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The calcium-dependent protease calpain causes endothelial dysfunction in type 2 diabetes

Timothy J Stalker1, Yulan Gong, Rosario Scalia

  • 1Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107-6799, USA.

Diabetes
|March 29, 2005
PubMed

Insights

In diabetic rats, the protease calpain drives vascular inflammation and endothelial dysfunction by disrupting nitric oxide (NO) production. Inhibiting calpain activity improved vascular health, suggesting it as a potential therapeutic target for diabetic complications.

Area of Science:

  • Biochemistry
  • Physiology
  • Molecular Biology

Background:

  • Cardiovascular complications are a major cause of death in diabetic patients.
  • Endothelial dysfunction, linked to impaired nitric oxide (NO) synthase activity, contributes to diabetic vasculopathy.
  • The precise mechanisms underlying diabetic endothelial dysfunction remain unclear, hindering effective treatment.

Purpose of the Study:

  • To investigate the role of the calcium-dependent protease calpain in endothelial dysfunction and vascular inflammation in a genetic model of type 2 diabetes.
  • To explore calpain's impact on leukocyte trafficking, adhesion molecule expression, and nitric oxide (NO) bioavailability.
  • To determine if calpain inhibition can ameliorate these diabetes-associated vascular changes.

Main Methods:

  • Utilized Zucker diabetic fatty (ZDF) rats as a model for type 2 diabetes.
  • Assessed calpain activity and leukocyte trafficking in the microcirculation.
  • Administered calpain inhibitors to evaluate effects on leukocyte-endothelium interactions and adhesion molecule expression.
  • Measured in vivo endothelial NO availability using specialized techniques.
  • Employed immunoprecipitation to study the interaction between endothelial NO synthase (eNOS) and heat shock protein 90 (HSP90).

Main Results:

  • ZDF rats exhibited increased calpain activity and leukocyte trafficking in their microcirculation.
  • Calpain inhibition significantly reduced leukocyte-endothelium interactions and normalized increased adhesion molecule expression.
  • Endothelial NO levels were reduced by 60% in ZDF rats, an effect reversed by calpain inhibition.
  • Calpain activity led to the dissociation of eNOS and HSP90, impairing NO production.

Conclusions:

  • Calpain activation is a novel mechanism contributing to endothelial dysfunction and vascular inflammation in diabetes.
  • Inhibition of calpain activity demonstrates therapeutic potential for mitigating diabetic vascular complications.
  • Calpains represent a promising molecular target for future treatments aimed at preventing or treating diabetes-related cardiovascular issues.

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