Impaired trafficking of β1 subunits inhibits BK channels in cerebral arteries of hypertensive rats

Marie Dennis Leo, Xue Zhai, Wen Yin, Jonathan Jaggar

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Hypertension is a risk factor for cerebrovascular diseases, including stroke and dementia. During hypertension, arteries become constricted and are less responsive to vasodilators, including nitric oxide (NO). The regulation of arterial contractility by smooth muscle cell (myocyte) large-conductance calcium (Ca2+)-activated potassium (BK) channels is altered during hypertension, although mechanisms involved are unclear. We tested the hypothesis that dysfunctional trafficking of pore-forming BK channel (BKα) and auxiliary β1 subunits contributes to changes in cerebral artery contractility of stroke-prone spontaneously hypertensive rats (SP-SHRs). Our data indicate that the amounts of total and surface BKα and β1 proteins are similar in unstimulated arteries of age-matched SP-SHRs and normotensive Wistar-Kyoto rats. In contrast, stimulated surface-trafficking of β1 subunits by NO or membrane depolarization is inhibited in SP-SHR myocytes. PKCα (protein kinase C α) and PKCβII total protein and activity were both higher in SP-SHR than in Wistar-Kyoto rat arteries. NO or depolarization robustly activated Rab11, a small trafficking GTPase, in Wistar-Kyoto rat arteries but weakly activated Rab11 in SP-SHRs. Bisindolylmaleimide, a PKC inhibitor, and overexpression of a PKC phosphorylation-deficient Rab11A mutant (Rab11A S177A) restored stimulated β1 subunit surface-trafficking in SP-SHR myocytes. BK channel activation by NO was inhibited in SP-SHR myocytes and restored by Rab11A S177A expression. Vasodilation to NO and lithocholate, a BKα/β1 channel activator, was inhibited in pressurized SP-SHR arteries and reestablished by bisindolylmaleimide. In summary, data indicate that spontaneously active PKC inhibits Rab11A-mediated β1 subunit trafficking in arterial myocytes of SP-SHRs, leading to dysfunctional NO-induced BK channel activation and vasodilation.

Original languageEnglish (US)
Pages (from-to)765-775
Number of pages11
JournalHypertension
Volume72
Issue number3
DOIs
StatePublished - Jan 1 2018

Fingerprint

Large-Conductance Calcium-Activated Potassium Channels
Cerebral Arteries
Inbred SHR Rats
Stroke
Nitric Oxide
Arteries
Muscle Cells
Protein Kinase C
Inbred WKY Rats
Hypertension
Vasodilation
Smooth Muscle Myocytes
Lithocholic Acid
Cerebrovascular Disorders
Monomeric GTP-Binding Proteins
Protein C Inhibitor
Potassium Channels
Protein Kinase Inhibitors
Vasodilator Agents
Dementia

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Impaired trafficking of β1 subunits inhibits BK channels in cerebral arteries of hypertensive rats. / Leo, Marie Dennis; Zhai, Xue; Yin, Wen; Jaggar, Jonathan.

In: Hypertension, Vol. 72, No. 3, 01.01.2018, p. 765-775.

Research output: Contribution to journalArticle

@article{200d8c5212ee40b39f24c920116043d5,
title = "Impaired trafficking of β1 subunits inhibits BK channels in cerebral arteries of hypertensive rats",
abstract = "Hypertension is a risk factor for cerebrovascular diseases, including stroke and dementia. During hypertension, arteries become constricted and are less responsive to vasodilators, including nitric oxide (NO). The regulation of arterial contractility by smooth muscle cell (myocyte) large-conductance calcium (Ca2+)-activated potassium (BK) channels is altered during hypertension, although mechanisms involved are unclear. We tested the hypothesis that dysfunctional trafficking of pore-forming BK channel (BKα) and auxiliary β1 subunits contributes to changes in cerebral artery contractility of stroke-prone spontaneously hypertensive rats (SP-SHRs). Our data indicate that the amounts of total and surface BKα and β1 proteins are similar in unstimulated arteries of age-matched SP-SHRs and normotensive Wistar-Kyoto rats. In contrast, stimulated surface-trafficking of β1 subunits by NO or membrane depolarization is inhibited in SP-SHR myocytes. PKCα (protein kinase C α) and PKCβII total protein and activity were both higher in SP-SHR than in Wistar-Kyoto rat arteries. NO or depolarization robustly activated Rab11, a small trafficking GTPase, in Wistar-Kyoto rat arteries but weakly activated Rab11 in SP-SHRs. Bisindolylmaleimide, a PKC inhibitor, and overexpression of a PKC phosphorylation-deficient Rab11A mutant (Rab11A S177A) restored stimulated β1 subunit surface-trafficking in SP-SHR myocytes. BK channel activation by NO was inhibited in SP-SHR myocytes and restored by Rab11A S177A expression. Vasodilation to NO and lithocholate, a BKα/β1 channel activator, was inhibited in pressurized SP-SHR arteries and reestablished by bisindolylmaleimide. In summary, data indicate that spontaneously active PKC inhibits Rab11A-mediated β1 subunit trafficking in arterial myocytes of SP-SHRs, leading to dysfunctional NO-induced BK channel activation and vasodilation.",
author = "Leo, {Marie Dennis} and Xue Zhai and Wen Yin and Jonathan Jaggar",
year = "2018",
month = "1",
day = "1",
doi = "10.1161/HYPERTENSIONAHA.118.11147",
language = "English (US)",
volume = "72",
pages = "765--775",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - Impaired trafficking of β1 subunits inhibits BK channels in cerebral arteries of hypertensive rats

