Modelling of Cardiac β- adrenoceptor desensitisation to understand heart failure therapy

1. Modelling of Cardiac β-adrenoceptor desensitisation to understand heart failure therapy Karin Lundengård, CMIV Jordi Altimiras, IFM

2. Outline • Project and groups • βAR in the heart and heart failure therapy • Modeling methodology • The models • Future prospects

3. Altimiras' group at IFM Research Interests: Phenotypic plasticity of cardiovascular function during fetal development: mechanisms and consequences

4. Project collaboration • Collaboration with Gunnar Cedersund, IKE/IMT and Elin Nyman, IKE • LCSB

5. Outline • Project and groups • βAR in the heart and heart failure therapy • Modeling methodology • The models • Future prospects

6. β-adrenoceptors in the heart • Catecholamines are key stimulators of cardiac function (positive chronotropic and inotropic effects) by binding to β-adrenoceptors Loss of βAR sensitivity to adrenergic agonists occurs in heart failure

7. Cardiac function Release of catecholamines HEART FAILURE! Chronic β-AR stimulation Receptor desensitisation Cardiac function

8. Heart failure therapy • Based on ACE inhibitors and β-blockers • β-blockade substantially improves pump function in the long term Baspresentation LiU

9. Tilley and Rockman. Expert Rev.Cardiovasc.Ther. 4:417 (2006) • « An entire explanation for improved cardiac function in patients using β-blockers is unknown… » • « … and, in fact may be quite complicated, considering the numerous intracellular signaling pathways associated with β-adrenergic receptors » Aims of our work • Collect experimental data on βAR desensitization • Construct and optimize a βAR signaling model

10. Outline • Project and groups • βAR in the heart and heart failure therapy • Modeling methodology • The models • Future prospects

11. Modelling Methodology • Mechanistic model, ODEs • Time series data • Iteratively with experiments Optimization Hypothesis Model Experiments

12. Outline • Project and groups • βAR in the heart and heart failure therapy • Modeling methodology • The models • Future prospects

13. d(B1)/dt = k1d*B1int + k1c*B1p - kbas1*B1 - B1*(kiso+kip1)*H1 d(B1act)/dt = kbas1*B1 + B1*(kiso+kip1)*H1 - k1a*B1act*(kGRK*GRKact+PKAact) d(B1p)/dt = k1a*B1act*(kGRK*GRKact+PKAact) - (k1b+k1c)*B1p d(B1int)/dt = k1b*B1p – k1d*B1int d(B2)/dt = k2d*B2int + k2c*B2p - kbas2*B2 - B2*(kiso+kip2+kter)*H2 d(B2act)/dt = kbas2*B2 + B2*(kiso+kip2+kter)*H2 - k2a*B2act*(kGRK*GRKact+PKAact) d(B2p)/dt = k2a*B2act*(kGRK*GRKact+PKAact) - (k2b+k2c)*B2p d(B2int)/dt = k2b*B2p - k2d*B2int d(Gs)/dt = k3b*Gsact - k3a*Gs*(B1act+B2act) d(Gsact)/dt = k3a*Gs*(B1act+B2act) - k3b*Gsact d(Gi)/dt = k3d*Giact - k3c*B2p*Gi d(Giact)/dt = k3c*B2p*Gi - k3d*Giact d(AC)/dt = k4b*ACact - k4a*Gsact/(kinh+Giact)*AC d(ACact)/dt = k4a*Gsact/(kinh+Giact)*AC - k4b*ACact d(cAMP)/dt = cAMP0 + ACact*k5 – kPKA*PKAact*cAMP d(GRK)/dt = - cAMP*k6a*GRK + k6b*GRKact d(GRKact)/dt = cAMP*k6a*GRK - k6b*GRKact d(PKA)/dt = - cAMP*k6c*PKA + k6d*PKAact d(PKAact)/dt = cAMP*k6c*PKA - k6d*PKAact

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33. Outline • Project and groups • βAR in the heart and heart failure therapy • Modeling methodology • The models • Future prospects

34. Future prospects • Study β-AR desensitization and beta-blocker effects in the murine myocardial infarction model in collaboration with Prof. de Muinck, Clinical Physiology • Further development of the model to account for the effects of beta-blockade • Why don’t fetal βARs desensitize?

35. Thank you for your attention!Questions? www.liu.se