Abstract Thu154: Phosphorylation of CHIP Protects Ovariectomized Female Mice From Myocardial Infarction

Introduction: Loss of proteostasis has been implicated in the increased cardiovascular risk observed in postmenopausal women, yet the underlying mechanism is unknown. Estrogen is known to enhance the activity of protein kinase G (PKG), which we identified as being able to phosphorylate the C-terminus of Hsc70-Interacting Protein (CHIP) at serine 20 as a mechanism to restore proteostasis. CHIP, a prominent ubiquitin ligase in the heart, is known for its cardioprotective function, however, the role of CHIP following the loss of estrogen remains unknown. Hypothesis: We hypothesize increasing CHIP S20 phosphorylation will enhance proteostasis and protect female hearts from myocardial damage in the setting of estrogen deficiency. Methods/Approach: To mimic postmenopausal conditions female CHIP phospho-mimetic (S20E, SE), phospho-null (S20A, SA), and wild-type (WT) mice underwent ovariectomy (OVX) surgery. One-month post-OVX, mice were subjected to myocardial infarction (MI) or sham surgeries (n=12/group). Cardiac function was assessed one-week post-MI via echocardiography, after which tissue was collected to assess proteotoxicity and myocardial remodeling. Results: CHIP SE mice exhibited preserved cardiac function and morphology following MI, irrespective of OVX status. In contrast, OVX WT, and more prominently CHIP SA mice, presented with decreased cardiac function, left ventricular chamber dilation, and myocardial fibrosis. Compared to CHIP WT OVX mice, protein aggregates were increased in the hearts of CHIP SA OVX mice, indicative of proteotoxic stress, while CHIP SE OVX mice showed minimal accumulation. We did not observe any differences in cardiac function or proteostasis in sham mice regardless of genotype and OVX/intact surgery. Conclusion: In conclusion, CHIP phosphorylation at S20 enhanced proteostasis and preserved cardiac function following MI in OVX mice. These findings suggest that CHIP phosphorylation is a critical protective mechanism against postmenopausal cardiovascular risk and may serve as a promising therapeutic target. Future studies will explore pharmacological approaches to enhance CHIP phosphorylation as a potential strategy for mitigating heart disease in postmenopausal women.