Angiogenesis therapy with human tissue kallikrein for the treatment of ischemic diseases

C. Emanueli, Paolo Madeddu

Research output: Contribution to journalArticle

Abstract

Angiogenesis is essential for the repair of wounds and tissues damaged by ischemia. The regenerative process is tightly regulated by master angiogenic factors, cytokines and the downstream mediator NO. In addition, modulators of vascular growth, such as COX-2-generated prostanoids, contribute to the process by stabilizing the hypoxia-inducible factor and stimulating the expression of VEGF. Recently, we discovered that human tissue kallikrein, a member of the serine proteinase superfamily, possesses potent angiogenic effects. It has been categorized as a pleiotropic angiogenic agent acting via enzymatic cleavage of kininogen and subsequent release of kinin peptides. Kinins bind G-protein coupled receptors, subtype B 1 and B 2, and exert proliferative effects on endothelial cells via an lP3K-Akt-NO mediated mechanism independent of VEGF. In addition, kinins stimulate the release of angiogenic prostacyclin. Gene transfer of human tissue kallikrein rescues ischemic tissues in otherwise normal mice, as well as in hypertensive or diabetic animals. In addition, prophylactic gene delivery of tissue kallikrein to diabetic skeletal muscles prevents the development of microangiopathy and stimulates collateralization, thus protecting from the consequences of supervening arterial occlusion. Human tissue kallikrein could represent a new therapeutic agent, complementary or alternative to VEGF for the treatment of ischemia-related diseases.

Original languageEnglish
Pages (from-to)679-687
Number of pages9
JournalArchives des Maladies du Coeur et des Vaisseaux
Volume97
Issue number6
Publication statusPublished - Jun 2004

Keywords

  • Angiogenesis
  • Diabetes
  • Endothelium
  • Gene therapy
  • Kallikrein
  • Kinins
  • VEGF

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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