NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats

Yong Hoon Kim, Jung Hwan Hwang, Kyung Shim Kim, Jung Ran Noh, Gil Tae Gang, Sang Woo Kim, Seung Pil Jang, Sang Ju Lee, Sung Ho Her, Kyeong Hoon Jeong, Tae Hwan Kwak, Woo Jin Park, Irina V. Balyasnikova, Minho Shong, Chul Ho Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

AimsAngiotensin-converting enzyme (ACE) plays a key role in blood pressure (BP) homeostasis via regulation of angiotensin II. Active ACE ectodomain is enzymatically cleaved and released into body fluids, including plasma, and elevated plasma ACE levels are associated with increased BP. β-lapachone (βL) has been shown to increase cellular NAD+/NADH ratio via activation of NAD(P)H:quinone oxidoreductase 1 (NQO1). In this study, we evaluated whether NQO1 activation by βL modulates BP through regulation of ACE shedding in an animal model of hypertension.Methods and resultsSpontaneously hypertensive rats (SHR) and a human ACE-overexpressing rat lung microvascular endothelial cell line (RLMVEC-hACE) were used to investigate the mechanism by which βL exerts a hypotensive effect. In vitro studies revealed that βL significantly increased intracellular Ca2+ ([Ca 2+]i) levels and CaMKII Thr286 phosphorylation, followed by diminished ACE cleavage secretion into culture media. Inhibition of βL-induced [Ca2+]i level changes through intracellular Ca 2+ chelation, Nqo1-specific siRNA or ryanodine receptor blockade abolished not only βL-induced increase in [Ca2+]i levels and CaMKII phosphorylation, but also βL-mediated decrease in ACE shedding. The effect of βL on ACE shedding was also blocked by inhibition of CaMKII. In SHR, βL reduced BP following increase of CaMKII Thr286 phosphorylation in the lung and decrease of ACE activity and angiotensin II levels in plasma.ConclusionThis is the first study demonstrating that ACE shedding is regulated by NQO1 activation, which is possibly correlated with relieving hypertension in SHR. These findings provide strong evidence suggesting that NQO1 might be a new target for ACE modulation and BP control.

Original languageEnglish (US)
Pages (from-to)743-750
Number of pages8
JournalCardiovascular research
Volume99
Issue number4
DOIs
StatePublished - Sep 1 2013

Keywords

  • Angiotensin-converting enzyme
  • Blood pressure
  • CaMKII
  • NQO1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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