AU - Leo, Marie Dennis

AU - Zhai, Xue

AU - Yin, Wen

AU - Jaggar, Jonathan

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Hypertension is a risk factor for cerebrovascular diseases, including stroke and dementia. During hypertension, arteries become constricted and are less responsive to vasodilators, including nitric oxide (NO). The regulation of arterial contractility by smooth muscle cell (myocyte) large-conductance calcium (Ca2+)-activated potassium (BK) channels is altered during hypertension, although mechanisms involved are unclear. We tested the hypothesis that dysfunctional trafficking of pore-forming BK channel (BKα) and auxiliary β1 subunits contributes to changes in cerebral artery contractility of stroke-prone spontaneously hypertensive rats (SP-SHRs). Our data indicate that the amounts of total and surface BKα and β1 proteins are similar in unstimulated arteries of age-matched SP-SHRs and normotensive Wistar-Kyoto rats. In contrast, stimulated surface-trafficking of β1 subunits by NO or membrane depolarization is inhibited in SP-SHR myocytes. PKCα (protein kinase C α) and PKCβII total protein and activity were both higher in SP-SHR than in Wistar-Kyoto rat arteries. NO or depolarization robustly activated Rab11, a small trafficking GTPase, in Wistar-Kyoto rat arteries but weakly activated Rab11 in SP-SHRs. Bisindolylmaleimide, a PKC inhibitor, and overexpression of a PKC phosphorylation-deficient Rab11A mutant (Rab11A S177A) restored stimulated β1 subunit surface-trafficking in SP-SHR myocytes. BK channel activation by NO was inhibited in SP-SHR myocytes and restored by Rab11A S177A expression. Vasodilation to NO and lithocholate, a BKα/β1 channel activator, was inhibited in pressurized SP-SHR arteries and reestablished by bisindolylmaleimide. In summary, data indicate that spontaneously active PKC inhibits Rab11A-mediated β1 subunit trafficking in arterial myocytes of SP-SHRs, leading to dysfunctional NO-induced BK channel activation and vasodilation.

AB - Hypertension is a risk factor for cerebrovascular diseases, including stroke and dementia. During hypertension, arteries become constricted and are less responsive to vasodilators, including nitric oxide (NO). The regulation of arterial contractility by smooth muscle cell (myocyte) large-conductance calcium (Ca2+)-activated potassium (BK) channels is altered during hypertension, although mechanisms involved are unclear. We tested the hypothesis that dysfunctional trafficking of pore-forming BK channel (BKα) and auxiliary β1 subunits contributes to changes in cerebral artery contractility of stroke-prone spontaneously hypertensive rats (SP-SHRs). Our data indicate that the amounts of total and surface BKα and β1 proteins are similar in unstimulated arteries of age-matched SP-SHRs and normotensive Wistar-Kyoto rats. In contrast, stimulated surface-trafficking of β1 subunits by NO or membrane depolarization is inhibited in SP-SHR myocytes. PKCα (protein kinase C α) and PKCβII total protein and activity were both higher in SP-SHR than in Wistar-Kyoto rat arteries. NO or depolarization robustly activated Rab11, a small trafficking GTPase, in Wistar-Kyoto rat arteries but weakly activated Rab11 in SP-SHRs. Bisindolylmaleimide, a PKC inhibitor, and overexpression of a PKC phosphorylation-deficient Rab11A mutant (Rab11A S177A) restored stimulated β1 subunit surface-trafficking in SP-SHR myocytes. BK channel activation by NO was inhibited in SP-SHR myocytes and restored by Rab11A S177A expression. Vasodilation to NO and lithocholate, a BKα/β1 channel activator, was inhibited in pressurized SP-SHR arteries and reestablished by bisindolylmaleimide. In summary, data indicate that spontaneously active PKC inhibits Rab11A-mediated β1 subunit trafficking in arterial myocytes of SP-SHRs, leading to dysfunctional NO-induced BK channel activation and vasodilation.

UR - http://www.scopus.com/inward/record.url?scp=85055600075&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055600075&partnerID=8YFLogxK

U2 - 10.1161/HYPERTENSIONAHA.118.11147

DO - 10.1161/HYPERTENSIONAHA.118.11147

M3 - Article

VL - 72

SP - 765

EP - 775

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 3

ER -