Perivascular adipose tissue-derived relaxing factors

Release by peptide agonists via proteinase-activated receptor-2 (PAR2) and non-PAR2 mechanisms

Y. Li, K. Mihara, M. Saifeddine, A. Krawetz, D. Lau, H. Li, Hong Ding, Christopher Triggle, M. D. Hollenberg

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE We hypothesized that proteinase-activated receptor-2 (PAR2)-mediated vasorelaxation in murine aorta tissue can be due in part to the release of adipocyte-derived relaxing factors (ADRFs). EXPERIMENTAL APPROACH Aortic rings from obese TallyHo and C57Bl6 intact or PAR2-null mice either without or with perivascular adipose tissue (PVAT) were contracted with phenylephrine and relaxation responses to PAR2-selective activating peptides (PAR2-APs: SLIGRL-NH 2 and 2-furoyl-LIGRLO-NH 2), trypsin and to PAR2-inactive peptides (LRGILS-NH 2, 2-furoyl-OLRGIL-NH 2 and LSIGRL-NH 2) were measured. Relaxation was monitored in the absence or presence of inhibitors that either alone or in combination were previously shown to inhibit ADRF-mediated responses: L-NAME (NOS), indomethacin (COX), ODQ (guanylate cyclase), catalase (H 2O 2) and the K + channel-targeted reagents, apamin, charybdotoxin, 4-aminopyridine and glibenclamide. KEY RESULTS Endothelium-intact PVAT-free preparations did not respond to PAR2-inactive peptides (LRGILS-NH 2, LSIGRL-NH 2, 2-furoyl-OLRGIL-NH 2), whereas active PAR2-APs (SLIGRL-NH 2; 2-furoyl-LIGRLO-NH 2) caused an L-NAME-inhibited relaxation. However, in PVAT-containing preparations treated with L-NAME/ODQ/indomethacin together, both PAR2-APs and trypsin caused relaxant responses in PAR2-intact, but not PAR2-null-derived tissues. The PAR2-induced PVAT-dependent relaxation (SLIGRL-NH 2) persisted in the presence of apamin plus charybdotoxin, 4-aminopyridine and glibenclamide, but was blocked by catalase, implicating a role for H 2O 2. Surprisingly, the PAR2-inactive peptides, LRGILS-NH 2 and 2-furoyl-OLRGIL-NH 2 (but not LSIGRL-NH 2), caused relaxation in PVAT-containing preparations from both PAR2-null and PAR2-intact (C57Bl, TallyHo) mice. The LRGILS-NH 2-induced relaxation was distinct from the PAR2 response, being blocked by 4-aminopyridine, but not catalase. CONCLUSIONS Distinct ADRFs that may modulate vascular tone in pathophysiological settings can be released from murine PVAT by both PAR2-dependent and PAR2-independent mechanisms.

Original languageEnglish
Pages (from-to)1990-2002
Number of pages13
JournalBritish Journal of Pharmacology
Volume164
Issue number8
DOIs
Publication statusPublished - Dec 2011

Fingerprint

PAR-2 Receptor
Adipose Tissue
Peptides
seryl-leucyl-isoleucyl-glycyl-arginyl-leucine
4-Aminopyridine
NG-Nitroarginine Methyl Ester
Adipocytes
Catalase
Charybdotoxin
Apamin
Glyburide
Indomethacin
Trypsin

Keywords

  • adipocyte-derived relaxing factor
  • catalase
  • hydrogen peroxide
  • ion channels
  • mouse
  • PAR2
  • perivascular adipose tissue
  • potassium channels
  • protease-activated receptors
  • proteinase-activated receptors
  • relaxation

ASJC Scopus subject areas

  • Pharmacology

Cite this

Perivascular adipose tissue-derived relaxing factors : Release by peptide agonists via proteinase-activated receptor-2 (PAR2) and non-PAR2 mechanisms. / Li, Y.; Mihara, K.; Saifeddine, M.; Krawetz, A.; Lau, D.; Li, H.; Ding, Hong; Triggle, Christopher; Hollenberg, M. D.

In: British Journal of Pharmacology, Vol. 164, No. 8, 12.2011, p. 1990-2002.

