The relationship between the MMP system, adrenoceptors and phosphoprotein phosphatases

Br J Pharmacol. 2012 Jun;166(4):1225-43. doi: 10.1111/j.1476-5381.2012.01917.x.

Abstract

The MMPs and their inhibitors [tissue inhibitor of MMPs (TIMPs)] form the mainstay of extracellular matrix homeostasis. They are expressed in response to numerous stimuli including cytokines and GPCR activation. This review highlights the importance of adrenoceptors and phosphoprotein phosphatases (PPP) in regulating MMPs in the cardiovascular system, which may help explain some of the beneficial effects of targeting the adrenoceptor system in tissue remodelling and will establish emerging crosstalk between these three systems. Although α- and β-adrenoceptor activation increases MMP but decreases TIMP expression, MMPs are implicated in the growth stimulatory effects of adrenoceptor activation through transactivation of epidermal growth factor receptor. Furthermore, they have recently been found to catalyse the proteolysis of β-adrenoceptors and modulate vascular tone. While the mechanisms underpinning these effects are not well defined, reversible protein phosphorylation by kinases and phosphatases may be key. In particular, PPP (Ser/Thr phosphatases) are not only critical in resensitization and internalization of adrenoceptors but also modulate MMP expression. The interrelationship is complex as isoprenaline (ISO) inhibits okadaic acid [phosphoprotein phosphatase type 1/phosphoprotein phosphatase type 2A (PP2A) inhibitor]-mediated MMP expression. While this may be simply due to its ability to transiently increase PP2A activity, there is evidence for MMP-9 that ISO prevents okadaic acid-mediated expression of MMP-9 through a β-arrestin, NF-κB-dependent pathway, which is abolished by knock-down of PP2A. It is essential that crosstalk between MMPs, adrenoceptors and PPP are investigated further as it will provide important insight into how adrenoceptors modulate cardiovascular remodelling, and may identify new targets for pharmacological manipulation of the MMP system.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adrenergic Agonists / pharmacology
  • Adrenergic Agonists / therapeutic use
  • Adrenergic Antagonists / pharmacology
  • Adrenergic Antagonists / therapeutic use
  • Animals
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / chemistry
  • Matrix Metalloproteinases / genetics
  • Matrix Metalloproteinases / metabolism*
  • Molecular Targeted Therapy
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / chemistry
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Transport / drug effects
  • Proteolysis / drug effects
  • Receptors, Adrenergic / metabolism*
  • Signal Transduction / drug effects

Substances

  • Adrenergic Agonists
  • Adrenergic Antagonists
  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Receptors, Adrenergic
  • Phosphoprotein Phosphatases
  • Matrix Metalloproteinases