# Investigation of therapeutic potential of exogenous ubiquitin following myocardial ischemia/reperfusion injury

> **NIH VA I01** · JAMES H QUILLEN VA MEDICAL CENTER · 2020 · —

## Abstract

Ischemic heart disease (IHD) is a leading cause of death among veterans. Myocardial infarction (MI) is
a serious outcome of IHD, and is generally attributable to the detrimental effects of myocardial
ischemia/reperfusion (I/R) injury. Cardiac inflammation and extracellular matrix deposition (scar
formation) are essential events in the cardiac remodeling post-MI. Therapeutic approaches targeting
these events may hold promise for patients with MI. This proposal investigates the therapeutic potential
of ubiquitin (UB; a small molecular weight protein typically associated with tagging proteins for
proteasomal degradation) in myocardial remodeling following myocardial ischemia and I/R injury. The
proposal is based on our novel observations that exogenous UB plays a protective role in β-
adrenergic receptor-stimulated myocardial remodeling. In human THP1 leukemia cells, CXCR4 is
identified as a receptor for extracellular UB. Our preliminary data using - i) isolated heart model of global
ischemia/reperfusion (I/R; Langendorff model); and ii) in vivo myocardial I/R injury in mice now suggest
a protective role of exogenous UB in myocardial remodeling following I/R injury. UB treatment
decreased infarct size, reduced cardiac inflammatory response and improved heart function 3 days
post-I/R. In vitro, UB treatment inhibited migration of neutrophils, and enhanced phagocytic activity of
macrophages. In adult cardiac fibroblasts, UB treatment activated ERK1/2, and increased expression
of vascular endothelial growth factor-A (VEGF-A). UB co-immunoprecipitated with CXCR4, and CXCR4
antagonism negated the effects of extracellular UB on ERK1/2 activation and VEGF-A expression. UB
treatment augmented α-smooth muscle actin (a marker for myofibroblast differentiation) expression
and collagen gel contractile activity of fibroblasts, while decreasing migration of fibroblasts into the
wound area and inhibiting FBS-stimulated cell proliferation. These observations led us to hypothesize
that exogenous UB, most likely acting via CXCR4, modulates cardiac inflammatory response and
extracellular matrix biology by affecting phenotype and/or function of neutrophils, macrophages and
fibroblasts, thereby playing a cardioprotective role in myocardial remodeling following ischemia and I/R
injury. Aim 1 will investigate, in vivo, the therapeutic potential of exogenous UB in myocardial
remodeling following myocardial ischemia and I/R injury. Aim 2 will examine, in vivo, the role of CXCR4
in modulation of cardioprotective effects of exogenous UB using CXCR4 antagonist, UB mutants and
cell type-specific CXCR4 knockout mice. Aim 3 will investigate the cellular and molecular mechanisms
by which exogenous UB affects cardiac inflammatory response and extracellular matrix biology to
coordinate post-I/R cardioprotective response. The Innovation of this project lies in the investigation
of therapeutic potential of exogenous UB in myocardial remodeling following myocardial ischemia
and I/R inj...

## Key facts

- **NIH application ID:** 9852295
- **Project number:** 5I01BX004045-02
- **Recipient organization:** JAMES H QUILLEN VA MEDICAL CENTER
- **Principal Investigator:** KRISHNA SINGH
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852295

## Citation

> US National Institutes of Health, RePORTER application 9852295, Investigation of therapeutic potential of exogenous ubiquitin following myocardial ischemia/reperfusion injury (5I01BX004045-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9852295. Licensed CC0.

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