Cardiovascular disease is the leading cause of morbidity and mortality in the United States with >50% of mortality attributed to coronary artery disease. Though ischemic preconditioning, an endogenous protective mechanism used to salvage ischemic myocardium, was described nearly 25 years ago, there has been little to no clinical translation. Protective mechanisms in the heart utilize a number of pathways; however, unifying control points that might integrate this protective response need further characterization. Nuclear factor-kappa B (NF-?B) and protein kinase A (PKA) are critical regulators of gene transcription in the heart and have contradictory roles in cell death and survival. Activation of NF-?B and PKA is protective to the heart; however, NF-?B and PKA also promote cardiac cell death in the setting of ischemia or oxidant stress. The answer to the question as to why these two important regulators of gene transcription and cardiac physiology produce such a dichotomous response dependent on the stress applied to the system may provide insights into how protective signaling in the heart is integrated. Our laboratories have discovered a novel scaffolding protein known as A- kinase interacting protein 1 (AKIP1) that is expressed at low levels in the heart and is induced by stress. Our preliminary data show that AKIP1 binds to and regulates nuclear localization of PKA catalytic subunit and increases nuclear PKA activity. Preliminary data further show that AKIP1 interacts with and enhances NF-?B nuclear localization in a PKA phosphorylation dependent manner where disruption of AKIP1 binding to PKA enhances nuclear NF-?B. Others have shown that post-translational modification of AKIP1 (e.g., neddylation) recruits the histone deacetylase (SIRT1) to inhibit NF-?B-mediated transcription. Such data suggest that AKIP1 regulates both localization and transcriptional activation of NF-?B and PKA. We hypothesize that AKIP1 may be a key molecular regulator/scaffold that assembles PKA and NF-?B signaling complexes to alter the physiological response of the heart in the basal and stressed state. Understanding the dynamics and physiologic implications of the interaction of PKA and NF-?B with AKIP1 may provide a novel therapeutic control point for limiting cardiac injury associated with ischemic stress. The following aims will test this hypothesis.
Aim 1 : Determine how hypoxic and oxidant stress alter AKIP1 interactions with NF-?B and PKA and how disruption of this interaction alters stress adaptation in cardiac myocytes.
Aim 2 : Determine how AKIP1 regulates global and specific effects on the translocation and transcriptional activity of PKA and NF-?B.
Aim 3 : Determine the impact of AKIP1 interaction with PKA and NF-?B on protection from ischemia-reperfusion injury.

Public Health Relevance

The current proposal aims to unravel the molecular mechanism of cardiac injury and protein-protein disruption strategies to produce protection from ischemia-reperfusion injury in the heart. We will assess the role of A- kinase interaction protein in regulating the function of two key proteins in the heart that determine the balance between cell death and survival. The work described in this proposal focuses on elucidating mechanisms that have the potential to yield novel therapeutic targets for patients at risk of myocardial ischemia and heart attacks.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001963-08
Application #
9898261
Study Section
Cardiovascular Studies A (CARA)
Project Start
2013-04-01
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161
Egawa, Junji; Zemljic-Harpf, Alice; Mandyam, Chitra D et al. (2018) Neuron-Targeted Caveolin-1 Promotes Ultrastructural and Functional Hippocampal Synaptic Plasticity. Cereb Cortex 28:3255-3266
Schilling, Jan M; Head, Brian P; Patel, Hemal H (2018) Caveolins as Regulators of Stress Adaptation. Mol Pharmacol 93:277-285
Kong, Cherrie H T; Bryant, Simon M; Watson, Judy J et al. (2018) The Effects of Aging on the Regulation of T-Tubular ICa by Caveolin in Mouse Ventricular Myocytes. J Gerontol A Biol Sci Med Sci 73:711-719
Haushalter, Kristofer J; Casteel, Darren E; Raffeiner, Andrea et al. (2018) Phosphorylation of protein kinase A (PKA) regulatory subunit RI? by protein kinase G (PKG) primes PKA for catalytic activity in cells. J Biol Chem 293:4411-4421
Ichikawa, Yasuhiro; Zemljic-Harpf, Alice E; Zhang, Zheng et al. (2017) Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits. PLoS One 12:e0177660
Thomas, Joanna L; Pham, Hai; Li, Ying et al. (2017) Hypoxia-inducible factor-1? activation improves renal oxygenation and mitochondrial function in early chronic kidney disease. Am J Physiol Renal Physiol 313:F282-F290
Egawa, Junji; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma. FASEB J 31:3403-3411
Busija, Anna R; Patel, Hemal H; Insel, Paul A (2017) Caveolins and cavins in the trafficking, maturation, and degradation of caveolae: implications for cell physiology. Am J Physiol Cell Physiol 312:C459-C477
Mandyam, Chitra D; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice. Biol Psychiatry 81:101-110
Wagner, Nana-Maria; Gross, Eric R; Patel, Hemal H (2016) A Slick Way Volatile Anesthetics Reduce Myocardial Injury. Anesthesiology 124:986-8

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