β-blockade abolishes the augmented cardiac tPA release induced by transactivation of heterodimerised bradykinin receptor-2 and β2-adrenergic receptor in vivo

Trude Aspelin; Morten Eriksen; Arnfinn Ilebekk; Alessandro Cataliotti; Cathrine Rein Carlson; Torstein Lyberg

doi:10.1160/th14-01-0059

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2014; 112(05): 951-959
DOI: 10.1160/th14-01-0059

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

β-blockade abolishes the augmented cardiac tPA release induced by transactivation of heterodimerised bradykinin receptor-2 and β₂-adrenergic receptor in vivo

Trude Aspelin

¹Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway

,

Morten Eriksen

²Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway

,

Arnfinn Ilebekk

²Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway

,

Alessandro Cataliotti

²Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway

,

Cathrine Rein Carlson

²Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway

³KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway

,

Torstein Lyberg

¹Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway

› Institutsangaben

Abstract

Summary

Bradykinin (BK) receptor-2 (B₂R) and β₂-adrenergic receptor (β₂AR) have been shown to form heterodimers in vitro. However, in vivo proofs of the functional effects of B2R-β₂AR heterodimerisation are missing. Both BK and adrenergic stimulation are known inducers of tPA release. Our goal was to demonstrate the existence of B₂R-β₂AR heterodimerisation in myocardium and to define its functional effect on cardiac release of tPA in vivo. We further investigated the effects of a non-selective β-blocker on this receptor interplay. To investigate functional effects of B₂R-β₂AR heterodimerisation (i. e. BK transactivation of β₂AR) in vivo, we induced serial electrical stimulation of cardiac sympathetic nerves (SS) in normal pigs that underwent concomitant BK infusion. Both SS and BK alone induced increases in cardiac tPA release. Importantly, despite B2R desensitisation, simultaneous BK infusion and SS (BK+SS) was characterised by 2.3 ± 0.3-fold enhanced tPA release compared to SS alone. When β-blockade (propranolol) was introduced prior to BK+SS, tPA release was inhibited. A persistent B₂R-β₂AR heterodimer was confirmed in BK-stimulated and nonstimulated left ventricular myocardium by immunoprecipitation studies and under non-reducing gel conditions. All together, these results strongly suggest BK transactivation of β₂AR leading to enhanced β₂AR-mediated release of tPA. Importantly, non-selective β-blockade inhibits both SS-induced release of tPA and the functional effects of B₂R-β₂AR heterodimerisation in vivo, which may have important clinical implications.

Keywords

Tissue plasminogen activator - receptor heterodimerisation - betablocker - bradykinin receptor-2 - beta-2-adrenergic receptor

Volltext

Referenzen

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