Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart

Abstract

Recent studies from our lab and others have shown that the hematopoietic cytokine erythropoietin (EPO) can protect the heart from ischemic damage in a red blood cell-independent manner. Here we examined any protective effects of the long-acting EPO analog darbepoetin alfa (DA) in a rat model of ischemia-reperfusion (I/R) injury. Rats were subjected to 30-min ischemia followed by 72-h reperfusion. In a dose-response study, DA (2, 7, 11, and 30 mug/kg) or vehicle was administered as a single bolus at the start of ischemia. To determine the time window of potential cardioprotection, a single high dose of DA (30 mug/kg) was given at either the initiation or the end of ischemia or at 1 or 24 h after reperfusion. After 3 days, cardiac function and infarct size were assessed. Acute myocyte apoptosis was quantified by TUNEL staining on myocardial sections and by caspase-3 activity assays. DA significantly reduced infarct size from 32.8 +/- 3.5% (vehicle) to 11.0 +/- 3.3% in a dose-dependent manner, while there was no difference in ischemic area between groups. Treatment with DA as late as 24 h after the beginning of reperfusion still demonstrated a significant reduction in infarct size (17.0 +/- 1.6%). Consistent with infarction data, DA improved in vivo cardiac reserve compared with vehicle. Finally, DA significantly decreased myocyte apoptosis and caspase-3 activity after I/R. These data indicate that DA protects the heart against I/R injury and improves cardiac function, apparently through a reduction of myocyte apoptosis. Of clinical importance pointing toward a relevant therapeutic utility, we report that even if given 24 h after I/R injury, DA can significantly protect the myocardium.

Raves and risks for erythropoietin

“…Interestingly, EPO administration in patients also can significantly increase plasma levels of EPO well above this range of 1.0 ng/ml, suggesting that the effects of EPO observed during in vitro studies may parallel the cellular processes altered by EPO in patients with DM [6]. Furthermore, EPO can block apoptotic DNA degradation in ECs during elevated glucose similar to other models of oxidative stress in cardiac and vascular cell models [16][17][18][19]. …”

“…In neuronal cells of the brain or retina, EPO can prevent injury from hypoxic ischemia [11,[21][22][23][24][25] It is important to note that as a large molecule, EPO may maintain the establishment of EC communication and function that could become crucial in a number of scenarios, such as repair of the blood-brain barrier during injury [16,17]. In addition, by assuring EC integrity, EPO prevents ischemic cardiac demise by reducing myocardial injury and cardiomyocyte apoptosis [18,19,45], modulating cardiac remodeling [19], and improving cardiac function [18,45] (Table 2). Overall, EPO can protect against myocardial cell apoptosis and decrease infarct size, resulting in improved left ventricular contractility.…”

“…In addition, by assuring EC integrity, EPO prevents ischemic cardiac demise by reducing myocardial injury and cardiomyocyte apoptosis [18,19,45], modulating cardiac remodeling [19], and improving cardiac function [18,45] (Table 2). Overall, EPO can protect against myocardial cell apoptosis and decrease infarct size, resulting in improved left ventricular contractility.…”

GSK-3α directly regulates β-adrenergic signaling and the response of the heart to hemodynamic stress in mice

“…Hemodynamic parameters, including heart rate, LV end-diastolic pressure, and +dP/dt and -dP/dt, were recorded in closed-chest mode, both at baseline and in response to increasing doses of isoproterenol (0.1, 0.5, 1, 5, and 10 ng), administered via cannulation of the right internal jugular vein (42).…”

Erythropoietin and Oxidative Stress

“…It is important to note that as a large molecule, EPO may maintain the establishment of EC communication and function that could become crucial in a number of scenarios, such as repair of the blood-brain barrier during injury (Martinez-Estrada, et al, 2003). In addition, by assuring EC integrity, EPO prevents ischemic cardiac demise by reducing myocardial injury and cardiomyocyte apoptosis (Burger, et al, 2006), lessening myocardial ischemia (Bullard, et al, 2005), modulating cardiac remodeling (Miki, et al, 2006, Toma, et al, 2007, reducing ventricular dysfunction (Parsa, et al, 2004, Parsa, et al, 2003, and improving cardiac function (Gao, et al, 2007, Westenbrink, et al, 2007. Therefore, EPO plays a critical role in the vascular and renal systems with the maintenance of erythrocyte (Foller, et al, 2007) and podocyte (Eto, et al, 2007) integrity, regulates the survival of ECs , Chong, et al, 2002b, and may act as a powerful endogenous protectant during cardiac injury (Asaumi, et al, 2007).…”