Sex Differences in Endogenous Formaldehyde Production and One-Carbon Metabolism: Potential Links to Cardioprotection

点击翻译按钮获取中文摘要

PROJECT SUMMARY Ischemic heart disease is a leading cause of death in the US, often manifesting as ischemia/reperfusion injury. Premenopausal women are at lower risk for ischemic heart disease than age-matched men, but this protection is lost following menopause, supporting a role for estrogen. In prior studies, we found that female hearts have two-fold more formaldehyde compared to males and higher activities of the two enzymes that metabolize formaldehyde to formate. Formaldehyde is a byproduct of one-carbon metabolism, and formate can be used in subsequent one-carbon reactions. Therefore, it is possible that formate may be used in one-carbon metabolism to drive cardioprotective signaling in the female heart, possibly by producing the protective molecules tetrahydrobiopterin and glutathione, but additional research is required to define female-specific cardioprotection. Tetrahydrobiopterin is a cofactor for nitric oxide synthase, a primary nitric oxide source which we have found to be protective during ischemia/reperfusion injury. Additionally, one-carbon metabolism produces the antioxidant glutathione, and females have been found to be more resistant to oxidative stress compared to males. Therefore, I hypothesize that the female heart produces formaldehyde via one-carbon metabolism which is then metabolized to formate for use in the one-carbon pathway to promote cardioprotective signaling via tetrahydrobiopterin and glutathione production. This hypothesis will be tested in the following aims: 1) Identify the role of estrogen in formaldehyde and formate production during ischemia/reperfusion injury, 2) Define the link between formate and nitric oxide production in the heart during ischemia/reperfusion injury, and 3) Define the link between formate and antioxidant capacity in the heart during ischemia/reperfusion injury. Upon successful completion, this proposal will elucidate critical protective signaling pathways in the female heart, which are largely unknown, and potentially unlock critical therapeutic insights for cardioprotection in men and postmenopausal women.