Erythropoietin protects against doxorubicin-induced heart failure

Abstract

The hormone erythropoietin (EPO) has been demonstrated to have cardioprotective properties. The present study investigates the role of EPO to prevent heart failure following cancer treatment with doxorubicin [adriamycin (AD)]. Male Wistar rats (150 Ϯ 10 g) were treated with saline (vehicle control group); with EPO, subcutaneously at 1,000 IU/kg body wt, three times per week for 4 wk (EPO group); with adriamycin, intraperitoneally at 2.5 mg/kg body wt, three times per week for 2 wk (AD group); and with adriamycin and EPO (EPO-AD group). Echocardiographic measurements showed that EPO-AD treatment prevented the AD-induced decline in cardiac function. Each of the hearts was then exposed to ischemia and reperfusion during Langendorff perfusion. The percentage of recovery after ischemia-reperfusion was significantly greater in EPO-AD than the AD-treated group for left ventricular developed pressure, maximal increase in pressure, and rate pressure product. The level of oxidative stress was significantly higher in AD (5 M for 24 h)-exposed isolated cardiomyocytes; EPO (5 U/ml for 48 h) treatment prevented this. EPO treatment also decreased AD-induced cardiomyocyte apoptosis, which was associated with the decrease in the Bax-to-Bcl2 ratio and caspase-3 activation. Immunostaining of myocardial tissue for CD31 showed a significant decrease in the number of capillaries in AD-treated animals. EPO-AD treatment restored the number of capillaries. In conclusion, EPO treatment effectively prevented ADinduced heart failure. The protective effect of EPO was associated with a decreased level of oxidative stress and apoptosis in cardiomyocytes as well as improved myocardial angiogenesis. apoptosis; myocardial infarction; oxidative stress THE ANTINEOPLASTIC DRUG DOXORUBICIN is effective in the treatment of a broad spectrum of malignancies, but its clinical use is limited by adverse side effects: irreversible degenerative cardiomyopathy and congestive heart failure (30, 33). The efficacy of doxorubicin [adriamycin (AD)] as a cytotoxic agent for the treatment of various human tumors prompted a search for treatments to reduce or prevent doxorubicin-induced cardiomyopathy and congestive heart failure (24). So far, however, available treatments to protect the heart from doxorubicin-induced damage have been varied and limited.The cytokine erythropoietin (EPO) is produced by the kidney and is indispensable for the proliferation, survival, and differentiation of erythroid progenitor cells (39). EPO receptors have also been identified in nonhematopoietic tissues, including the heart (34, 38). Recent studies (7,27,31) suggest that EPO also exerts a cardioprotective effect against infarction and ischemia-reperfusion injury. EPO administration before or during ischemia significantly enhanced left ventricular (LV) contractility and the recovery of cardiac function after myocardial ischemia and reperfusion injury. Several studies (8,18) suggested that EPO treatment improved ventricular contractile function in animal models of heart failure and tha...

Prevention of β-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL

“…EPO can block apoptotic injury through the maintenance of mitochondrial membrane potential and the inhibition of caspase activity during cardiovascular injury, renal disease, metabolic injury, and neurodegeneration [20, 22, 23, 28, 78-80]. Wnt signaling also has been shown to modulate mitochondrial and caspase apoptotic pathways in a number of cell types [4, 43, 71].…”

Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin

“…Diseases associated with aging, cardiac disorders, immune system impairment, gastrointestinal disease, or cellular metabolism may be the result of the release of reactive oxygen species (ROS) that lead to oxidative stress (Ammar et al , 2011; Chong et al , 2005d; Du et al , 2012; Escobar et al , 2012; Rjiba-Touati et al , 2012). In regards to the nervous system, cell injury related to toxin exposure (Wang et al , 2012b; Xie et al , 2012), cerebral ischemia (Chong et al , 2010a; Du et al , 2012; Li et al , 2006b; Simao et al , 2011), inflammation (Kato et al , 2011; Kigerl et al , 2012; L'Episcopo et al , 2012; Shang et al , 2009b, 2010), and Aβ exposure (Chong et al , 2005c; Lee et al , 2012; Liu et al , 2010b; Shang et al , 2012; Zeng et al , 2011) can be the result of oxidant stress.…”

Erythropoietin: New Directions for the Nervous System

“…EPO also can promote bone formation in spinal fusion models [65], modulate vascular dilatation [66], may reduce cerebral aneurysm formation [67] and prevent endothelial cell injury [25–76], protect non-neuronal cells [37,77–80], block disability during infection [28,29,46,81], limit β-amyloid (Aβ) degeneration [26,79,82,83], and may foster memory function [26]. In related systems that directly affect central nervous system function such as the cardiac system, EPO can prevent cardiac injury during chemotherapy [84], improve cardiac contractile function [85], limit cardiac failure through the reduction of inflammation, fibrosis, and oxidative stress [86], and reduce nitrosative stress [87]. These benefits of EPO in the cardiovascular system should correlate with improved cerebral perfusion during cardiac injury.…”

“…Oxidative stress impacts every system of the body and can lead to cell death in the vasculature system [73,99–103], the immune system [104–106], the cardiac system [84,107–110], and the brain [111–119]. Oxidative stress also may be a contributing factor to the complications of diabetes mellitus [109,120–125] and cerebral cognitive loss [126,127].…”

“…EPO has been shown to prevent mitochondrial depolarization and the subsequent release of cytochrome c [56,68,69,167,168]. EPO can control mitochondrial signaling through Bad, Bax, Puma [27,55,58,76,79,84,91]. EPO also blocks Apaf-1 activation [25,78] and prevents the early activation of several caspases such as caspase 1, caspase 3, and caspase 9 [25,27,44,55,57,59,72,79,87,169,170].…”