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Myocardial-restricted ablation of the GTPase RAD results in a pro-adaptive heart response in mice.

ABSTRACT: Existing therapies to improve heart function target β-adrenergic receptor (β-AR) signaling and Ca²⁺ handling and often lead to adverse outcomes. This underscores an unmet need for positive inotropes that improve heart function without any adverse effects. The GTPase Ras associated with diabetes (RAD) regulates L-type Ca²⁺ channel (LTCC) current (I_Ca,L). Global RAD-knockout mice (gRAD^-/-) have elevated Ca²⁺ handling and increased cardiac hypertrophy, but RAD is expressed also in noncardiac tissues, suggesting the possibility that pathological remodeling is due also to noncardiac effects. Here, we engineered a myocardial-restricted inducible RAD-knockout mouse (RAD^Δ/Δ). Using an array of methods and techniques, including single-cell electrophysiological and calcium transient recordings, echocardiography, and radiotelemetry monitoring, we found that RAD deficiency results in a sustained increase of inotropy without structural or functional remodeling of the heart. I_Ca,L was significantly increased, with RAD loss conferring a β-AR-modulated phenotype on basal I_Ca,L Cardiomyocytes from RAD^Δ/Δ hearts exhibited enhanced cytosolic Ca²⁺ handling, increased contractile function, elevated sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2a) expression, and faster lusitropy. These results argue that myocardial RAD ablation promotes a beneficial elevation in Ca²⁺ dynamics, which would obviate a need for increased β-AR signaling to improve cardiac function.

SUBMITTER: Ahern BM

PROVIDER: S-EPMC6635439 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Myocardial-restricted ablation of the GTPase RAD results in a pro-adaptive heart response in mice.

Ahern Brooke M BM Levitan Bryana M BM Veeranki Sudhakar S Shah Mihir M Ali Nemat N Sebastian Andrea A Su Wen W Gong Ming C MC Li Jiayang J Stelzer Julian E JE Andres Douglas A DA Satin Jonathan J

The Journal of biological chemistry 20190530 28

Existing therapies to improve heart function target β-adrenergic receptor (β-AR) signaling and Ca2+ handling and often lead to adverse outcomes. This underscores an unmet need for positive inotropes that improve heart function without any adverse effects. The GTPase Ras associated with diabetes (RAD) regulates L-type Ca2+ channel (LTCC) current (ICa,L). Global RAD-knockout mice (gRAD-/-) have elevated Ca2+ handling and increased cardiac hype ...[more]

PMID: 31147441

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Project description:Sinoatrial node cardiomyocytes (SANcm) possess automatic, rhythmic electrical activity. SAN rate is influenced by autonomic nervous system input, including sympathetic nerve increases of heart rate (HR) via activation of β-adrenergic receptor signaling cascade (β-AR). L-type calcium channel (LTCC) activity contributes to membrane depolarization and is a central target of β-AR signaling. Recent studies revealed that the small G-protein Rad plays a central role in β-adrenergic receptor directed modulation of LTCC. These studies have identified a conserved mechanism in which β-AR stimulation results in PKA-dependent Rad phosphorylation: depletion of Rad from the LTCC complex, which is proposed to relieve the constitutive inhibition of CaV1.2 imposed by Rad association. Here, using a transgenic mouse model permitting conditional cardiomyocyte selective Rad ablation, we examine the contribution of Rad to the control of SANcm LTCC current (ICa,L) and sinus rhythm. Single cell analysis from a recent published database indicates that Rad is expressed in SANcm, and we show that SANcm ICa,L was significantly increased in dispersed SANcm following Rad silencing compared to those from CTRL hearts. Moreover, cRadKO SANcm ICa,L was not further increased with β-AR agonists. We also evaluated heart rhythm in vivo using radiotelemetered ECG recordings in ambulating mice. In vivo, intrinsic HR is significantly elevated in cRadKO. During the sleep phase cRadKO also show elevated HR, and during the active phase there is no significant difference. Rad-deletion had no significant effect on heart rate variability. These results are consistent with Rad governing LTCC function under relatively low sympathetic drive conditions to contribute to slower HR during the diurnal sleep phase HR. In the absence of Rad, the tonic modulated SANcm ICa,L promotes elevated sinus HR. Future novel therapeutics for bradycardia targeting Rad - LTCC can thus elevate HR while retaining βAR responsiveness.

Dataset Information

Myocardial-restricted ablation of the GTPase RAD results in a pro-adaptive heart response in mice.

Publications

Myocardial-restricted ablation of the GTPase RAD results in a pro-adaptive heart response in mice.

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