Sex-dependent S-nitrosothiol Signaling

Our recent study demonstrated that female hearts exhibit 65% more S-nitrosated proteins compared to male hearts (Shao et al., 2016) and protection from ischemia-reperfusion injury. Consistent with this increase in protein S-nitrosation, we also found an increase in endothelial nitric oxide synthase expression and activation, and higher nitric oxide production in female hearts compared to males. Interestingly, we also found S-nitrosoglutathione reductase (GSNOR) activity levels to be higher in female hearts, which suggests that GSNOR may play a protective role in the female heart. Indeed, we recently demonstrated that the loss of GSNOR reduced ischemia-reperfusion injury in male hearts, but exacerbated injury in female hearts (Casin et al., 2018). Further mechanistic experiments revealed that GSNOR is essential for protecting the female heart from ischemia-reperfusion injury by metabolizing endogenous formaldehyde, which we identified to be a novel component of ischemia-reperfusion injury. Current studies are focused on identifying the source and toxicity of formaldehyde in the male and female heart during ischemia-reperfusion injury. Additional studies seek to define the role of estrogen in the regulation of GSNOR function in the female heart.

Overall, this project seeks to define the role of protein S-nitrosation and formaldehyde in sex-dependent cardioprotection with the ultimate goal of identifying therapeutic targets for the treatment of ischemic heart disease in men and women.