# Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $388,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Heart failure (HF) is characterized by markedly elevated levels of catecholamines that bind to adrenergic
receptors (ARs) in the heart. The toxic effects of excessive beta (β)-AR stimulation are well described, and
drugs that block β-ARs are cornerstones of contemporary HF therapy. Cardiac alpha (α)1-ARs have received
less attention, however data from cell and animal studies indicate that they protect against the development of
HF. There are two α1-AR subtypes in the heart: α1A, and α1B. The α1B mediates cardiac hypertrophy
induced by non-selective α1-AR agonists like phenylephrine. Activation of the α1A protects against
cardiomyocyte death and increases contractility in the failing heart, though the mechanisms underlying these
adaptive effects are poorly understood. We recently showed that an oral selective α1A agonist drug,
dabuzalgron, preserves ATP content and mitochondrial function in mouse HF models. These protective effects
were abrogated by trametinib, a MEK-ERK1/2 inhibitor used to treat melanoma. Our recent preliminary data
expand upon these novel findings by suggesting that α1A activation may improve cardiac energetics through
increased glucose utilization, coupling augmented glycolysis to glucose oxidation through enhanced oxidative
phosphorylation. The overarching hypothesis of this proposal is that α1A-ARs protect the failing heart through
an ERK1/2-mediated increase in glucose metabolism that counteracts the deleterious metabolic effects of
chronic β1 hyperstimulation in HF. In Aim 1, we will use a cardiomyocyte-specific α1A-AR knockout mouse in
two mouse models of pathological hypertrophy and HF to confirm the requirement of cardiomyocyte α1As for
the cardioprotective effects of dabuzalgron. In Aim 2, we will find if α1A-AR activation enhances glucose
utilization to provide energy for the failing heart using transverse aortic constriction in vivo coupled with in vitro
studies using selective pharmacology and gene silencing to identify key metabolic processes and signaling
pathways affected by α1A activation. Aim 3 will define the role of ERK1/2 activation in α1A-mediated
metabolic cardioprotection, using both trametinib and genetic modification of MEK-ERK axis to provide new
insights on the role of ERK1/2 signaling in the regulation of glucose metabolism and mitochondrial function.
Collectively the proposed experiments will expand our understanding of cardiac α1A-ARs and challenge the
prevailing paradigm that chronic catecholamine surge exerts uniformly deleterious effects in the failing heart.

## Key facts

- **NIH application ID:** 9856895
- **Project number:** 5R01HL140067-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Brian C Jensen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2017-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856895

## Citation

> US National Institutes of Health, RePORTER application 9856895, Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation (5R01HL140067-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9856895. Licensed CC0.

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