Vascular smooth muscle cell contractile protein expression is increased through protein kinase G-dependent and-independent pathways by glucose-6-phosphate dehydrogenase inhibition and deficiency

Sukrutha Chettimada, Sachindra Raj Joshi, Vidhi Dhagia, Alessandro Aiezza, Thomas M. Lincoln, Rakhee Gupte, Joseph M. Miano, Sachin A. Gupte

Research output: Contribution to journalArticle

Abstract

Homeostatic control of vascular smooth muscle cell (VSMC) differentiation is critical for contractile activity and regulation of blood flow. Recently, we reported that precontracted blood vessels are relaxed and the phenotype of VSMC is regulated from a synthetic to contractile state by glucose-6-phosphate dehydrogenase (G6PD) inhibition. In the current study, we investigated whether the increase in the expression of VSMC contractile proteins by inhibition and knockdown of G6PD is mediated through a protein kinase G (PKG)-dependent pathway and whether it regulates blood pressure. We found that the expression of VSMC-restricted contractile proteins, myocardin (MYOCD), and miR-1 and miR-143 are increased by G6PD inhibition or knockdown. Importantly, RNA-sequence analysis of aortic tissue from G6PDdeficient mice revealed uniform increases in VSMC-restricted genes, particularly those regulated by the MYOCD-serum response factor (SRF) switch. Conversely, expression of Krüppel-like factor 4 (KLF4) is decreased by G6PD inhibition. Interestingly, the G6PD inhibitioninduced expression of miR-1 and contractile proteins was blocked by Rp-β-phenyl-1,N2-etheno-8-bromo-guanosine-3’,5’-cyclic monophosphorothioate, a PKG inhibitor. On the other hand, MYOCD and miR-143 levels are increased by G6PD inhibition through a PKG-independent manner. Furthermore, blood pressure was lower in the G6PD-deficient compared with wild-type mice. Therefore, our results suggest that the expression of VSMC contractile proteins induced by G6PD inhibition occurs via PKG1α-dependent and-independent pathways.

Original languageEnglish (US)
Pages (from-to)H904-H912
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume311
Issue number4
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Glucosephosphate Dehydrogenase Deficiency
Cyclic GMP-Dependent Protein Kinases
Contractile Proteins
Glucosephosphate Dehydrogenase
Vascular Smooth Muscle
Smooth Muscle Myocytes
Serum Response Factor
Blood Pressure
RNA Sequence Analysis
Guanosine
Protein Kinase Inhibitors
Blood Vessels
Cell Differentiation
Phenotype

Keywords

  • Epigenetics
  • Metabolism
  • NADPH redox
  • Pentose phosphate pathway
  • Protein kinase G
  • RNA-seq
  • Vascular smooth muscle phenotype

ASJC Scopus subject areas

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

Cite this

Vascular smooth muscle cell contractile protein expression is increased through protein kinase G-dependent and-independent pathways by glucose-6-phosphate dehydrogenase inhibition and deficiency. / Chettimada, Sukrutha; Joshi, Sachindra Raj; Dhagia, Vidhi; Aiezza, Alessandro; Lincoln, Thomas M.; Gupte, Rakhee; Miano, Joseph M.; Gupte, Sachin A.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 311, No. 4, 01.01.2016, p. H904-H912.

Research output: Contribution to journalArticle

Chettimada, Sukrutha ; Joshi, Sachindra Raj ; Dhagia, Vidhi ; Aiezza, Alessandro ; Lincoln, Thomas M. ; Gupte, Rakhee ; Miano, Joseph M. ; Gupte, Sachin A. / Vascular smooth muscle cell contractile protein expression is increased through protein kinase G-dependent and-independent pathways by glucose-6-phosphate dehydrogenase inhibition and deficiency. In: American Journal of Physiology - Heart and Circulatory Physiology. 2016 ; Vol. 311, No. 4. pp. H904-H912.
@article{3c6da530a07641449c45d9923177de3d,
title = "Vascular smooth muscle cell contractile protein expression is increased through protein kinase G-dependent and-independent pathways by glucose-6-phosphate dehydrogenase inhibition and deficiency",
abstract = "Homeostatic control of vascular smooth muscle cell (VSMC) differentiation is critical for contractile activity and regulation of blood flow. Recently, we reported that precontracted blood vessels are relaxed and the phenotype of VSMC is regulated from a synthetic to contractile state by glucose-6-phosphate dehydrogenase (G6PD) inhibition. In the current study, we investigated whether the increase in the expression of VSMC contractile proteins by inhibition and knockdown of G6PD is mediated through a protein kinase G (PKG)-dependent pathway and whether it regulates blood pressure. We found that the expression of VSMC-restricted contractile proteins, myocardin (MYOCD), and miR-1 and miR-143 are increased by G6PD inhibition or knockdown. Importantly, RNA-sequence analysis of aortic tissue from G6PDdeficient mice revealed uniform increases in VSMC-restricted genes, particularly those regulated by the MYOCD-serum response factor (SRF) switch. Conversely, expression of Kr{\"u}ppel-like factor 4 (KLF4) is decreased by G6PD inhibition. Interestingly, the G6PD inhibitioninduced expression of miR-1 and contractile proteins was blocked by Rp-β-phenyl-1,N2-etheno-8-bromo-guanosine-3’,5’-cyclic monophosphorothioate, a PKG inhibitor. On the other hand, MYOCD and miR-143 levels are increased by G6PD inhibition through a PKG-independent manner. Furthermore, blood pressure was lower in the G6PD-deficient compared with wild-type mice. Therefore, our results suggest that the expression of VSMC contractile proteins induced by G6PD inhibition occurs via PKG1α-dependent and-independent pathways.",
keywords = "Epigenetics, Metabolism, NADPH redox, Pentose phosphate pathway, Protein kinase G, RNA-seq, Vascular smooth muscle phenotype",
author = "Sukrutha Chettimada and Joshi, {Sachindra Raj} and Vidhi Dhagia and Alessandro Aiezza and Lincoln, {Thomas M.} and Rakhee Gupte and Miano, {Joseph M.} and Gupte, {Sachin A.}",
year = "2016",
month = "1",
day = "1",
doi = "10.1152/ajpheart.00335.2016",
language = "English (US)",
volume = "311",
pages = "H904--H912",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - Vascular smooth muscle cell contractile protein expression is increased through protein kinase G-dependent and-independent pathways by glucose-6-phosphate dehydrogenase inhibition and deficiency

