Dataset Information

The Effect of Estrogen on Intracellular Ca²⁺ and Na⁺ Regulation in Heart Failure.

ABSTRACT: Contradictory findings of estrogen supplementation in cardiac disease highlight the need to investigate the involvement of estrogen in the progression of heart failure in an animal model that lacks traditional comorbidities. Heart failure was induced by aortic constriction (AC) in female guinea pigs. Selected AC animals were ovariectomized (ACOV), and a group of these received 17β-estradiol supplementation (ACOV+E). One hundred-fifty days post-AC surgery, left-ventricular myocytes were isolated, and their electrophysiology and Ca²⁺ and Na⁺ regulation were examined. Long-term absence of ovarian hormones exacerbates the decline in cardiac function during the progression to heart failure. Estrogen supplementation reverses these aggravating effects.

SUBMITTER: Firth JM

PROVIDER: S-EPMC7524784 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

The Effect of Estrogen on Intracellular Ca<sup>2+</sup> and Na<sup>+</sup> Regulation in Heart Failure.

Firth Jahn M JM Yang Hsiang-Yu HY Francis Alice J AJ Islam Najah N MacLeod Kenneth T KT

JACC. Basic to translational science 20200902 9

Contradictory findings of estrogen supplementation in cardiac disease highlight the need to investigate the involvement of estrogen in the progression of heart failure in an animal model that lacks traditional comorbidities. Heart failure was induced by aortic constriction (AC) in female guinea pigs. Selected AC animals were ovariectomized (ACOV), and a group of these received 17β-estradiol supplementation (ACOV+E). One hundred-fifty days post-AC surgery, left-ventricular myocytes were isolated, ...[more]

PMID: 33015413

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Project description:Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca2+ waves which activate a Na+ -Ca2+ exchange (NCX) current, leading to delayed after-depolarisations and triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold and are commonly induced experimentally by raising external Ca2+ , although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca2+ was measured in voltage-clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca2+ content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine-induced NCX currents. Raising external Ca2+ induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca2+ content was smaller in HF due to a lower threshold. Raising external Ca2+ had no effect on total influx via the L-type Ca2+ current, ICa-L , and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca2+ entry which sustains Ca2+ efflux during waves in the steady state. Wave frequency and background Ca2+ entry were decreased by Gd3+ or the TRPC6 inhibitor BI 749327. These agents also blocked Mn2+ entry. Inhibiting connexin hemi-channels, TRPC1/4/5, L-type channels or NCX had no effect on background entry. In conclusion, raising external Ca2+ induces waves via a background Ca2+ influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content. KEY POINTS: Heart failure is a pro-arrhythmic state and arrhythmias are a major cause of death. At the cellular level, Ca2+ waves resulting in delayed after-depolarisations are a key trigger of arrhythmias. Ca2+ waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca2+ . We investigate the mechanism by which raising external Ca2+ causes waves, and how this is modified in heart failure. We demonstrate that a novel sarcolemmal background Ca2+ influx via the TRPC6 channel is responsible for SR Ca2+ overload and Ca2+ waves. The increased propensity for Ca2+ waves in heart failure results from an increase of background influx, and a lower threshold SR content. The results of the present study highlight a novel mechanism by which Ca2+ waves may arise in heart failure, providing a basis for future work and novel therapeutic targets.

Dataset Information

The Effect of Estrogen on Intracellular Ca²⁺ and Na⁺ Regulation in Heart Failure.

Publications

The Effect of Estrogen on Intracellular Ca<sup>2+</sup> and Na<sup>+</sup> Regulation in Heart Failure.

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Dataset Information

The Effect of Estrogen on Intracellular Ca2+ and Na+ Regulation in Heart Failure.

Publications

The Effect of Estrogen on Intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; and Na&lt;sup&gt;+&lt;/sup&gt; Regulation in Heart Failure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The Effect of Estrogen on Intracellular Ca²⁺ and Na⁺ Regulation in Heart Failure.

The Effect of Estrogen on Intracellular Ca<sup>2+</sup> and Na<sup>+</sup> Regulation in Heart Failure.