Research output: Contribution to journalArticle

@article{a7a98ba1cb8a416ab83a72651d7b7750,
title = "Perivascular adipose tissue-derived relaxing factors: Release by peptide agonists via proteinase-activated receptor-2 (PAR2) and non-PAR2 mechanisms",
abstract = "BACKGROUND AND PURPOSE We hypothesized that proteinase-activated receptor-2 (PAR2)-mediated vasorelaxation in murine aorta tissue can be due in part to the release of adipocyte-derived relaxing factors (ADRFs). EXPERIMENTAL APPROACH Aortic rings from obese TallyHo and C57Bl6 intact or PAR2-null mice either without or with perivascular adipose tissue (PVAT) were contracted with phenylephrine and relaxation responses to PAR2-selective activating peptides (PAR2-APs: SLIGRL-NH 2 and 2-furoyl-LIGRLO-NH 2), trypsin and to PAR2-inactive peptides (LRGILS-NH 2, 2-furoyl-OLRGIL-NH 2 and LSIGRL-NH 2) were measured. Relaxation was monitored in the absence or presence of inhibitors that either alone or in combination were previously shown to inhibit ADRF-mediated responses: L-NAME (NOS), indomethacin (COX), ODQ (guanylate cyclase), catalase (H 2O 2) and the K + channel-targeted reagents, apamin, charybdotoxin, 4-aminopyridine and glibenclamide. KEY RESULTS Endothelium-intact PVAT-free preparations did not respond to PAR2-inactive peptides (LRGILS-NH 2, LSIGRL-NH 2, 2-furoyl-OLRGIL-NH 2), whereas active PAR2-APs (SLIGRL-NH 2; 2-furoyl-LIGRLO-NH 2) caused an L-NAME-inhibited relaxation. However, in PVAT-containing preparations treated with L-NAME/ODQ/indomethacin together, both PAR2-APs and trypsin caused relaxant responses in PAR2-intact, but not PAR2-null-derived tissues. The PAR2-induced PVAT-dependent relaxation (SLIGRL-NH 2) persisted in the presence of apamin plus charybdotoxin, 4-aminopyridine and glibenclamide, but was blocked by catalase, implicating a role for H 2O 2. Surprisingly, the PAR2-inactive peptides, LRGILS-NH 2 and 2-furoyl-OLRGIL-NH 2 (but not LSIGRL-NH 2), caused relaxation in PVAT-containing preparations from both PAR2-null and PAR2-intact (C57Bl, TallyHo) mice. The LRGILS-NH 2-induced relaxation was distinct from the PAR2 response, being blocked by 4-aminopyridine, but not catalase. CONCLUSIONS Distinct ADRFs that may modulate vascular tone in pathophysiological settings can be released from murine PVAT by both PAR2-dependent and PAR2-independent mechanisms.",
keywords = "adipocyte-derived relaxing factor, catalase, hydrogen peroxide, ion channels, mouse, PAR2, perivascular adipose tissue, potassium channels, protease-activated receptors, proteinase-activated receptors, relaxation",
author = "Y. Li and K. Mihara and M. Saifeddine and A. Krawetz and D. Lau and H. Li and Hong Ding and Christopher Triggle and Hollenberg, {M. D.}",
year = "2011",
month = "12",
doi = "10.1111/j.1476-5381.2011.01501.x",
language = "English",
volume = "164",
pages = "1990--2002",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "8",

}

TY - JOUR

T1 - Perivascular adipose tissue-derived relaxing factors

T2 - Release by peptide agonists via proteinase-activated receptor-2 (PAR2) and non-PAR2 mechanisms

AU - Li, Y.

AU - Mihara, K.

AU - Saifeddine, M.

AU - Krawetz, A.

AU - Lau, D.

AU - Li, H.

AU - Ding, Hong

AU - Triggle, Christopher

AU - Hollenberg, M. D.

