Shear stress-induced Ca2+ influx triggers endoplasmic reticulum stress and cardiomyocyte apoptosis: implications for mitral regulation.

BACKGROUND

Mitral regurgitation is highly prevalent and elevates the risk of heart failure. Regurgitant flow induced shear stress disrupts Ca2+ homeostasis in atrial cardiomyocytes. Overloaded Ca2+ is a crucial regulator of endoplasmic reticulum stress-mediated apoptosis, although the regulatory mechanisms remain unclear. We aimed to explore the relationship between shear stress and Ca2+ homeostasis. METHODS AND

RESULTS

Through employing an in vitro model replicating atrial cardiomyocytes during mitral regurgitation, we observed that shear stress increased Ca2+ oscillation and the amplitude of Ca2+ waves through extracellular Ca2+ influx. Suppression of mechanosensitive Ca2+ channels or store-operated calcium entry resulted in decreased intracellular Ca2+ concentration and oscillation. Conversely, the inhibition of voltage-gated Ca2+ channels did not significantly impact the Ca2+ concentration. Remarkably, shear stress elevated the expression of endoplasmic reticulum stress and apoptosis-related proteins in HL-1 cells in a time-dependent manner. Also, in a novel rodent mitral regurgitation model, shear stress increased apoptosis and endoplasmic reticulum stress expression compared to sham rats.

CONCLUSIONS

Our findings underscore that shear stress induces apoptosis through mechanosensitive and store-operated Ca2+ channels, leading to Ca2+ overload and endoplasmic reticulum stress. Understanding the mechanisms behind shear stress-disturbed Ca2+ homeostasis may enhance the treatment of mitral regurgitation-induced heart failure.