- 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, Laiakis EC, Mattson DL, Johnson BD, Kronenberg A, North PE, Komorowski R, Mäder M, Baker JE.) FASEB Bioadv. 2020 Dec;2(12):705-719 PMID: 33336158 PMCID: PMC7734425 12/19/2020
(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 PMID: 31095446 SCOPUS ID: 2-s2.0-85068362644 05/17/2019
(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 PMID: 30355158 PMCID: PMC6205737 SCOPUS ID: 2-s2.0-85055600525 10/26/2018
(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 PMID: 27501776 SCOPUS ID: 2-s2.0-84991709365 08/10/2016
(Lam V, Su J, Hsu A, Gross GJ, Salzman NH, Baker JE.) PLoS One. 2016;11(8):e0160840 PMID: 27505423 PMCID: PMC4978455 SCOPUS ID: 2-s2.0-84983638440 08/10/2016
(Allaudeen AP, Koka P, Pant T, Chandramohan Y, Sivanesan S, Baker JE, Dhanasekaran A.) International Journal of Pharmacy and Pharmaceutical Sciences. 2016;8(12):34-40 SCOPUS ID: 2-s2.0-85003875042 01/01/2016
(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 PMID: 26171225 PMCID: PMC4492761 07/15/2015
(Baker JE, Su J, Koprowski S, Dhanasekaran A, Aufderheide TP, Gross GJ.) J Pharmacol Exp Ther. 2015 Mar;352(3):429-37 PMID: 25512369 SCOPUS ID: 2-s2.0-84921466193 12/17/2014
(Quirk BJ, Sonowal P, Jazayeri MA, Baker JE, Whelan HT.) Photomed Laser Surg. 2014 Sep;32(9):505-11 PMID: 25093393 PMCID: PMC4142831 SCOPUS ID: 2-s2.0-84906490690 08/06/2014
(Sharma A, Fish BL, Moulder JE, Medhora M, Baker JE, Mader M, Cohen EP.) Lab Anim (NY). 2014 Feb;43(2):63-6 PMID: 24451361 PMCID: PMC3989930 SCOPUS ID: 2-s2.0-84892989748 01/24/2014
(Parvin A, Pranap R, Shalini U, Devendran A, Baker JE, Dhanasekaran A.) PLoS One. 2014;9(9):e107453 PMID: 25237819 PMCID: PMC4169563 SCOPUS ID: 2-s2.0-84907202527 09/23/2014
(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 PMID: 23919311 PMCID: PMC4042860 SCOPUS ID: 2-s2.0-84884273934 08/08/2013