# AKIP1 regulation of PKA and NF-KB in the heart

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2020 · —

## Abstract

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-κB) 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-κB and PKA is protective to the heart; however,
NF-κB 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-κB
nuclear localization in a PKA phosphorylation dependent manner where disruption of AKIP1 binding to PKA
enhances nuclear NF-κB. Others have shown that post-translational modification of AKIP1 (e.g., neddylation)
recruits the histone deacetylase (SIRT1) to inhibit NF-κB-mediated transcription. Such data suggest that AKIP1
regulates both localization and transcriptional activation of NF-κB and PKA. We hypothesize that AKIP1 may be
a key molecular regulator/scaffold that assembles PKA and NF-κB 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-κB 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-κB 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-κB. Aim 3: Determine the
impact of AKIP1 interaction with PKA and NF-κB on protection from ischemia-reperfusion injury.

## Key facts

- **NIH application ID:** 9898261
- **Project number:** 5I01BX001963-08
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Hemal H Patel
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-04-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898261

## Citation

> US National Institutes of Health, RePORTER application 9898261, AKIP1 regulation of PKA and NF-KB in the heart (5I01BX001963-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898261. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*