# Gap Junctional Patterning in the Arrhythmic Heart

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2020 · $556,537

## Abstract

PROJECT SUMMARY/ABSTRACT
The unregulated opening of hemichannels (HCs) formed by the gap junction (GJ) protein Cx43 during
myocardial infarction (MI) contributes injury spread, cardiac muscle loss and the formation of an arrhythmic
substrate. In the previous period, we demonstrated that the Cx43 mimetic peptide αCT1 spares left ventricular
muscle and contractile function in a mouse ischemia reperfusion (I/R) injury model and determined that the
molecular mechanism of this 25 amino acid peptide’s cardioprotective activity was via binding to the H2 domain
of Cx43. This interaction induces a cardioprotective Protein Kinase C phosphorylation of Cx43 at serine 368
(S368) – a post-translational modification known to reduce the activity of HCs. It was further shown that the
main niche for HCs – the GJ perinexus – demonstrates high concentrations of Nav1.5/Scn5a voltage-gated
sodium channels (VGSCs) and that the VGSC beta subunit β1/Scn1b maintains perinexal adhesion, enabling
formation of trans-activating sodium channels that have key assignments in cardiac conduction and arrhythmia.
The previous funding period also included completion and publication of results from two Phase II clinical trials
on αCT1. In new preliminary data, we show that a short (9 amino acid) variant of αCT1, called αCT11: (1)
Potently reduces ventricular infarct size by 48 % in an in vivo mouse model of MI, with significant preservation
of echocardiographically-assessed contractile function when given post-ischemia; and (2) Preserves conduction
and inhibits transition to discordant alternans in an ex vivo ischemia model. We have reported that like αCT1,
the αCT11 mechanism is via Cx43 H2 binding and S368 phosphorylation. However, unlike αCT1 (which
incorporates an antennapedia penetration sequence) our data indicates that the αCT11 reaches it cytoplasmic
target, the Cx43 H2 domain, via permeating HCs. During the next funding period our aims are to: (1) Undertake
rigorous testing of post-MI αCT11 efficacy in preserving cardiac muscle and preventing arrhythmias in vivo; (2)
Determine whether αCT11’s mode-of-action involves the short peptide permeating HCs; and (3) Test a novel
approach to loading of exosomes with αCT11 and undertake proof-of-principle testing of this formulation in
preclinical models of MI. The significance of these aims are underpinned by: (1) αCT1 now being in Phase III
testing on more than 500 patients; (2) That there is no clinical approach for cardioprotection post-MI; and (3) The
growing evidence that Cx43 HC activation is key to other ischemia-related pathologies, including diabetic foot
ulcers and cerebral stroke. The studies proposed herein will provide mechanistic understanding and lay the
basis for translation of new drugs targeting HCs. It is our premise that this work is a necessary prelude to clinical
testing of HC-targeting drugs in humans as muscle-sparing and anti-arrhythmic therapies in the critical hours
following a heart attack.

## Key facts

- **NIH application ID:** 9887208
- **Project number:** 2R01HL056728-18
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** ROBERT G GOURDIE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $556,537
- **Award type:** 2
- **Project period:** 1997-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9887208

## Citation

> US National Institutes of Health, RePORTER application 9887208, Gap Junctional Patterning in the Arrhythmic Heart (2R01HL056728-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9887208. Licensed CC0.

---

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