Anti-oxidant effects of estrogen reduce [Ca2+]i during metabolic inhibition

Area of Science:

• Cardiovascular Physiology
• Cellular Biology
• Endocrinology

Background:

• 17beta-estradiol (betaE2) was previously shown to inhibit intracellular calcium ([Ca(2+)](i)) and sodium ([Na(+)](i)) increases during metabolic inhibition (MI) in mouse cardiomyocytes.
• The underlying mechanism for this cardioprotective effect of betaE2 remains unclear, prompting investigation into its antioxidant properties and interaction with the estrogen receptor (ER).

Purpose of the Study:

• To elucidate the mechanism by which 17beta-estradiol (betaE2) exerts its acute cardioprotective effects during metabolic inhibition (MI).
• To determine if the protective action involves estrogen receptor (ER) interaction or an antioxidant effect on Na(+)-K(+) ATPase function in cardiac myocytes.

Main Methods:

• Experiments utilized male mouse ventricular myocytes, measuring intracellular calcium ([Ca(2+)](i)) using fluo-3 and flow cytometry.
• Cell viability was assessed via propidium iodide fluorescence to exclude dead cells from analysis.
• Pharmacological agents were used to block the estrogen receptor (tamoxifen), Na(+)-Ca(2+) exchanger (KB-R7943), Na(+)-K(+) ATPase (low K+ or ouabain), L-type Ca(2+) channel (nifedipine), and superoxide radicals (Tiron).

Main Results:

• betaE2 reduced the rise in [Ca(2+)](i) during MI, even when the ER was blocked by tamoxifen.
• Hormones with a phenolic structure (estrone, estriol) also inhibited Ca(2+) overload, unlike testosterone.
• The betaE2 effect was diminished by inhibiting Na(+)-Ca(2+) exchanger or Na(+)-K(+) ATPase, but not L-type Ca(2+) channels.
• A superoxide scavenger (Tiron) abolished the betaE2 effect, indicating a role for free radicals.

Conclusions:

• The acute cardioprotective effect of estrogen during metabolic inhibition (MI) appears to be mediated by an ER-independent antioxidant action.
• This antioxidant effect improves the function of the Na(+)-K(+) ATPase, thereby reducing intracellular calcium overload.
• Estrogen's protective role in MI involves enhancing the efficiency of ion transport mechanisms in cardiac myocytes through antioxidant pathways.