Dr. John E. Baker
Research and Selected Publications

Research Interests

The overall objective of my research program is to understand the mechanisms by which adaptation of the heart to chronic hypoxia increases resistance to subsequent ischemia. Many children undergoing cardiac surgery in the first year of life exhibit varying degrees of cyanotic heart disease where the myocardium is chronically perfused with hypoxic blood. 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.

To investigate the effects of chronic hypoxia on myocardial function and the signal transduction mechanism responsible for subsequent cardioprotection, we have developed an animal model in which rabbits are raised in a hypoxic environment from birth. This model of chronic hypoxia simulates the essential characteristics of cyanotic heart disease and has been used to demonstrate that hypoxia from birth increases tolerance of the heart to ischemia.

Chronic hypoxia from birth increases the release of nitrite plus nitrate, the concentration of cGMP and the activity of a constitutive NOS isozyme in neonatal rabbit hearts. More importantly, increased NOS activity and nitric oxide production are essential for increasing resistance of the heart to global ischemia. The mechanisms by which chronic hypoxia increases NOS activity in hearts however, remain unknown. We have shown that chronic hypoxia induces major changes in NOS3 and caveolin-3 that may explain, in part, why chronic hypoxia increases resistance to subsequent ischemia. First, chronic hypoxia increases NOS3 protein without altering steady state message levels for any of the three NOS isoforms. Analysis and comparison of the autoradiogram of protected-fragment bands in ribonuclease protection assays demonstrate that NOS3 is the most abundant transcript of the three NOS isozymes. Second, chronic hypoxia decreases the amount of caveolin-3 in heart homogenates as well as the amount of caveolin-3 that can be co-precipitated with NOS3. Third, chronic hypoxia induces maximal increases in the biological nitric oxide index during perfusion that can not be enhanced further by perfusion with the nitric oxide donor, GSNO. These changes are consistent with the idea that nitric oxide increases resistance to global ischemia and that chronic hypoxia induces maximal NOS3 activity to increase resistance.

Chronic hypoxia from birth increases current through the sarcolemmal K_ATP channel and results in increased NO production from NOS3 in sarcolemmal caveolae. The relationship between NO and the K_ATP channel in normoxic and chronically hypoxic hearts however, remains unknown. We have shown that (i) intracellular NO, released from GSNO and NO released from spermine NONOate, in normoxic hearts and native NO, from increased nitric oxide synthase activity, in chronically hypoxic hearts, activates the sarcolemmal K_ATP channel, resulting in hyperpolarization and shortening of action potential duration (ii) activation of the K_ATP channel by NO in both normoxic and chronically hypoxic hearts occurs by a cGMP dependent mechanism and (iii) NO is released from GSNO in the intracellular environment.

Selected Publications

Baker JE, Holman P, Kalyanaraman B, Griffith OW, Pritchard KA Jr. Adaptation to Chronic Hypoxia Confers Tolerance to Subsequent Myocardial Ischemia by Increased Nitric Oxide Production. In: "Heart in Stress" Eds. Das DK. Ann New York Acad Sci 874:236-253, 1999

Baker JE, Holman P, Gross GJ. Preconditioning in Immature Rabbit Hearts: Role of K_ATP Channels. Circulation 99: 1249-1254, (1999)

Baker JE, Konorev EA, Gross GJ, Chilian WM, Jacob HJ., Resistance to Myocardial Ischemia in Five Rat Strains: Is There a Genetic Component of Cardioprotection?; Am J Physiol:Heart Circulat Physiol 278: H1395-H1400, 2000

Kong X, Tweddell JS, Gross GJ, Baker JE., Kong X, Tweddell JS, Gross GJ, Baker JE.; J Mol Cell Cardiol 33:1041-1045, 2001

Pritchard Jr KA, Ackerman AW, Gross ER, Stepp DW, Shi Y, Fontana JT, Baker JE, Sessa WC., Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase.; J Biol Chem 276:17621-17624, 2001

Baker JE, Contney SJ, Singh R, Kalyanaraman B, Gross GJ, Bosnjak ZJ., Nitric Oxide Activates the Sarcolemmal KATP Channel in Normoxic and Chronically Hypoxic Hearts by a Cyclic GMP Dependent Mechanism.; J Mol Cell Cardiol 33:331-341, 2001

Last modified on: Monday, 13-Oct-2003 16:33:43 CDT