Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice
Nadine Beetz, … , Ulrich Broeckel, Lutz Hein
Nadine Beetz, … , Ulrich Broeckel, Lutz Hein
Published November 23, 2009
Citation Information: J Clin Invest. 2009;119(12):3597-3612. https://doi.org/10.1172/JCI38433.
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Research Article

Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice

Abstract

Hypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributing significantly to an individual’s lifetime risk of developing the condition. Here, we investigated the role of the G protein regulator phosducin (Pdc) in hypertension. Mice with a targeted deletion of the gene encoding Pdc (Pdc–/– mice) had increased blood pressure despite normal cardiac function and vascular reactivity, and displayed elevated catecholamine turnover in the peripheral sympathetic system. Isolated postganglionic sympathetic neurons from Pdc–/– mice showed prolonged action potential firing after stimulation with acetylcholine and increased firing frequencies during membrane depolarization. Furthermore, Pdc–/– mice displayed exaggerated increases in blood pressure in response to post-operative stress. Candidate gene–based association studies in 2 different human populations revealed several SNPs in the PDC gene to be associated with stress-dependent blood pressure phenotypes. Individuals homozygous for the G allele of an intronic PDC SNP (rs12402521) had 12–15 mmHg higher blood pressure than those carrying the A allele. These findings demonstrate that PDC is an important modulator of sympathetic activity and blood pressure and may thus represent a promising target for treatment of stress-dependent hypertension.

Authors

Nadine Beetz, Michael D. Harrison, Marc Brede, Xiangang Zong, Michal J. Urbanski, Anika Sietmann, Jennifer Kaufling, Michel Barrot, Mathias W. Seeliger, Maria Augusta Vieira-Coelho, Pavel Hamet, Daniel Gaudet, Ondrej Seda, Johanne Tremblay, Theodore A. Kotchen, Mary Kaldunski, Rolf Nüsing, Bela Szabo, Howard J. Jacob, Allen W. Cowley Jr., Martin Biel, Monika Stoll, Martin J. Lohse, Ulrich Broeckel, Lutz Hein

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Figure 3

Vascular function in Pdc-deficient mice at a young age.

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Vascular function in Pdc-deficient mice at a young age. (A–D) Longitudin...
(A–D) Longitudinal sections through the iliac artery of wild-type (A) and Pdc–/– mice (B) revealed no alterations in microscopic structure, media thickness (C), or vascular smooth muscle cell cross-sectional area (D) in Pdc–/– mice (n = 4 per genotype, age 1.5–2 months). Scale bars: 20 μm. E, endothelium; M media layer; A, adventitia. (E) Internal diameter of isolated iliac artery segments mounted in a small vessel myograph and prestretched to a wall tension corresponding to 100 mmHg intraluminal pressure (n = 6 per genotype). (F) Vasoconstrictory response to depolarization by 80 mM K+ or α1 adrenoceptor activation by phenylephrine was similar in Pdc–/– and Pdc+/+ iliac artery segments (n = 6–10). (G) Vasorelaxation induced by the muscarinic receptor agonist carbachol was unaltered in Pdc–/– compared with Pdc+/+ vessels. Vessel segments were precontracted by 10 μM phenylephrine (n = 6 vessels per genotype).