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Extracellular-Nitric Oxide-Mediated Platelet-cGMP Production in Type 2 Diabetics Correlates Inversely with Plasma Membrane Cholesterol Levels

¹Department of Chemistry & Biochemistry, University of Windsor, Windsor, Ontario, Canada.

²Institute of Biochemistry, Università Politecnica delle Marche, Ancona, Italy

³ Current address: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA

⁴ Current address: Harvard Institute of Proteomics, Harvard Medical School, 320 Charles Street, Cambridge, Massachusetts 02141, USA

*Corresponding Author:

Bulent Mutus

Department of Chemistry & Biochemistry

University of Windsor

Windsor Ontario, Canada N9B 3P4.

Phone: (519) 253-3000 ext. 3533

Fax: (519) 973-7098

E-mail: mutusb@uwindsor.ca

Abstract

Recently, we showed that the diffusion of nitric oxide (NO) and NO-mediated signaling was affected by the levels of plasma membrane cholesterol in fibroblasts [1].  The generality of these observations, which would imply that perturbations in NO-signaling mediated by increased membrane cholesterol levels, could be a common pathological trigger in vascular cells, was tested in platelets from normal and dyslipidemic type 2 diabetic (T2D) subjects. Plasma LDL-cholesterol correlated directly with platelet plasma membrane cholesterol (Y=0.28X+0.16; R²=0.39). The average platelet plasma membrane cholesterol concentration was ~2-fold larger in T2D than in control subjects (P<0.05). Cyclic GMP production in response to exogenous NO was ~4-fold larger in controls than in T2D (P<0.05). Artificial elevation of membrane cholesterol resulted in ~50 % decrease in the initial rates of NO-uptake. Elevated plasma cholesterol could be a contributing factor to T2D-induced platelet hyperactivity, since it correlated with increased plasma membrane cholesterol, the attenuation of NO-diffusion into platelets and the lowering of cGMP biosynthesis.  

Keywords:  nitric oxide; platelet plasma membrane cholesterol; type 2 diabetes nitric oxide-mediated cyclic GMP production; trans-membrane nitric oxide diffusion.

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