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Role for TRIM72 in Cardioprotection

IHD

TRIM72 is a membrane repair protein which has recently emerged as a potential therapeutic target for ischemic heart disease (Kohr et al., 2015). TRIM72 has also been characterized as an E3 ubiquitin ligase, that targets the insulin receptor and insulin receptor substrate 1 (IRS1).

Our recent study demonstrated that cysteine 144 of TRIM72 serves as a critical redox-dependent switch (Kohr et al., 2014). TRIM72 oxidation at cysteine 144 leads to the degradation of TRIM72, and this correlates with enhanced cell death in response to oxidative stress. However, S-nitrosation (induced via cardioprotection or with nitric oxide donors) or mutation (cysteine to serine conversion) of TRIM72 at cysteine 144, prevents the oxidation-induced degradation of TRIM72, thus leading to the preservation of cellular function and viability. We recently generated a novel knock-in mouse model expressing a mutant version of TRIM72  (cysteine 144 converted to serine), and we are using this mouse to further characterize the cardioprotective role of TRIM72 using in vivo and ex vivo models of ischemia-reperfusion injury. Interestingly, male TRIM72 C144S knock-in mice show reduced injury following ischemia-reperfusion (Filmore et al., 2019), suggesting a protective role for the TRIM72 C144S mutation. Current studies are focused on identifying the cytoprotective function of the TRIM72 C144S mutant in the heart.

Overall, this project seeks to define the cytoprotective role of TRIM72 in the heart, and further solidify TRIM72 as a therapeutic target for the treatment of ischemic heart disease.