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

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

Phenotypic plasticity of cardiovascular function during fetal development: mechanisms and consequences

Research Interests:

4

Project collaboration

Collaboration with Gunnar Cedersund, IKE/IMT and Elin Nyman, IKE

LCSB

5

Outline

Project and groups



The models

Future prospects

6

β-adrenoceptors in the heartCatecholamines 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

Chronic β-AR stimulation

Receptor desensitisation

Cardiac functionHEART FAILURE!

8Baspresentation LiU

Heart failure therapyBased on ACE inhibitors and β-blockers

β-blockade substantially improves pump function in the long term

9

« 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 »

Tilley and Rockman. Expert Rev.Cardiovasc.Ther. 4:417 (2006)

Aims of our workCollect experimental data on βAR desensitization

Construct and optimize a βAR signaling model

10

Outline

Project and groups



The models

Future prospects

11

Modelling Methodology

Mechanistic model, ODEs

Time series data

Iteratively with experiments

Hypothesis Model

Optimization

Experiments

12

Outline

Project and groups



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

26

1 2

29

1 2

32

Theoretical data

Return of signal

Experimental data

Predict resting time

Original model

Minimal models

All smaller models

33

Outline

Project and groups



The models

Future prospects

34

Future prospectsStudy 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?

www.liu.se

Thank you for your attention!

Questions?

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

Documents

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