AU - Chettimada, Sukrutha

AU - Joshi, Sachindra Raj

AU - Dhagia, Vidhi

AU - Aiezza, Alessandro

AU - Lincoln, Thomas M.

AU - Gupte, Rakhee

AU - Miano, Joseph M.

AU - Gupte, Sachin A.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Homeostatic control of vascular smooth muscle cell (VSMC) differentiation is critical for contractile activity and regulation of blood flow. Recently, we reported that precontracted blood vessels are relaxed and the phenotype of VSMC is regulated from a synthetic to contractile state by glucose-6-phosphate dehydrogenase (G6PD) inhibition. In the current study, we investigated whether the increase in the expression of VSMC contractile proteins by inhibition and knockdown of G6PD is mediated through a protein kinase G (PKG)-dependent pathway and whether it regulates blood pressure. We found that the expression of VSMC-restricted contractile proteins, myocardin (MYOCD), and miR-1 and miR-143 are increased by G6PD inhibition or knockdown. Importantly, RNA-sequence analysis of aortic tissue from G6PDdeficient mice revealed uniform increases in VSMC-restricted genes, particularly those regulated by the MYOCD-serum response factor (SRF) switch. Conversely, expression of Krüppel-like factor 4 (KLF4) is decreased by G6PD inhibition. Interestingly, the G6PD inhibitioninduced expression of miR-1 and contractile proteins was blocked by Rp-β-phenyl-1,N2-etheno-8-bromo-guanosine-3’,5’-cyclic monophosphorothioate, a PKG inhibitor. On the other hand, MYOCD and miR-143 levels are increased by G6PD inhibition through a PKG-independent manner. Furthermore, blood pressure was lower in the G6PD-deficient compared with wild-type mice. Therefore, our results suggest that the expression of VSMC contractile proteins induced by G6PD inhibition occurs via PKG1α-dependent and-independent pathways.

AB - Homeostatic control of vascular smooth muscle cell (VSMC) differentiation is critical for contractile activity and regulation of blood flow. Recently, we reported that precontracted blood vessels are relaxed and the phenotype of VSMC is regulated from a synthetic to contractile state by glucose-6-phosphate dehydrogenase (G6PD) inhibition. In the current study, we investigated whether the increase in the expression of VSMC contractile proteins by inhibition and knockdown of G6PD is mediated through a protein kinase G (PKG)-dependent pathway and whether it regulates blood pressure. We found that the expression of VSMC-restricted contractile proteins, myocardin (MYOCD), and miR-1 and miR-143 are increased by G6PD inhibition or knockdown. Importantly, RNA-sequence analysis of aortic tissue from G6PDdeficient mice revealed uniform increases in VSMC-restricted genes, particularly those regulated by the MYOCD-serum response factor (SRF) switch. Conversely, expression of Krüppel-like factor 4 (KLF4) is decreased by G6PD inhibition. Interestingly, the G6PD inhibitioninduced expression of miR-1 and contractile proteins was blocked by Rp-β-phenyl-1,N2-etheno-8-bromo-guanosine-3’,5’-cyclic monophosphorothioate, a PKG inhibitor. On the other hand, MYOCD and miR-143 levels are increased by G6PD inhibition through a PKG-independent manner. Furthermore, blood pressure was lower in the G6PD-deficient compared with wild-type mice. Therefore, our results suggest that the expression of VSMC contractile proteins induced by G6PD inhibition occurs via PKG1α-dependent and-independent pathways.

KW - Epigenetics

KW - Metabolism

KW - NADPH redox

KW - Pentose phosphate pathway

KW - Protein kinase G

KW - RNA-seq

KW - Vascular smooth muscle phenotype

UR - http://www.scopus.com/inward/record.url?scp=84990062836&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84990062836&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00335.2016

DO - 10.1152/ajpheart.00335.2016

M3 - Article

C2 - 27521420

AN - SCOPUS:84990062836

VL - 311

SP - H904-H912

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 4

ER -