Modulation of adrenal catecholamine secretion by in vivo gene transfer and manipulation of G protein-coupled receptor kinase-2 activity

Anastasios Lymperopoulos, Giuseppe Rengo, Carmela Zincarelli, Stephen Soltys, Walter J. Koch

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Abstract

We recently reported that the upregulation of adrenal G protein-coupled receptor kinase-2 (GRK2) causes enhanced catecholamine (CA) secretion by desensitizing sympatho-inhibitory α2-adrenergic receptors (α2ARs) of chromaffin cells, and thereby aggravating heart failure (HF). In this study, we sought to develop an efficient and reproducible in vivo adrenal gene transfer method to determine whether manipulation of adrenal GRK2 levels/activity regulates physiological CA secretion in rats. We specifically investigated two different in vivo gene delivery methods: direct injection into the suprarenal glands, and retrograde delivery through the suprarenal veins. We delivered adenoviral (Ad) vectors containing either GRK2 or an inhibitor of GRK2 activity, the β ARKct. We found both delivery approaches equally effective at supporting robust (>80% of the whole organ) and adrenal-restricted transgene expression, in the cortical region as well as in the medullar region. Additionally, rats with AdGRK2-infected adrenals exhibit enhanced plasma CA levels when compared with control rats (AdGFP-injected adrenals), whereas plasma CA levels after Adβ ARKct infection were significantly lower. Finally, in isolated chromaffin cells, α2ARs of AdGRK2-infected cells failed to inhibit CA secretion whereas Adβ ARKct-infected cells showed normal α2AR responsiveness. These results not only indicate that in vivo adrenal gene transfer is an effective way of manipulating adrenal gland signalling, but also identify GRK2 as a critically important molecule involved in CA secretion.

Original languageEnglish
Pages (from-to)302-307
Number of pages6
JournalMolecular Therapy
Volume16
Issue number2
DOIs
Publication statusPublished - Feb 2008

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G-Protein-Coupled Receptor Kinase 2
Catecholamines
Genes
Chromaffin Cells
Adrenergic Receptors
Adrenal Glands
Transgenes
Veins
Up-Regulation
Heart Failure
Injections
Infection

ASJC Scopus subject areas

  • Molecular Biology

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Modulation of adrenal catecholamine secretion by in vivo gene transfer and manipulation of G protein-coupled receptor kinase-2 activity. / Lymperopoulos, Anastasios; Rengo, Giuseppe; Zincarelli, Carmela; Soltys, Stephen; Koch, Walter J.

In: Molecular Therapy, Vol. 16, No. 2, 02.2008, p. 302-307.

Research output: Contribution to journalArticle

Lymperopoulos, Anastasios ; Rengo, Giuseppe ; Zincarelli, Carmela ; Soltys, Stephen ; Koch, Walter J. / Modulation of adrenal catecholamine secretion by in vivo gene transfer and manipulation of G protein-coupled receptor kinase-2 activity. In: Molecular Therapy. 2008 ; Vol. 16, No. 2. pp. 302-307.
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