PY - 2011/12

Y1 - 2011/12

N2 - BACKGROUND AND PURPOSE We hypothesized that proteinase-activated receptor-2 (PAR2)-mediated vasorelaxation in murine aorta tissue can be due in part to the release of adipocyte-derived relaxing factors (ADRFs). EXPERIMENTAL APPROACH Aortic rings from obese TallyHo and C57Bl6 intact or PAR2-null mice either without or with perivascular adipose tissue (PVAT) were contracted with phenylephrine and relaxation responses to PAR2-selective activating peptides (PAR2-APs: SLIGRL-NH 2 and 2-furoyl-LIGRLO-NH 2), trypsin and to PAR2-inactive peptides (LRGILS-NH 2, 2-furoyl-OLRGIL-NH 2 and LSIGRL-NH 2) were measured. Relaxation was monitored in the absence or presence of inhibitors that either alone or in combination were previously shown to inhibit ADRF-mediated responses: L-NAME (NOS), indomethacin (COX), ODQ (guanylate cyclase), catalase (H 2O 2) and the K + channel-targeted reagents, apamin, charybdotoxin, 4-aminopyridine and glibenclamide. KEY RESULTS Endothelium-intact PVAT-free preparations did not respond to PAR2-inactive peptides (LRGILS-NH 2, LSIGRL-NH 2, 2-furoyl-OLRGIL-NH 2), whereas active PAR2-APs (SLIGRL-NH 2; 2-furoyl-LIGRLO-NH 2) caused an L-NAME-inhibited relaxation. However, in PVAT-containing preparations treated with L-NAME/ODQ/indomethacin together, both PAR2-APs and trypsin caused relaxant responses in PAR2-intact, but not PAR2-null-derived tissues. The PAR2-induced PVAT-dependent relaxation (SLIGRL-NH 2) persisted in the presence of apamin plus charybdotoxin, 4-aminopyridine and glibenclamide, but was blocked by catalase, implicating a role for H 2O 2. Surprisingly, the PAR2-inactive peptides, LRGILS-NH 2 and 2-furoyl-OLRGIL-NH 2 (but not LSIGRL-NH 2), caused relaxation in PVAT-containing preparations from both PAR2-null and PAR2-intact (C57Bl, TallyHo) mice. The LRGILS-NH 2-induced relaxation was distinct from the PAR2 response, being blocked by 4-aminopyridine, but not catalase. CONCLUSIONS Distinct ADRFs that may modulate vascular tone in pathophysiological settings can be released from murine PVAT by both PAR2-dependent and PAR2-independent mechanisms.

AB - BACKGROUND AND PURPOSE We hypothesized that proteinase-activated receptor-2 (PAR2)-mediated vasorelaxation in murine aorta tissue can be due in part to the release of adipocyte-derived relaxing factors (ADRFs). EXPERIMENTAL APPROACH Aortic rings from obese TallyHo and C57Bl6 intact or PAR2-null mice either without or with perivascular adipose tissue (PVAT) were contracted with phenylephrine and relaxation responses to PAR2-selective activating peptides (PAR2-APs: SLIGRL-NH 2 and 2-furoyl-LIGRLO-NH 2), trypsin and to PAR2-inactive peptides (LRGILS-NH 2, 2-furoyl-OLRGIL-NH 2 and LSIGRL-NH 2) were measured. Relaxation was monitored in the absence or presence of inhibitors that either alone or in combination were previously shown to inhibit ADRF-mediated responses: L-NAME (NOS), indomethacin (COX), ODQ (guanylate cyclase), catalase (H 2O 2) and the K + channel-targeted reagents, apamin, charybdotoxin, 4-aminopyridine and glibenclamide. KEY RESULTS Endothelium-intact PVAT-free preparations did not respond to PAR2-inactive peptides (LRGILS-NH 2, LSIGRL-NH 2, 2-furoyl-OLRGIL-NH 2), whereas active PAR2-APs (SLIGRL-NH 2; 2-furoyl-LIGRLO-NH 2) caused an L-NAME-inhibited relaxation. However, in PVAT-containing preparations treated with L-NAME/ODQ/indomethacin together, both PAR2-APs and trypsin caused relaxant responses in PAR2-intact, but not PAR2-null-derived tissues. The PAR2-induced PVAT-dependent relaxation (SLIGRL-NH 2) persisted in the presence of apamin plus charybdotoxin, 4-aminopyridine and glibenclamide, but was blocked by catalase, implicating a role for H 2O 2. Surprisingly, the PAR2-inactive peptides, LRGILS-NH 2 and 2-furoyl-OLRGIL-NH 2 (but not LSIGRL-NH 2), caused relaxation in PVAT-containing preparations from both PAR2-null and PAR2-intact (C57Bl, TallyHo) mice. The LRGILS-NH 2-induced relaxation was distinct from the PAR2 response, being blocked by 4-aminopyridine, but not catalase. CONCLUSIONS Distinct ADRFs that may modulate vascular tone in pathophysiological settings can be released from murine PVAT by both PAR2-dependent and PAR2-independent mechanisms.

KW - adipocyte-derived relaxing factor

KW - catalase

KW - hydrogen peroxide

KW - ion channels

KW - mouse

KW - PAR2

KW - perivascular adipose tissue

KW - potassium channels

KW - protease-activated receptors

KW - proteinase-activated receptors

KW - relaxation

UR - http://www.scopus.com/inward/record.url?scp=81855180535&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81855180535&partnerID=8YFLogxK

U2 - 10.1111/j.1476-5381.2011.01501.x

DO - 10.1111/j.1476-5381.2011.01501.x

M3 - Article

VL - 164

SP - 1990

EP - 2002

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 8

ER -