S-nitrosoglutathione acts as a small molecule modulator of human fibrin clot architecture

Ryon M. Bateman, Christopher G. Ellis, Makoto Suematsu, Keith R. Walley

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Altered fibrin clot architecture is increasingly associated with cardiovascular diseases; yet, little is known about how fibrin networks are affected by small molecules that alter fibrinogen structure. Based on previous evidence that S-nitrosoglutathione (GSNO) alters fibrinogen secondary structure and fibrin polymerization kinetics, we hypothesized that GSNO would alter fibrin microstructure. Methodology/Principal Findings: Accordingly, we treated human platelet-poor plasma with GSNO (0.01-3.75 mM) and imaged thrombin induced fibrin networks using multiphoton microscopy. Using custom designed computer software, we analyzed fibrin microstructure for changes in structural features including fiber density, diameter, branch point density, crossing fibers and void area. We report for the first time that GSNO dose-dependently decreased fibrin density until complete network inhibition was achieved. At low dose GSNO, fiber diameter increased 25%, maintaining clot void volume at approximately 70%. However, at high dose GSNO, abnormal irregularly shaped fibrin clusters with high fluorescence intensity cores were detected and clot void volume increased dramatically. Notwithstanding fibrin clusters, the clot remained stable, as fiber branching was insensitive to GSNO and there was no evidence of fiber motion within the network. Moreover, at the highest GSNO dose tested, we observed for the first time, that GSNO induced formation of fibrin agglomerates. Conclusions/Significance: Taken together, low dose GSNO modulated fibrin microstructure generating coarse fibrin networks with thicker fibers; however, higher doses of GSNO induced abnormal fibrin structures and fibrin agglomerates. Since GSNO maintained clot void volume, while altering fiber diameter it suggests that GSNO may modulate the remodeling or inhibition of fibrin networks over an optimal concentration range.

Original languageEnglish
Article numbere43660
JournalPLoS One
Volume7
Issue number8
DOIs
Publication statusPublished - 2012 Aug 20

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Fibrin Modulating Agents
S-Nitrosoglutathione
fibrin
Fibrin
Modulators
Molecules
Fibers
dosage
microstructure
fibrinogen
Fibrinogen
Microstructure

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

S-nitrosoglutathione acts as a small molecule modulator of human fibrin clot architecture. / Bateman, Ryon M.; Ellis, Christopher G.; Suematsu, Makoto; Walley, Keith R.

In: PLoS One, Vol. 7, No. 8, e43660, 20.08.2012.

Research output: Contribution to journalArticle

Bateman, Ryon M. ; Ellis, Christopher G. ; Suematsu, Makoto ; Walley, Keith R. / S-nitrosoglutathione acts as a small molecule modulator of human fibrin clot architecture. In: PLoS One. 2012 ; Vol. 7, No. 8.
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abstract = "Background: Altered fibrin clot architecture is increasingly associated with cardiovascular diseases; yet, little is known about how fibrin networks are affected by small molecules that alter fibrinogen structure. Based on previous evidence that S-nitrosoglutathione (GSNO) alters fibrinogen secondary structure and fibrin polymerization kinetics, we hypothesized that GSNO would alter fibrin microstructure. Methodology/Principal Findings: Accordingly, we treated human platelet-poor plasma with GSNO (0.01-3.75 mM) and imaged thrombin induced fibrin networks using multiphoton microscopy. Using custom designed computer software, we analyzed fibrin microstructure for changes in structural features including fiber density, diameter, branch point density, crossing fibers and void area. We report for the first time that GSNO dose-dependently decreased fibrin density until complete network inhibition was achieved. At low dose GSNO, fiber diameter increased 25{\%}, maintaining clot void volume at approximately 70{\%}. However, at high dose GSNO, abnormal irregularly shaped fibrin clusters with high fluorescence intensity cores were detected and clot void volume increased dramatically. Notwithstanding fibrin clusters, the clot remained stable, as fiber branching was insensitive to GSNO and there was no evidence of fiber motion within the network. Moreover, at the highest GSNO dose tested, we observed for the first time, that GSNO induced formation of fibrin agglomerates. Conclusions/Significance: Taken together, low dose GSNO modulated fibrin microstructure generating coarse fibrin networks with thicker fibers; however, higher doses of GSNO induced abnormal fibrin structures and fibrin agglomerates. Since GSNO maintained clot void volume, while altering fiber diameter it suggests that GSNO may modulate the remodeling or inhibition of fibrin networks over an optimal concentration range.",
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