NADPH Oxidase 1 Mediates Acute Blood Pressure Response to Angiotensin II by Contributing to Calcium Influx in Vascular Smooth Muscle Cells

Jung Min Park, Van Quan Do, Yoon Seok Seo, Hyun Jong Kim, Joo Hyun Nam, Ming Zhe Yin, Hae Jin Kim, Sung Joon Kim, Kathy K. Griendling, Moo Yeol Lee

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Background: Reactive oxygen species (ROS) and calcium ions (Ca2+) are among the major effectors of Ang II (angiotensin II) in vascular smooth muscle cells. ROS are related to Ca2+signaling or contraction induced by Ang II, but little is known about their detailed functions. Here, NOX (NADPH oxidase), a major ROS source responsive to Ang II, was investigated regarding its contribution to Ca2+signaling. Methods: Vascular smooth muscle cells were primary cultured from rat aorta. Ca2+and ROS were monitored mainly using fura-2 and HyPer family probes‚ respectively. Signals activating NOX were examined with relevant pharmacological inhibitors and genetic manipulation techniques. Results: Ang II-induced ROS generation was found to be biphasic: the first phase of ROS production, which was mainly mediated by NOX1, was small and transient, preceding a rise in Ca2+, and the second phase of ROS generation, mediated by NOX1 and NOX4, was slow but sizeable, continuing over tens of minutes. NOX1-derived superoxide in the first phase is required for Ca2+influx through nonselective cation channels. AT1R (Ang II type 1 receptor)-Gβγ-PI3Kγ(phosphoinositide 3-kinase γ) signaling pathway was responsible for the rapid activation of NOX1 in the first phase, while in the second phase, NOX1 was further activated by a separate AT1R-Gαq/11-PLC (phospholipase C)-PKCβ(protein kinase C β) signaling axis. Consistent with these observations, aortas from NOX1-knockout mice exhibited reduced contractility in response to Ang II, and thus the acute pressor response to Ang II was also attenuated in NOX1-knockout mice. Conclusions: NOX1 mediates Ca2+signal generation and thereby contributes to vascular contraction and blood pressure elevation by Ang II.

Original languageEnglish
Pages (from-to)E117-E130
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume42
Issue number5
DOIs
StatePublished - 1 May 2022

Keywords

  • angiotensin II
  • calcium
  • NADPH oxidases
  • reactive oxygen species
  • smooth muscle

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