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Matrix metalloproteinases cleave the beta2-adrenergic receptor in spontaneously hypertensive rats

Stephen F Rodrigues1, Edward D Tran, Zuleica B Fortes

  • 1Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

American Journal of Physiology. Heart and Circulatory Physiology
|April 13, 2010
PubMed

Insights

Matrix metalloproteinases (MMPs) activity is elevated in hypertensive rats, leading to beta(2)-adrenergic receptor cleavage. This MMP-driven cleavage contributes to blood vessel dysfunction and increased blood pressure in spontaneously hypertensive rats.

Area of Science:

  • Cardiovascular Physiology
  • Biochemistry
  • Pharmacology

Background:

  • Spontaneously hypertensive rats (SHRs) exhibit enhanced matrix metalloproteinase (MMP) activity and membrane receptor cleavage compared to normotensive Wistar-Kyoto (WKY) rats.
  • The beta(2)-adrenergic receptor (beta(2)-AR) is known to be susceptible to MMP action.
  • SHR arterioles show an altered response to beta(2)-AR agonists and antagonists.

Purpose of the Study:

  • To investigate the hypothesis that MMPs in SHR plasma cleave the extracellular domain of beta(2)-AR.
  • To determine the role of MMPs in the reduced beta(2)-AR density and increased arteriolar tone observed in SHRs.

Main Methods:

  • In vivo assessment of vasoconstrictor responses to MMP-7 and MMP-9 injection in rats, with and without MMP inhibitors.
  • Ex vivo incubation of Wistar rat aorta and heart muscle with plasma from Wistar, WKY, and SHR rats, with and without MMP inhibitors (doxycycline, EDTA).
  • Immunohistochemical analysis to quantify the density of extracellular and intracellular beta(2)-AR domains.

Main Results:

  • MMP-7 and MMP-9 injection induced vasoconstriction, which was blocked by an MMP inhibitor.
  • The density of the extracellular beta(2)-AR domain was reduced in SHRs' aortic endothelial cells and cardiac microvessels compared to WKY or Wistar rats.
  • Exposure of control rat tissues to SHR plasma, but not WKY plasma, decreased extracellular beta(2)-AR density; this effect was prevented by MMP inhibitors.

Conclusions:

  • MMPs in SHR plasma contribute to the cleavage of the extracellular domain of beta(2)-AR in blood vessels.
  • This MMP-mediated beta(2)-AR cleavage may play a role in the increased arteriolar tone and hypertension observed in SHRs.
  • Targeting MMP activity could be a potential therapeutic strategy for managing hypertension.

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