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Small ubiquitin-like modifier (SUMO1-3) conjugation (SUMOylation), a post-translational modification, modulates activity of a large number of nuclear proteins, including transcriptional factors and chromatin-associated proteins, and plays a crucial role in heart development and pathogenesis of heart diseases. It was reported that levels of SUMO1 significantly decrease in human failing hearts, overexpression of SUMO1 improves cardiac function in a mouse model of heart failure. To clarify whether SUMO1 does indeed play a critical role in heart disease, we compared outcome after transverse aortic constriction (TAC) in wild- type (WT) and Sumo1 knockout (SUMO1-KO) mice.
SUMO1-KO and WT littermate mice were subjected to TAC. Echocardiography analysis of cardiac function was performed at 8 weeks after TAC. The effect of SUMO1 deletion on regulation of expression of hypertrophy-related genes was evaluated by qPCR, Western blot, and chromatin immunoprecipitation assay.
Compared to WT mice, SUMO1-KO mice showed a significantly lower ratio of left ventricular (LV) weight to body weight (5.73±0.49 mg/g vs 6.76±1.11mg/g; p<0.05,n=8) and smaller transverse section area of cardiomyocyte (259±47 um2 vs 328±56 um2, p<0.05,n=3). Moreover, in SUMO1-KO mice, LV diameters in end-diastole and end-systole were significantly shorter (2.51±0.34mm vs 3.32±0.87mm, 1.22±0.24mm vs 2.06±1.09mm, p<0.05,n=10,), while percentage of LV fractional shortening was higher (51.64±6.24% vs 40.63±15.46%; p<0.05,n=10) compared with WT. Furthermore, the TAC-induced increase in mRNA and protein levels of ANF, BNP, SKA, and β-MHC was significantly less in SUMO1-KO than in WT mice. Finally, we found that the enrichment of chromatin-bound SUMO2/3 on promoters of selected hypertrophy-related genes was higher in SUMO1-KO than in WT mice after TAC.
Our results do not support a model whereby SUMO1 is critical for outcome after TAC. The data imply that increased chromatin-bound SUMO2/3 at the promoters of key hypertrophy-related genes suppressed their expression and thereby contributed to the beneficial effect of SUMO1 deletion. This suggests a novel, not yet recognized, aspect of redundancy of the SUMOylation system. Therefore, SUMO2/3 may be better suited than SUMO1 to counterbalance SUMO1 depletion in heart failure.