Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction

Abstract

Sumoylation is a posttranslational modification implicated in a variety of cellular activities, and its role in a number of human pathogeneses such as cleft lip/palate has been well documented. However, the importance of the SUMO conjugation pathway in cardiac development and functional disorders is newly emerging. We previously reported that knockout of SUMO-1 in mice led to congenital heart diseases (CHDs). To further investigate the effects of imbalanced SUMO conjugation on heart development and function and its underlying mechanisms, we generated transgenic (Tg) mice with cardiac-specific expression of SENP2, a SUMO-specific protease that deconjugates sumoylated proteins, to evaluate the impact of desumoylation on heart development and function. Overexpression of SENP2 resulted in premature death of mice with CHDs—atrial septal defects (ASDs) and/or ventricular septal defects (VSDs). Immunobiochemistry revealed diminished cardiomyocyte proliferation in SENP2-Tg mouse hearts compared with that in wild type (WT) hearts. Surviving SENP2-Tg mice showed growth retardation, and developed cardiomyopathy with impaired cardiac function with aging. Cardiac-specific overexpression of the SUMO-1 transgene reduced the incidence of cardiac structural phenotypes in the sumoylation defective mice. Moreover, cardiac overexpression of SENP2 in the mice with Nkx2.5 haploinsufficiency promoted embryonic lethality and severity of CHDs, indicating the functional interaction between SENP2 and Nkx2.5 in vivo. Our findings indicate the indispensability of a balanced SUMO pathway for proper cardiac development and function.

The Ubiquitin-Like SUMO System and Heart Function

“…52 This conclusion is also supported by the finding that forced expression of SENP1 through a virus-based approach induces dilated cardiomyopathy and mitochondrial abnormalities in adult mice 52 (Table). Similar deleterious effects of enhanced SUMO deconjugation in adult heart were also observed after forced expression of SENP2 or SENP5 in the heart, leading to cardiomyopathies and cardiac dysfunction 54,55 (Table). Increased expression of SENP5 is linked to alterations in mitochondrial dynamics and mitochondrial fission, which is assumed to rely on enhanced recruitment of mitochondria and oligomerization of the dynamin-related protein (DRP1).…”

“…38 The SUMO-dependent regulation of these specific factors has been described in detail [39][40][41] but new findings in mouse models with alterations in the SUMO pathway provide a novel integrated view on SUMO function during embryonic development (Table). Interestingly, both hypo-or hyperSUMOylation because of dysfunction of either the conjugation or deconjugation system result in embryonic or cardiac defects, indicating that a tight control of the degree of SUMOylation is essential for normal cardiac development 44,54 (Table). Inhibition of SUMO conjugation by genetic inactivation of the SUMO-conjugating E2 enzyme Ubc9 causes early embryonic lethality in mice between embryonic stage 3.5 and embryonic stage 7.5, 42 demonstrating that attachment of SUMO is essential for embryonic viability (Table).…”

“…44 However, it is noteworthy that other groups failed to detect a phenotype in SUMO1 KO mice possibly because of differences in the genetic background and gene-targeting strategies. 45,46 The importance of a tightly regulated level of SUMOylation is also underlined by the observation of cardiac abnormalities in mice with cardiomyocyte-specific overexpression of the SUMO isopeptidase SENP2 (α-myosin heavy chain-SENP2-transgenic), 54 which decreases SUMO1 modification essentially mimicking the lack of SUMO1. In addition, cardiac-specific overexpression of SUMO1 correcting defective SUMO1 conjugation in α-myosin heavy chain-SENP2-transgenic mice rescues developmental defects and triggers cardiomyocyte proliferation 54 (Table).…”

“…[56][57][58] Accordingly, a number of Nkx2.5 targets are downregulated in SENP2 transgenic mice, and the compound mutant SENP2-transgenic/Nkx2.5 +/− mice exhibit a more severe phenotype. 54 On the contrary, mutations of Nkx2.5 linked to CHDs show an altered SUMOylation pattern. [56][57][58] Taken together, the available data suggest that SUMO1-at least partially-exerts its function during embryogenesis by maximizing the activity of Nkx2.5.…”

“…44,[59][60][61][62] It is worth noting that a subgroup of α-myosin heavy chain-SENP2-transgenic mice does not develop cardiac septal defects, but show cardiac hypertrophy and fibrosis (cardiomyopathy) during aging, indicating that balanced SUMOylation is also important for heart function in adult animals. 54 Because cardiac-specific overexpression of SUMO1-transgenic does only rescue the embryonic but not the adult heart phenotype of α-myosin heavy chain-SENP2-transgenic mice, it is tempting to speculate that enforced SENP2-mediated deconjugation of SUMO2/3 but not of SUMO1 primarily contributes to the adult phenotype. In support of this idea, cardiac-specific overexpression of SENP5, which deconjugates mainly SUMO2/3 from target proteins, does not result in embryonic heart defects, but induces cardiomyopathy in adult mice.…”