# Understanding the role of chondroitin sulfate proteoglycan 4-sulfation in the heart following myocardial infarction

> **NIH NIH F31** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $45,520

## Abstract

PROJECT SUMMARY
Sudden cardiac failure from cardiac arrhythmias is a leading cause of death for patients who have suffered a
myocardial infarction (MI). Heterogeneity in sympathetic neurotransmission to damaged areas of the heart is
thought to generate these arrhythmias. Following an early period of denervation after MI, the damaged cardiac
tissue, or cardiac scar, has the capacity to stimulate nerve reinnervation due to high amounts of secreted Nerve
Growth Factor (NGF) which activates tropomyosin receptor kinase A (TrkA). Despite this, nerves do not grow
back into the scar due to the presence of chondroitin sulfate proteoglycans (CSPGs), resulting in a patchwork of
innervation and denervation throughout the heart. The resulting denervated tissue is unable to respond to
sympathetic neurotransmission leading to a heterogeneous response that generates cardiac arrhythmias.
Previous work in our lab demonstrated that blocking CSPG signaling in sympathetic nerves restores sympathetic
innervation of the cardiac scar and reduces arrhythmia susceptibility after MI. Therapeutic interventions to block
CSPG signaling and restore sympathetic innervation of the cardiac scar would be a viable strategy to reduce
post-MI arrhythmias and risk of sudden cardiac death but therapeutic design is limited by our understanding of
CSPG signaling.
CSPGs are a diverse family of molecules composed of different core proteins modified by glycosaminoglycans
(GAG) side chains that can be further modified by sulfation. Evidence from research in the central nervous
system (CNS) suggests that inhibition of axon outgrowth occurs primarily via 4S-CSPGs following nerve injury.
Despite the critical role of CSPGs in preventing reinnervation of the cardiac scar it is unknown whether 4S-
CSPGs specifically inhibit sympathetic axon outgrowth. This study will provide a mechanistic understanding of
how CSPG sulfation in the cardiac scar affects sympathetic denervation in our mouse model of MI using the
enzyme Arasulfatase B which selectively degrades 4S-CSPGs. Furthermore, CSPG-sulfation-induced signaling
studies focusing downstream of TrkA signaling networks will elucidate the molecular mechanism behind
sympathetic axon outgrowth inhibition. To understand signaling pathways a FRET based imaging platform will
be used to examine multiple signaling pathways in parallel. These results will identify novel therapeutic targets
to restore sympathetic axon outgrowth in the presence of CSPGs

## Key facts

- **NIH application ID:** 9990429
- **Project number:** 1F31HL152490-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Matthew Russell Blake
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-04-16 → 2022-04-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990429

## Citation

> US National Institutes of Health, RePORTER application 9990429, Understanding the role of chondroitin sulfate proteoglycan 4-sulfation in the heart following myocardial infarction (1F31HL152490-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990429. Licensed CC0.

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