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Bovine hereditary cardiomyopathy: an animal model of human dilated cardiomyopathy
T Eschenhagen1, M Diederich, S H Kluge
1Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg, FRG.
Insights
Bovine hereditary cardiomyopathy (bCMP) shows altered beta-adrenergic signaling, resembling human heart failure. This study highlights bCMP as a valuable model for dilated cardiomyopathy (DCM) research.
Area of Science:
- Cardiology
- Molecular Biology
- Animal Models
Background:
- Bovine hereditary cardiomyopathy (bCMP) shares clinical similarities with human idiopathic dilated cardiomyopathy (DCM).
- Understanding the molecular mechanisms underlying bCMP is crucial for its use as a model for human heart disease.
Purpose of the Study:
- To investigate the isometric force of contraction, catecholamine levels, adrenoceptor density, Gi proteins, and adenylyl cyclase activity in bCMP.
- To compare these parameters between bCMP and control hearts.
Main Methods:
- Isometric force of contraction measurements in right ventricular trabeculae.
- Quantification of plasma and tissue catecholamines.
- Assessment of beta- and alpha 1-adrenoceptor density and binding affinity.
- Measurement of Gi proteins and adenylyl cyclase activity.
Main Results:
- Decreased isoprenaline potency (8-fold) and unchanged maximal inotropic effect in bCMP.
- Increased plasma noradrenaline (240%) and dopamine (105-218%), with decreased tissue noradrenaline (36-63%) and adrenaline (58-69%).
- Drastic reduction in beta-adrenoceptor density (90%) with unchanged binding affinity; alpha-adrenoceptor unchanged.
- Increased Gi proteins (28-99%) and decreased basal and stimulated adenylyl cyclase activity (26-66%).
Conclusions:
- bCMP exhibits marked sympatho-adrenergic system activation, beta-adrenoceptor downregulation, Gi protein upregulation, and adenylyl cyclase desensitization.
- These alterations mirror those found in human heart failure and DCM.
- bCMP serves as a suitable animal model for human DCM due to its genetic basis and pathological similarities.
Unlabelled:
Bovine hereditary cardiomyopathy (bCMP) displays clinical characteristics of human idiopathic dilated cardiomyopathy (DCM). We studied isometric force of contraction in right ventricular trabeculae, plasma and tissue catecholamines, beta- and alpha 1-adrenoceptor density, Gi proteins and adenylyl cyclase activity in eight hearts with bCMP and eight control hearts (right and left atria and ventricles each).
Results:
Compared to control, the potency of isoprenaline in bCMP was eight-fold decreased, whereas the maximal positive inotropic effect of isoprenaline as well as the efficacy and potency of calcium were unchanged. Plasma noradrenaline was increased by 240%. Tissue noradrenaline and adrenaline were decreased by 36-63% and 58-69%, whereas dopamine was increased by 105-218%. beta-adrenoceptor density was drastically reduced by 90%, but binding affinity was unchanged. alpha-Adrenoceptor density and binding affinity were unchanged. Total PTX-substrates were increased in bCMP by 28-99%. Basal adenylyl cyclase activity was decreased by 36-47%. Similarly, stimulation by GTP, GMPPNP, isoprenaline, sodium fluoride, manganese or forskolin was attenuated by 26-62% (atria) and 45-66% (ventricles). In conclusion, we found marked activation of the sympatho-adrenergic system, downregulation of beta-adrenoceptors, upregulation of Gi proteins, global desensitization of adenylyl cyclase and selective subsensitivity to beta-adrenergic inotropic stimulation. These results closely resemble the characteristic alterations in the beta-adrenoceptor-G protein-adenylyl cyclase pathway in human heart failure, indicating that they are general features of heart failure. The similarity to human DCM, the inheritance and the availability of large tissue samples make bCMP a suitable model for human DCM.