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 journalArticle

7 Citations (Scopus)

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 Ca 2+ ([Ca 2+ ]i) levels and CaMKII Thr 286 phosphorylation, followed by diminished ACE cleavage secretion into culture media. Inhibition of βL-induced [Ca 2+ ]i level changes through intracellular Ca 2+ chelation, Nqo1-specific siRNA or ryanodine receptor blockade abolished not only βL-induced increase in [Ca 2+ ]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 Thr 286 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

Fingerprint

Peptidyl-Dipeptidase A
Inbred SHR Rats
Enzymes
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Blood Pressure
NAD
Phosphorylation
Hypertension
Lung
Ryanodine Receptor Calcium Release Channel
Body Fluids
Angiotensin II
Small Interfering RNA
Culture Media
Oxidoreductases
Homeostasis
Endothelial Cells
Animal Models
Cell Line

Keywords

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

ASJC Scopus subject areas

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

Cite this

Kim, Y. H., Hwang, J. H., Kim, K. S., Noh, J. R., Gang, G. T., Kim, S. W., ... Lee, C. H. (2013). NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats. Cardiovascular research, 99(4), 743-750. https://doi.org/10.1093/cvr/cvt147
Kim, Yong Hoon ; Hwang, Jung Hwan ; Kim, Kyung Shim ; Noh, Jung Ran ; Gang, Gil Tae ; Kim, Sang Woo ; Jang, Seung Pil ; Lee, Sang Ju ; Her, Sung Ho ; Jeong, Kyeong Hoon ; Kwak, Tae Hwan ; Park, Woo Jin ; Balyasnikova, Irina V. ; Shong, Minho ; Lee, Chul Ho. / NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats. In: Cardiovascular research. 2013 ; Vol. 99, No. 4. pp. 743-750.
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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 Ca 2+ ([Ca 2+ ]i) levels and CaMKII Thr 286 phosphorylation, followed by diminished ACE cleavage secretion into culture media. Inhibition of βL-induced [Ca 2+ ]i level changes through intracellular Ca 2+ chelation, Nqo1-specific siRNA or ryanodine receptor blockade abolished not only βL-induced increase in [Ca 2+ ]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 Thr 286 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.",
keywords = "Angiotensin-converting enzyme, Blood pressure, CaMKII, NQO1",
author = "Kim, {Yong Hoon} and Hwang, {Jung Hwan} and Kim, {Kyung Shim} and Noh, {Jung Ran} and Gang, {Gil Tae} and Kim, {Sang Woo} and Jang, {Seung Pil} and Lee, {Sang Ju} and Her, {Sung Ho} and Jeong, {Kyeong Hoon} and Kwak, {Tae Hwan} and Park, {Woo Jin} and Balyasnikova, {Irina V.} and Minho Shong and Lee, {Chul Ho}",
year = "2013",
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Kim, YH, Hwang, JH, Kim, KS, Noh, JR, Gang, GT, Kim, SW, Jang, SP, Lee, SJ, Her, SH, Jeong, KH, Kwak, TH, Park, WJ, Balyasnikova, IV, Shong, M & Lee, CH 2013, 'NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats', Cardiovascular research, vol. 99, no. 4, pp. 743-750. https://doi.org/10.1093/cvr/cvt147

NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats. / Kim, Yong Hoon; Hwang, Jung Hwan; Kim, Kyung Shim; Noh, Jung Ran; Gang, Gil Tae; Kim, Sang Woo; Jang, Seung Pil; Lee, Sang Ju; Her, Sung Ho; Jeong, Kyeong Hoon; Kwak, Tae Hwan; Park, Woo Jin; Balyasnikova, Irina V.; Shong, Minho; Lee, Chul Ho.

In: Cardiovascular research, Vol. 99, No. 4, 01.09.2013, p. 743-750.

Research output: Contribution to journalArticle

TY - JOUR

T1 - NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats

AU - Kim, Yong Hoon

AU - Hwang, Jung Hwan

AU - Kim, Kyung Shim

AU - Noh, Jung Ran

AU - Gang, Gil Tae

AU - Kim, Sang Woo

AU - Jang, Seung Pil

AU - Lee, Sang Ju

AU - Her, Sung Ho

AU - Jeong, Kyeong Hoon

AU - Kwak, Tae Hwan

AU - Park, Woo Jin

AU - Balyasnikova, Irina V.

AU - Shong, Minho

AU - Lee, Chul Ho

PY - 2013/9/1

Y1 - 2013/9/1

N2 - 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 Ca 2+ ([Ca 2+ ]i) levels and CaMKII Thr 286 phosphorylation, followed by diminished ACE cleavage secretion into culture media. Inhibition of βL-induced [Ca 2+ ]i level changes through intracellular Ca 2+ chelation, Nqo1-specific siRNA or ryanodine receptor blockade abolished not only βL-induced increase in [Ca 2+ ]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 Thr 286 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.

AB - 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 Ca 2+ ([Ca 2+ ]i) levels and CaMKII Thr 286 phosphorylation, followed by diminished ACE cleavage secretion into culture media. Inhibition of βL-induced [Ca 2+ ]i level changes through intracellular Ca 2+ chelation, Nqo1-specific siRNA or ryanodine receptor blockade abolished not only βL-induced increase in [Ca 2+ ]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 Thr 286 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.

KW - Angiotensin-converting enzyme

KW - Blood pressure

KW - CaMKII

KW - NQO1

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DO - 10.1093/cvr/cvt147

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EP - 750

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

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