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AJP - Heart and Circulatory Physiology publishes original investigations on the physiology of the heart, blood vessels, and lymphatics, including experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the intact animal to the cellular, subcellular, and molecular levels. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2009 by the American Physiological Society. ISSN: 0363-6135, ESSN: 1522-1539. Visit our website at http://www.the-aps.org/.
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Address for reprint requests and other correspondence: W. J. Koch, Center for Translational Medicine, George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Thomas Jefferson Univ., 1025 Walnut St., Rm. 317, Philadelphia, PA 19107 (e-mail: walter.koch@jefferson.edu). http://www.ajpheart.org
human EPO administration has been shown to exert a broad tissue-protective effect in a variety of experimental models. In the cardiovascular system, EPO has been shown to exert marked myocardial protective effects against ischemia-reperfusion injury via a reduction of LV infarct size and a signicantly decreased apoptotic cell death of cardiomyocytes, which leads to an enhanced recovery of LV function (5, 16). Mechanistically, studies have shown that EPO-EPO-R signaling can stimulate the JAK/STAT, MAPK, and phosphatidylinositol 3-kinase/Akt signaling pathways in cardiac cells, much like the signaling in hematopoietic cells (13, 14). Cardioprotection after ischemic injury characterized by increased angiogenesis in the heart has also been found using darbepoetin- , a longeracting synthetic EPO analog (11, 18). In apparent support of the cardioprotective actions of EPO and analogs, recent clinical trials have shown that in anemic patients with HF, EPO treatment increases and maintains Hb and LV ejection fraction with improved quality-of-life scores and exercise duration (10, 15, 19). However, the mechanism of these benecial effects of EPO in patients with anemic HF has not been fully understood or claried. In the study by Naito et al. (12a), important mechanisms behind the adaptive and maladaptive responses of the heart to a long-term anemia induced by iron deciency have been uncovered. First, they demonstrate in rats that iron deciency anemia (IDA) leads to cardiac hypertrophy at 12 wk with a maintained cardiac output. However, after 20 wk of IDA, serial echocardiographic measurements revealed signicant cardiac dysfunction characterized at the end of the study by an increase in the LV weight-to-tibia length ratio and the lung wet weightto-lung dry weight ratio. Moreover, at a molecular level, atrial natriuretic peptide, brain natriuretic peptide, and collagen type 3 gene expressions were increased, consistent with the myocardial interstitial brosis that was evident in IDA rats. Interestingly, circulating levels of EPO were inversely correlated with these phenotypic ndings, with upregulation at 12 wk and a signicant decrease at 20 wk, suggesting a change in EPOEPO-R signaling in the late-stage HF induced by IDA. This study revealed some potentially important mechanistic ndings implicating STAT3 activation as a culprit in IDAinduced maladaptation. Of note, serum EPO levels and the phosphorylation of STAT3 peaked at 12 wk and subsequently decreased at 20 wk, raising the possibility that a compensatory and decompensatory EPO-EPO-R signaling mechanism may exist in the hearts of rats with chronic IDA (12a). Consistent with this, a previous study has showed that activated (i.e., phosphorylated) STAT3 can occur in cardiac cells stimulated with EPO (14). Importantly, to further explore whether the preservation of increased EPO levels is associated with adaptive cardiac remodeling, Naito et al. (12a) evaluated the cardiac effects of EPO therapy on rats after they had been on an iron-decient diet for 12 wk. EPO administration attenuated the downregulation of cardiac STAT3 phosphorylation and
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Editorial Focus H560 prevented cardiac dysfunction in the IDA group. Meanwhile, blood Hb and systolic blood pressure were not altered in the IDA group receiving EPO. Increasing EPO levels in these rats clearly prevented the transition from adaptive cardiac hypertrophy to maladaptive LV remodeling and HF even with sustained IDA. Accordingly, the study implicates STAT3 activation to be critical for the EPO-dependent maintenance of LV function despite IDA. Overall, this study underscores the importance of maintaining EPO levels in HF patients and may open up a new therapeutic window to use this cardioprotective cytokine more frequently, even in patients without anemia. Of course, further studies, especially in larger animals and different models of HF, are warranted since EPO can increase the risk of thrombotic events. Nevertheless, Naito et al. (12a) have shed new light on this interesting eld.
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