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

## TL;DR

Shear stress from mitral regurgitation causes calcium overload in heart cells, leading to cell death and heart failure risks.

## Contribution

Identifies mechanosensitive and store-operated Ca2+ channels as key in shear stress-induced cardiomyocyte apoptosis.

## Key findings

- Shear stress increases Ca2+ oscillation via extracellular Ca2+ influx in atrial cardiomyocytes.
- Mechanosensitive and store-operated Ca2+ channels mediate ER stress and apoptosis in response to shear stress.
- Rodent mitral regurgitation models show elevated apoptosis and ER stress compared to controls.

## Abstract

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.

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.

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.

The online version contains supplementary material available at 10.1186/s40659-026-00671-4.