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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
1   Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway
,
Morten Eriksen
2   Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
,
Arnfinn Ilebekk
2   Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
,
Alessandro Cataliotti
2   Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
,
Cathrine Rein Carlson
2   Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
3   KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway
,
Torstein Lyberg
1   Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway
› Author Affiliations Financial support: Cathrine Rein Carlson is supported by the Norwegian Research Council.
Further Information

Publication History

Received: 20 January 2014

Accepted after major revision: 16 June 2014

Publication Date:
20 November 2017 (online)

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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

 

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