Objective:
Selective serotonin reuptake inhibitors (SSRIs) are known to reduce post-myocardial infarction (MI)-induced morbidity and mortality. However, the molecular mechanism underlying SSRI-induced cardioprotection remains unclear. We previous reported that fluvoxamine with high affinity for sigma-1 receptor ameliorates cardiac hypertrophy and dysfunction via sigma-1 receptor stimulation. In non-cardiomyocytes, sigma-1 receptor interacts with IP
3
receptor (IP
3
R), which may promote Ca
2+
transport to mitochondria. We here investigated the role of sigma-1 receptor for sarcoplasmic reticulum (SR)-mitochondrial Ca
2+
signaling in neonatal rat ventricular cardiomyocytes.
Methods:
Cultured cardiomyocytes were treated with angiotensin II (Ang II) during 72 hr followed by fluvoxamine and/or NE-100 treatment during the last 24 hr. Then, we investigated intracellular localization of sigma-1 receptor and IP
3
R. We also measured phenylephrine (PE)-induced mitochondrial Ca
2+
and cytosolic Ca
2+
mobilization and ATP content in Ang II-treated cardiomyocytes with or without fluvoxamine treatments.
Results:
Ang II stimulation for 72 hr elicited cardiomyocyte hypertrophy, downregulation of sigma-1 receptor expression and declined PE-induced Ca
2+
mobilization into cytosol and mitochondria. Fluvoxamine treatments restored sigma-1 receptor expression and PE-induced Ca
2+
mobilization into mitochondria. Moreover, fluvoxamine treatment completely restored Ang II-induced apoptosis. We also confirmed in vivo that fluvoxamine treatment rescue transverse aortic constriction-induced cardiac dysfunction and the reduced ATP concentration.
Conclusions:
These results suggested that fluvoxamine rescue cardiomyocytes from AngII-induced cardiac myocyte apoptosis through enhancement of SR-mitochondria Ca
2+
transport and mitochondrial ATP production via sigma-1 receptor stimulation.
Abundant sigma‐1 receptor expression in the rat dorsal root ganglion (659.14)