acute complications, e.g., arrhythmias, are resolved.
128 citations
TL;DR: Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) have been shown to slow the progression of left ventricular dysfunction in several different clinical settings, including anthracycline-induced cardiomyopathy.
Abstract: The survival rate of cancer patients has greatly increased over the last 20 years. However, to achieve this result, a considerable price has been paid in terms of the side effects associated with the intensive anticancer treatment. The most common adverse effect is cardiotoxicity which may compromise the clinical effectiveness of chemotherapy, affecting the patient’s survival and quality of life independently of the oncological prognosis. There are 2 types of cardiac toxicities, type I which is more serious and result in permanent damage to the myocardium and type II which is usually reversible. Chemotherapies varies in their incidence of inducing cardiomyopathy, and the onset which may occur acutely (during or shortly after treatment), sub-acutely (within days or weeks after completion of chemotherapy) or chronically (weeks to months after drug administration). Cardiac events associated with chemotherapy may consist of mild blood pressure changes, thrombosis, Electrocardiographic (ECG) changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure), and congestive heart failure (CHF). The risk for such effects depends upon: cumulative dose, rate of drug administration, mediastinal radiation, advanced age, younger age, female gender, pre-existing heart disease and hypertension. Serial measurements of LVEF and fractional shortening are the most common indices monitored to assess left ventricular systolic function and cardiotoxicity. This can be achieved by 2-dimensional, M-mode and color Doppler echocardiographic examination; also Cardiac troponins as a biological marker for myocardial damage can be used for monitoring in patients received anthracyclines. Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) have been shown to slow the progression of left ventricular dysfunction in several different clinical settings, including anthracycline-induced cardiomyopathy. Carvedilol and probably with anti-oxidants like Probucol and vitamin E benefits also. doi: 10.4021/jocmr2009.02.1225
128 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...Despite their proven capacity to improve long-term cancer patient survival(1), the utility of anthracycline, taxane and fluoropyrimidine chemotherapeutics is limited by irreversible cardiac toxicity(2)....
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...Though proven to improve patient survival over a 20-year period(1), the utility of many chemotherapeutics including anthracyclines, taxanes, and fluoropyrimidines is limited by adverse effects amongst them dose-dependent and often irreversible cardiac damage that can result in eventual heart failure(2)....
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