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Cholesterol Enrichment Impairs Capacitative Calcium Entry, eNOS Phosphorylation & Shear Stress-Induced NO Production

Allison M Andrews1, Tenderano T Muzorewa2, Kelly A Zaccheo2

  • 1Department of Pathology & Laboratory Medicine, Lewis Katz School of Medicine at Temple University, 3500N. Broad St., Philadelphia, PA 19140, USA.

Cellular and Molecular Bioengineering
|February 1, 2017
PubMed

Insights

High cholesterol impairs nitric oxide (NO) production by disrupting calcium signaling in endothelial cells. This finding clarifies a key mechanism in early atherosclerosis development.

Area of Science:

  • Cardiovascular Biology
  • Cellular Signaling
  • Atherosclerosis Research

Background:

  • Endothelial dysfunction, marked by reduced nitric oxide (NO), is central to early atherosclerosis.
  • Hypercholesterolemia is a primary risk factor, linked to impaired flow-induced dilation.
  • The precise mechanism linking high cholesterol to decreased NO production remains unclear.

Purpose of the Study:

  • To investigate how cholesterol enrichment impacts endothelial nitric oxide synthase (eNOS) activation via calcium signaling.
  • To test the hypothesis that cholesterol affects capacitive calcium entry (CCE) and subsequently reduces NO production.

Main Methods:

  • Cholesterol enrichment of endothelial cells.
  • Measurement of eNOS phosphorylation and intracellular calcium responses to ATP stimulation.
  • Assessment of NO production under shear stress.
  • Analysis of capacitive calcium entry (CCE) function.

Main Results:

  • Cholesterol enrichment abolished ATP-induced eNOS phosphorylation.
  • Elevated cholesterol preferentially inhibited capacitive calcium entry (CCE).
  • Shear stress-induced NO production and eNOS phosphorylation were significantly attenuated by cholesterol enrichment.

Conclusions:

  • Cholesterol enrichment disrupts endothelial calcium signaling pathways, specifically inhibiting CCE.
  • This disruption leads to decreased eNOS activation and reduced NO production, contributing to endothelial dysfunction in hypercholesterolemia.
  • Findings elucidate a mechanism linking high cholesterol to impaired vascular function in early atherosclerosis.

Keywords:
AtherosclerosisCapacitative calcium entryCholesterolEndothelial cellsNitric oxideShear stress

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