Helium-Induced Changes in Circulating Caveolin in Mice Suggest a Novel Mechanism of Cardiac Protection

Abstract

The noble gas helium (He) induces cardioprotection in vivo through unknown molecular mechanisms. He can interact with and modify cellular membranes. Caveolae are cholesterol and sphingolipid-enriched invaginations of the plasma-membrane-containing caveolin (Cav) proteins that are critical in protection of the heart. Mice (C57BL/6J) inhaled either He gas or adjusted room air. Functional measurements were performed in the isolated Langendorff perfused heart at 24 h post He inhalation. Electron paramagnetic resonance spectrometry (EPR) of samples was carried out at 24 h post He inhalation. Immunoblotting was used to detect Cav-1/3 expression in whole-heart tissue, exosomes isolated from platelet free plasma (PFP) and membrane fractions. Additionally, transmission electron microscopy analysis of cardiac tissue and serum function and metabolomic analysis were performed. In contrast to cardioprotection observed in in vivo models, the isolated Langendorff perfused heart revealed no protection after He inhalation. However, levels of Cav-1/3 were reduced 24 h after He inhalation in whole-heart tissue, and Cav-3 was increased in exosomes from PFP. Addition of serum to muscle cells in culture or naïve ventricular tissue increased mitochondrial metabolism without increasing reactive oxygen species generation. Primary and lipid metabolites determined potential changes in ceramide by He exposure. In addition to direct effects on myocardium, He likely induces the release of secreted membrane factors enriched in caveolae. Our results suggest a critical role for such circulating factors in He-induced organ protection.

Gaseous mediators: an updated review on the effects of helium beyond blowing up balloons

“…Thirty minutes or 24 h after the experimental protocol, hearts were excised and blood was withdrawn from animals. In strong contrast to our initial hypothesis, the mice heart showed a significant downregulation of caveolin-1 and caveolin-3 after 24 h [58]. Subsequent sub-fractionation of the whole heart showed that specifically the membrane fractions, but not the cytosolic fractions, had decreased levels of caveolin-1 and caveolin-3.…”

“…The addition of helium conditioned serum to muscle cells in cell culture or naïve ventricular tissue increased mitochondrial metabolism without increasing ROS generation. Measurements of primary and lipid metabolites showed potential changes in ceramide in helium-conditioned serum [58]. Data from this mice study is in line with our previous findings in human endothelial cells investigating the direct effects of helium in vitro [59].…”

“…Subsequent sub-fractionation of the whole heart showed that specifically the membrane fractions, but not the cytosolic fractions, had decreased levels of caveolin-1 and caveolin-3. Corresponding to the decreased caveolin levels in the heart tissue and in the membrane fractions, increased levels of caveolin-3 in platelet free plasma of mice having inhaled helium were found [58]. This was confirmed by lowered cholesterol levels, a primary binding protein of caveolin in the plasma membrane.…”

“…To confirm this, we mounted isolated mice hearts on a Langendorff system and repeated the respective experiments. The data showed that no helium protection was seen in this model lacking the in vivo blood flow [58]. It was further evaluated whether the secreted factors in the serum from helium-exposed mice have a measurable effect on mitochondrial function.…”

Inhalation of Heliox as a potential treatment for the ARDS caused by COVID-19

“…Helium induced changes in circulating caveolin in mice suggest a novel mechanism of cardiac protection [27]. In a rat model of resuscitation, one study examined the effects of helium pre-and postconditioning on the brain and heart [28].…”