My research is focused on understanding the mechanisms by which cyanotic congenital heart disease modifies the myocardium and how that modification impacts on protective mechanics during ischemia may provide insight into developing treatments for limiting myocardial damage during surgery. Chronic hypoxia from birth results in erythropoiesis as manifest by an increase in hemoglobin and hematocrit. Erythropoietin activates protein kinase signaling pathways and can increase resistance to cerebral ischemia. Recently erythropoietin has been observed to increase resistance of the heart to regional ischemia in vivo. However the signal transduction pathway involved and the end effectors mediating cardioprotection were not examined. The role of erythropoietin in conferring immediate cardioprotection in the setting of cardiac surgery in children, where the heart is subjected to global ischemia, is unknown. To determine a possible role for erythropoietin in cardioprotection during surgical ischemia and the underlying mechanisms we treated infant rabbit hearts with human recombinant erythropoietin prior to ischemia. The objectives of our study were to determine whether exposure of the heart to erythropoietin would immediately increase its resistance to subsequent ischemia, the erythropoietin concentration that confers optimal protection of the heart, the involvement and cellular location of protein kinase signaling pathways, and the role of potassium channels and nitric oxide synthase in mediating cardioprotection. Our study shows that erythropoietin exerts a concentration-and time-dependent cardioprotective effect. The mechanisms underlying erythropoietin-induced cardioprotection involves activation of PKC-epsilon, p38 MAP kinase and p42/44 MAP kinase with increased resistance to myocardial ischemia mediated by potassium channels but not by nitric oxide synthase. The optimal concentration of 1.0 U/ml needed to confer protection against cardiac ischemia is approximately 100 times above levels present during chronic hypoxia and 500 times above erythropoietin levels present in the circulation of normoxic rabbits. Increased resistance to myocardial ischemia is observed immediately after treatment with erythropoietin, indicating that induction of new genes is not necessary for its cardioprotective effect to be manifested. We believe our study is the first to demonstrate the biological effects of erythropoietin are mediated by a signal pathway that results in immediate activation of two potassium channels, the KATP and the KCa channel. These studies prompted us to hypothesize that erythropoietin would also be able to protect the infant human heart against injury during surgical repair of congenital heart disease. We plan to conduct a clinical trial to test this hypothesis in the setting of the cardiac operating room at Children's Hospital of Wisconsin.
Kong X, Tweddell JS, Gross GJ, Baker JE. Sarcolemmal and mitochondrial KATP channels mediate cardioprotection in chronically hypoxic hearts. J Mol Cell Cardiol 33:1041-1045, 2001
Tonkovic-Capin M, Gross GJ, Bosnjak ZJ, Tweddell JS, Fitzpatrick CM, Baker JE. Delayed cardioprotection by isoflurane: role of KATP channels. Am J Physiol:Heart Circ Physiol 283:H61-H68, 2002
Rafiee P, Shi Y, Kong X, Pritchard KA, Tweddell JS, Litwin SB, Mussatto K, Jaquiss RD, Su J, Baker JE. Activation of protein kinases in chronically hypoxic infant human and rabbit hearts: role in cardioprotection. Circulation 106:239-245, 2002
Shi Y, Baker JE, Zhang C, Tweddell JS, Su J, Pritchard Jr. KA. Chronic hypoxia increases endothelial nitric oxide synthase generation of nitric oxide by increasing heat shock protein 90 and serine phosphorylation. Circ Res 91:300-306, 2002
Zhu D, Medhora M, Campbell WB, Spitzbarth N, Baker JE, Jacobs ER. Chronic hypoxia activates lung 15-lipoxygenase, which catalyzes production of 15-HETE and enhances constriction in neonatal rabbit pulmonary arteries. Circ Res 92:992-1000, 2003
Rafiee P, Shi Y, Pritchard, Jr. KA, Ogawa H, Eis ALW, Komorowski RA, Fitzpatrick CM, Tweddell JS, Litwin SB, Mussatto K, Jaquiss RD, Baker JE. Cellular redistribution of inducible Hsp70 protein in the human and rabbit heart in response to the stress of chronic hypoxia: Role of protein kinases. J Biol Chem 278:43636-43644, 2003
Shi Y, Rafiee P, Su J, Pritchard Jr KA, Tweddell JS, Baker JE. Acute cardioprotective effects of erythropoietin in infant rabbits are mediated by activation of protein kinases and potassium channels. Basic Res Cardiol 99:173-182, 2004
Baker JE. Oxidative stress and adaptation of the infant heart to hypoxia and ischemia. Antioxidants & Redox Signaling 6:423-429, 2004
Fitzpatrick CM, Shi Y, Hutchins WC, Su J, Gross GJ, Ostadal B, Tweddell JS, Baker JE. Cardioprotection in chronically hypoxic rabbits persists upon exposure to normoxia: Role of nitric oxide synthase and KATP channels. Am J Physiol 288:H62-H68, 2005.
Shi Y, Hutchins WC, Su J, Siker D, Hogg N, Pritchard Jr. KA, Keszler A, Tweddell JS, Baker JE. Delayed cardioprotection with isoflurane: role of reactive oxygen and nitrogen. Am J Physiol 288:H175-H184, 2005
Rafiee P, Shi Y, Su J, Pritchard Jr. KA, Tweddell JS, Baker JE. Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. Basic Res Cardiol 100(3):187-197, 2005
Baker JE. Erythropoietin mimics ischemic preconditioning. In special issue on "Mechanisms of Drug-Induced Cardiac Preconditioning." Vascular Pharmacology 42(5-6):233-241, 2005