The Protein Acyl Transferase ZDHHC21 Modulates α1 Adrenergic Receptor Function and Regulates Hemodynamics.

TitleThe Protein Acyl Transferase ZDHHC21 Modulates α1 Adrenergic Receptor Function and Regulates Hemodynamics.
Publication TypeJournal Article
Year of Publication2016
AuthorsMarin, EP, Jozsef, L, Di Lorenzo, A, Held, KF, Luciano, AK, Melendez, J, Milstone, LM, Velazquez, H, Sessa, WC
JournalArterioscler Thromb Vasc Biol
Volume36
Issue2
Pagination370-9
Date Published2016 Feb
ISSN1524-4636
KeywordsAcyltransferases, Adrenergic alpha-1 Receptor Agonists, Animals, Aorta, Blood Pressure, Dose-Response Relationship, Drug, Epinephrine, Fibroblasts, Genotype, Heart Rate, HEK293 Cells, Hemodynamics, Humans, Hypotension, Lipoylation, Mesenteric Arteries, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation, Norepinephrine, Phenotype, Phenylephrine, Receptors, Adrenergic, alpha-1, Signal Transduction, Tachycardia, Time Factors, Transfection, Vasoconstriction
Abstract

OBJECTIVE: Palmitoylation, the reversible addition of the lipid palmitate to a cysteine, can alter protein localization, stability, and function. The ZDHHC family of protein acyl transferases catalyzes palmitoylation of numerous proteins. The role of ZDHHC enzymes in intact tissue and in vivo is largely unknown. Herein, we characterize vascular functions in a mouse that expresses a nonfunctional ZDHHC21 (F233Δ).

APPROACH AND RESULTS: Physiological studies of isolated aortae and mesenteric arteries from F233Δ mice revealed an unexpected defect in responsiveness to phenylephrine, an α1 adrenergic receptor agonist. In vivo, F233Δ mice displayed a blunted response to infusion of phenylephrine, and they were found to have elevated catecholamine levels and elevated vascular α1 adrenergic receptor gene expression. Telemetry studies showed that the F233Δ mice were tachycardic and hypotensive at baseline, consistent with diminished vascular tone. In biochemical studies, ZDHHC21 was shown to palmitoylate the α1D adrenoceptor and to interact with it in a molecular complex, thus suggesting a possible molecular mechanism by which the receptor can be regulated by ZDHHC21.

CONCLUSIONS: Together, the data support a model in which ZDHHC21 F233Δ diminishes the function of vascular α1 adrenergic receptors, leading to reduced vascular tone, which manifests in vivo as hypotension and tachycardia. This is to our knowledge the first demonstration of a ZDHHC isoform affecting vascular function in vivo and identifies a novel molecular mode of regulation of vascular tone and blood pressure.

DOI10.1161/ATVBAHA.115.306942
Alternate JournalArterioscler. Thromb. Vasc. Biol.
PubMed ID26715683
PubMed Central IDPMC4984414
Grant ListT32HL007950 / HL / NHLBI NIH HHS / United States
T32 HL007950 / HL / NHLBI NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
T32 GM007324 / GM / NIGMS NIH HHS / United States
R01 HL064793 / HL / NHLBI NIH HHS / United States
K08 HL103831 / HL / NHLBI NIH HHS / United States
R37 HL061371 / HL / NHLBI NIH HHS / United States
R01 HL096670 / HL / NHLBI NIH HHS / United States
R01 HL081190 / HL / NHLBI NIH HHS / United States