Beta-3 adrenergic receptors are upregulated in left ventricular myocardium of dogs with chronic heart failure

Document Type

Conference Proceeding

Publication Date

3-2020

Publication Title

J Am Coll Cardiol

Abstract

Background β-adrenergic receptors (ARs) belong to the superfamily of membrane proteins known as G-protein-coupled receptors. There are four subtypes of β-ARs-β1-AR, β2-AR, β3-AR and the β4-AR. The β1-AR is found primarily in the heart and comprises 75-80% of the β-ARs in the heart. The β2-ARs are also found in the heart and represent ~20% of total cardiac ARs. The β3-ARs are found minimally in the heart. The β4-AR is considered a low affinity state of the β1-AR, which awaits genetic and pharmacologic characterization. When stimulated, β1-ARs elicit a cAMP-dependent increase of contractility whereas stimulation of β2-ARs elicit cAMP-independent increase of contractility. In contrast, stimulation of the β3-ARs inhibits cardiac contraction. Heart Failure (HF) is associated with a near 50% reduction of β1-ARs and no change in the expression of β2-ARs. In this study, we examined mRNA and protein levels β3-ARs in LV myocardium of normal (NL) dogs and dogs with chronic HF (LV ejection fraction ≤35%). Methods Studies were performed in LV tissue obtained from 7 NL dogs and 7 dogs with HF produced by intracoronary microembolizations. mRNA expression of β3-ARs and GAPDH was measured in all dogs using real-time PCR. Protein level of β3-ARs and GAPDH was measured in SDS-extracts of LV tissue prepared from all dogs and subjected to Western blotting coupled with chemiluminescence detection and bands were quantified in densitometric units. Results There were no significant differences in levels of GAPDH mRNA and protein between NL dogs and HF dogs. mRNA expression of β3-ARs normalized to GAPDH was increased 3.1 fold in HF dogs compared to NL dogs. Protein levels of β3-ARs normalized to GAPDH were also markedly and significantly increased (~3.6 fold) in HF dogs compared to NL dogs 0.82 ± 0.05 vs. 0.23 ± 0.02, p<0.05). Conclusion β3-ARs expression and protein levels are markedly upregulated in LV myocardium of dogs with HF. This maladaptation, through its signaling pathway, likely contributes to the reduced LV function seen in HF. The results support recent observations of improved LV function in dogs with HF treated with β3-ARs blockers.

Volume

75

Issue

11

First Page

696

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