Chronic inborn erythrocytosis leads to cardiac dysfunction and premature death in mice overexpressing erythropoietin

Abstract

The most common cause of an increase of the hematocrit is secondary to elevated erythropoietin levels. Erythrocytosis is assumed to cause higher blood viscosity that could put the cardiovascular system at hemodynamic and rheological risks. Secondary erythrocytosis results from tissue hypoxia, and one can hardly define what cardiovascular consequences are caused by chronic erythrocytosis or hypoxia. Herein, a novel transgenic (tg) mouse line is characterized that is erythrocytotic because of chronic overexpression of the human erythropoietin gene. These mice grow up well, reaching a hematocrit of about 0.80 in adulthood. Blood volume of adult tg mice was markedly increased by 75%. Unexpectedly, blood pressure was not elevated and cardiac output was not decreased. Still, the adult tg mice showed features of cardiac dysfunction with increased heart weight. In vivo, high-frequency echocardiography revealed marked ventricular dilatation that was confirmed by histologic examination. Furthermore, by transmission electron microscopy, a prominent intracellular edema of the cardiomyocytes was seen. Exercise performance of the tg mice was dramatically reduced, unmasking the severity of their compromised cardiovascular function. In addition, life expectancy of the tg mice was significantly reduced to 7.4 months. Our findings suggest that severe erythrocytosis per se results in cardiac dysfunction and markedly reduced life span. (Blood. 2001;97:536-542)

A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia–reperfusion injury

“…Furthermore, in humans, recombinant human EPO (rhEPO) administration can lead to hypertension (37)(38)(39). It is also well known that EPO can cause thrombosis and therefore tissue injury (40). Even a single exposure of normal humans to EPO causes a dose-dependent increase in E-selectin within 2 days, which is consistent with significant endothelial cell activation (41).…”

Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration

“…Compared with wild-type (wt) controls, tg6 mice show 26-fold increased Epo levels in brain as well as a 12-fold elevation of Epo plasma levels (Wagner et al, 2001;Vogel et al, 2003). Here, heterozygous transgenic tg6 males were bred with two mouse models for human RP [for recent reviews on retinal degeneration animal models, see Hafezi et al (2000) and Chang et al (2002)].…”

Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain

“…The major source of the increased systemic IL-6 levels was identified to be the kidney, liver and spleen. These organs have already been shown to undergo significant degeneration in this mouse model and significantly contribute to reduced life span of the animal (Heinicke et al, 2006;Ogunshola et al, 2006;Ruschitzka et al, 2000;Vogel et al, 2003;Wagner et al, 2001). …”

“…Generation and characterization of this line showed these mice have a hematocrit of 0.8-0.9 after the first 8-9 weeks without increased blood pressure or altered cardiac output as well as reduced exercise performance and a significantly reduced life span of 9-12 months (Heinicke et al, 2006;Ogunshola et al, 2006;Ruschitzka et al, 2000;Vogel et al, 2003;Wagner et al, 2001). Interestingly both NO mediated relaxation and circulating NO levels are markedly elevated leading to increased vasodilation and protection from cardiac complications (Ruschitzka et al, 2000).…”