Key result
ARH1 deficiency significantly increased myocardial infarct size following in vivo ischemia/reperfusion injury (38.3% vs 18.1%) and impaired membrane repair, indicating the TRIM72 ADP-ribosylation cycle is critical for recovery.
A mono-ADP-ribosylation cycle involving TRIM72 is critical for membrane repair and wound healing following myocardial injury.
Hypothesis-generating for TRIM72-targeted repair in myocardial injury; leaves open clinical translation pending human studies.
Mono-ADP-ribosylation of an (arginine) protein catalyzed by ADP-ribosyltransferase 1 (ART1) - i.e., transfer of ADP-ribose from NAD to arginine - is reversed by ADP-ribosylarginine hydrolase 1 (ARH1) cleavage of the ADP-ribose-arginine bond. ARH1-deficient mice developed cardiomyopathy with myocardial fibrosis, decreased myocardial function under dobutamine stress, and increased susceptibility to ischemia/reperfusion injury. The membrane repair protein TRIM72 was identified as a substrate for ART1 and ARH1; ADP-ribosylated TRIM72 levels were greater in ARH1-deficient mice following ischemia/reperfusion injury. To understand better the role of TRIM72 and ADP-ribosylation, we used C2C12 myocytes. ARH1 knockdown in C2C12 myocytes increased ADP-ribosylation of TRIM72 and delayed wound healing in a scratch assay. Mutant TRIM72 (R207K, R260K) that is not ADP-ribosylated interfered with assembly of TRIM72 repair complexes at a site of laser-induced injury. The regulatory enzymes ART1 and ARH1 and their substrate TRIM72 were found in multiple complexes, which were coimmunoprecipitated from mouse heart lysates. In addition, the mono-ADP-ribosylation inhibitors vitamin K1 and novobiocin inhibited oligomerization of TRIM72, the mechanism by which TRIM72 is recruited to the site of injury. We propose that a mono-ADP-ribosylation cycle involving recruitment of TRIM72 and other regulatory factors to sites of membrane damage is critical for membrane repair and wound healing following myocardial injury.
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Ishiwata-Endo et al. (2018) studied Myocardial injury and membrane repair. ARH1 deficiency vs. Wild-type was evaluated on Myocardial infarct size after in vivo ischemia/reperfusion injury (p=<0.01). ARH1 deficiency significantly increased myocardial infarct size following in vivo ischemia/reperfusion injury (38.3% vs 18.1%) and impaired membrane repair, indicating the TRIM72 ADP-ribosylation cycle is critical for recovery.
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