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Insulin increases NADH/NAD+ redox state, which stimulates guanylate cyclase in vascular smooth muscle

Andrew M Kahn1, Julius C Allen, Sui Zhang

  • 1Department of Medicine. The University of Texas Health Science Center, Houston 77225, USA.

American Journal of Hypertension
|April 10, 2002
PubMed
Abstract

Insights

Insulin boosts cyclic GMP (cGMP) in vascular smooth muscle cells (VSMCs) by altering cellular redox state, not by directly activating guanylate cyclase. This pathway may enhance nitric oxide availability.

Area of Science:

  • Biochemistry
  • Cellular Biology
  • Vascular Physiology

Background:

  • Insulin inhibits vascular smooth muscle cell (VSMC) contraction and migration.
  • This inhibition is mediated by increased cyclic guanosine monophosphate (cGMP) production in VSMCs expressing inducible nitric oxide synthase (iNOS).
  • The precise mechanism by which insulin stimulates guanylate cyclase activity remained unclear.

Purpose of the Study:

  • To elucidate the mechanism by which insulin stimulates guanylate cyclase activity in canine VSMCs.
  • To investigate the role of cellular redox state and metabolic pathways in insulin-mediated cGMP production.

Main Methods:

  • Primary canine VSMCs were cultured and treated with insulin.
  • Measurements included lactate-to-pyruvate ratio (LPR) to assess redox state (NADH/NAD+), cGMP production, iNOS activity, and cell contraction.
  • Specific inhibitors like NG-monomethyl-L-arginine (L-NMMA) and metabolic modulators (pyruvate, oxaloacetate) were used.

Main Results:

  • Insulin significantly increased cGMP production and the LPR in VSMCs with iNOS, indicating a shift in the NADH/NAD+ redox state.
  • Insulin's stimulation of cGMP was dependent on iNOS activity and the increased LPR, as blocking these pathways with L-NMMA or metabolic intermediates inhibited the effect.
  • Insulin did not directly stimulate guanylate cyclase activity in cells lacking iNOS, suggesting an indirect mechanism involving iNOS-derived nitric oxide.

Conclusions:

  • Insulin enhances cGMP production in VSMCs expressing iNOS by increasing the cellular NADH/NAD+ redox state.
  • This metabolic alteration likely increases the availability of nitric oxide (NO) from iNOS, leading to cGMP production.
  • The findings suggest an indirect mechanism where insulin modulates cellular metabolism to influence NO-cGMP signaling.

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