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In ischemic congestive heart failure (CHF), anemia is associated with poor prognosis. Whether anemia develops in nonischemic CHF is uncertain. The hematopoietic inhibitors TNF-[alpha] and nitric oxide (NO) are activated in ischemic CHF. We examined whether mice with ischemic or nonischemic CHF develop anemia and whether TNF-[alpha] and NO are involved. We studied mice (n = 7-9 per group) with CHF either due to myocardial infarction (MI) or to overexpression of the [Ca.sup.2+]-binding protein calsequestrin (CSQ) or to induced cardiac disruption of the sarcoplasmic reticulum [Ca.sup.2+]-ATPase 2 gene (SERCA2 KO). Hematopoiesis was analyzed by colony formation of [CD34.sup.+] bone marrow cells. Hemoglobin concentration was 14.0 [+ or -] 0.4 g/dl (mean [+ or -] SD) in controls, while it was decreased to 10.1 [+ or -] 0.4, 9.7 [+ or -] 0.4, and 9.6 [+ or -] 0.3 g/dl in MI, CSQ, and SERCA2 KO, respectively (P < 0.05). Colony numbers per 100,000 [CD34.sup.+] cells in the three CHF groups were reduced to 33 [+ or -] 3 (MI), 34 [+ or -] 3 (CSQ), and 39 [+ or -] 3 (SERCA2 KO) compared with 68 [+ or -] 4 in controls (P < 0.05). Plasma TNF-[alpha] nearly doubled in MI, and addition of anti-TNF-[alpha] antibody normalized colony formation. Inhibition of colony formation was completely abolished with blockade of endothelial NO synthase in CSQ and SERCA2 KO, but not in MI. In conclusion, the mechanism of anemia in CHF depends on the etiology of cardiac disease; whereas TNF-[alpha] impairs hematopoiesis in CHF following MI, NO inhibits blood cell formation in nonischemic murine CHF. blood cells; ischemia; nitric oxide doi:10.1152/ajpregu.00250.2009

Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-T[Ag.sup.h]) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-T[Ag.sup.h] mice showed an increase in transcript and protein levels of hypoxia-inducible factor l[alpha] (HIF-1[alpha], vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1[alpha], EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-T[Ag.sup.h] mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1[alpha], EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-T[Ag.sup.h] mice developed cerebral angiogenesis through the HIF-1[alpha] VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-T[Ag.sup.h], the decrease in HIF-l[alpha], VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered. chronic anemia; erythropoietin; angiogenesis; hypoxia; cerebral cortex

It is known that renal tissue plays a role in normal iron homeostasis. The current study examines kidney function in iron metabolism under hemolytic anemia studying renal expression of Prohepcidin, Ferroportin (MTP1), and divalent metal transporter 1 (DMT1). The relationship between these proteins and iron pigments was also investigated. Immunohistochemical procedures to study renal expression of Prohepcidin, MTP1, and DMT1 were performed in healthy and anemic mice. Renal tissue iron was determined by Prussian blue iron staining. To assess anemia evolution and erythropoietic recovery, we used conventional tests. In healthy mice, Prohepcidin expression was marked in proximal tubules and inner medulla and absent in outer medulla. Cortical tissue of healthy mice also showed MTP1 immunostaining, mainly in the S2 segment of proximal tubules. Medullar tissue showed MTP1 expression in the inner zone. In addition, S2 segments showed intense DMT1 immunoreactivity with homogeneous DMT1 distribution throughout renal medulla. The main cortical findings in hemolytic anemia were in S2 segments of proximal tubules where we found that decreased Prohepcidin expression coincided with an increment in Ferroportin and DMT1 expression. This expression pattern was concomitant with increased iron in the same tubular zone. However, in medullar tissue both Prohepcidin and MTP1 decreased and DMT1 was detected mainly in larger diameter tubules. Our findings clearly demonstrate that in hemolytic anemia, renal Prohepcidin acts in coordination with renal Ferroportin and DMT1, indicating the key involvement of kidney in iron homeostasis when iron demand is high. Further research is required to learn more about these regulatory mechanisms. divalent metal transporter 1; anemia