Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice

Nat Commun. 2015 Oct 7;6:8482. doi: 10.1038/ncomms9482.

Abstract

Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoates / pharmacology
  • Blood Pressure / drug effects
  • Cardiovascular System / drug effects
  • Cardiovascular System / metabolism*
  • Gene Knock-In Techniques
  • Guanylate Cyclase / genetics*
  • Heme / genetics*
  • Hypertension / genetics
  • Hypotension / chemically induced
  • Hypotension / genetics
  • Mice
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Nitric Oxide / metabolism*
  • Oxidative Stress / drug effects
  • Platelet Aggregation / drug effects
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Soluble Guanylyl Cyclase
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Benzoates
  • Receptors, Cytoplasmic and Nuclear
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • BAY 58-2667
  • Heme
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase