- Cardiovascular Agents
- Cardiovascular Diseases
- Cardiovascular Physiological Phenomena
- Cardiovascular System
- radiation effects
- Radiation Effects
- Radiation Genetics
- Radiation Injuries
- Radiation Injuries, Experimental
- Radiation Tolerance
- Radiation, Ionizing
- Clinical Trial
- Clinical Trials, Phase II as Topic
- Drugs, Investigational
- Chair, Institutional Animal Care and Use Committee
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 KATP channel and results in increased NO production from NOS3 in sarcolemmal caveolae. The relationship between NO and the KATP 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 KATP channel, resulting in hyperpolarization and shortening of action potential duration (ii) activation of the KATP 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.
(Lenarczyk M, Kronenberg A, Mäder M, North PE, Komorowski R, Cheng Q, Little MP, Chiang IH, LaTessa C, Jardine J, Baker JE.) Radiat Res. 2019 07;192(1):63-74.
(Malik M, Suboc TM, Tyagi S, Salzman N, Wang J, Ying R, Tanner MJ, Kakarla M, Baker JE, Widlansky ME.) Circ Res. 2018 10 12;123(9):1091-1102.
(Rentea RM, Lam V, Biesterveld B, Fredrich KM, Callison J, Fish BL, Baker JE, Komorowski R, Gourlay DM, Otterson MF.) Am J Surg. 2016 Oct;212(4):602-608.
(Lam V, Su J, Hsu A, Gross GJ, Salzman NH, Baker JE.) PLoS One. 2016;11(8):e0160840.
(Lenarczyk M, Su J, Haworth ST, Komorowski R, Fish BL, Migrino RQ, Harmann L, Hopewell JW, Kronenberg A, Patel S, Moulder JE, Baker JE.) Pharmacol Res Perspect. 2015 Jun;3(3):e00145.
(Baker JE, Su J, Koprowski S, Dhanasekaran A, Aufderheide TP, Gross GJ.) J Pharmacol Exp Ther. 2015 Mar;352(3):429-37.
(Quirk BJ, Sonowal P, Jazayeri MA, Baker JE, Whelan HT.) Photomed Laser Surg. 2014 Sep;32(9):505-11.
(Sharma A, Fish BL, Moulder JE, Medhora M, Baker JE, Mader M, Cohen EP.) Lab Anim (NY). 2014 Feb;43(2):63-6.
(Parvin A, Pranap R, Shalini U, Devendran A, Baker JE, Dhanasekaran A.) PLoS One. 2014;9(9):e107453.
(Lenarczyk M, Lam V, Jensen E, Fish BL, Su J, Koprowski S, Komorowski RA, Harmann L, Migrino RQ, Li XA, Hopewell JW, Moulder JE, Baker JE.) Radiat Res. 2013 Sep;180(3):247-58.
Heparin oligosaccharides inhibit chemokine (CXC motif) ligand 12 (CXCL12) cardioprotection by binding orthogonal to the dimerization interface, promoting oligomerization, and competing with the chemokine (CXC motif) receptor 4 (CXCR4) N terminus.
(Ziarek JJ, Veldkamp CT, Zhang F, Murray NJ, Kartz GA, Liang X, Su J, Baker JE, Linhardt RJ, Volkman BF.) J Biol Chem. 2013 Jan 04;288(1):737-46.
(Lam V, Su J, Koprowski S, Hsu A, Tweddell JS, Rafiee P, Gross GJ, Salzman NH, Baker JE.) FASEB J. 2012 Nov;26(11):4388-9.