Shear stress-induced Ca(2+) 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 Ca(2+) homeostasis in atrial cardiomyocytes. Overloaded Ca(2+) 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 Ca(2+) homeostasis. METHODS AND RESULTS: Through employing an in vitro model replicating atrial cardiomyocytes during mitral regurgitation, we observed that shear stress increased Ca(2+) oscillation and the amplitude of Ca(2+) waves through extracellular Ca(2+) influx. Suppression of mechanosensitive Ca(2+) channels or store-operated calcium entry resulted in decreased intracellular Ca(2+) concentration and oscillation. Conversely, the inhibition of voltage-gated Ca(2+) channels did not significantly impact the Ca(2+) 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 Ca(2+) channels, leading to Ca(2+) overload and endoplasmic reticulum stress. Understanding the mechanisms behind shear stress-disturbed Ca(2+) homeostasis may enhance the treatment of mitral regurgitation-induced heart failure. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40659-026-00671-4.