Review articleRoles and mechanisms of SUMOylation on key proteins in myocardial ischemia/reperfusion injury
Introduction
Acute coronary occlusion is one of the leading causes of morbidity and mortality in the world [1]. Recovery of reperfusion is the primary therapy utilized to save viable myocardium, limit the size of myocardial infarction, preserve cardiac systolic function, and delay the development of heart failure [2]. However, recanalization of blood flow not only restores oxygen and nutrient supply but also damages the myocardium. This pathophysiological phenomenon is known as the myocardial ischemia/reperfusion (MI/R) injury. The underlying mechanisms of MI/R injury have not yet been fully elucidated. It is considered that oxidative stress, calcium overload, mitochondrial dysfunction, endoplasmic reticulum stress, activation of apoptotic and autophagic pathways, and epigenetic changes may be involved [3]. Over the past three decades, numerous studies have been devoted to elucidating the molecular mechanisms of MI/R injury, with a view to identifying therapeutic strategies to reduce the severity caused by reperfusion. However, there is still no effective therapy for the prevention of MI/R injury. Therefore, novel cardioprotective strategies are urgently needed to increase the resistance of cardiomyocytes to MI/R injury.
MI/R injury is a complex pathological process that involves many signaling pathways. It may be a better strategy to target a multifunctional cellular process and coordinate multiple signaling pathways involved in MI/R injury. From this point of view, small ubiquitin-related modifier (SUMO), which has been the focus of many studies in recent years, has proven to be a promising candidate.
SUMO was first discovered by Okura et al. in 1996 [4] and confirmed in the late 1990s as a mechanism conjugating lysine residues of proteins to regulate protein functions [5]. Four distinct human SUMO proteins (SUMO1, 2, 3, and 4) have been identified. SUMO1, 2, and 3 are widely distributed in the body, while SUMO4 is only found in kidney, spleen, and lymph nodes [6] and cannot be conjugated due to the lack of a C-terminal [7]. The expression level of SUMO2/3 protein is much higher than that of SUMO1 [6]. Although most of the SUMO substrates are located in the nucleus, SUMOylation is not limited to nuclear proteins, but can also be detected in extra-nuclear proteins [8]. All SUMOs are expressed as precursor proteins before conjugation. Conjugation requires three reaction steps: SUMO-activation, SUMO-conjugation, and SUMO-ligation. First, mature SUMO is activated by the E1 activating enzyme (SAE1/2). Then, SUMO is transferred to the only E2 conjugating enzyme, UBC9. Finally, SUMO is promoted to conjugate with substrates by the E3 ligase, which includes a protein inhibitor of activated STAT (PIAS) family, RanBR2, polycomb2, mitochondrial-anchored protein ligase (MAPL), and others [9]. SUMO conjugation pathway is a reversible process. Proteins conjugated by SUMO may be deSUMOylated by the SENtrin-specific protease (SENP) and deSUMOylating isopeptidases (DeSI) [10] (Fig. 1). Six members of the SENP family associated with deSUMOylation have been found in humans (SENP1–3, 5–7). SENPs show different specificity for all SUMO proteins and substrates [11]. SENP1 and SENP2 have deSUMOylation effects on all SUMO proteins [12], whereas SENP3, 5, 6, and 7 give priority to SUMO2/3 [13]. DeSUMOylation eliminates the effects of SUMOylation. However, one of the deSUMOylases, SENP, is closely related to SUMO-activation. Specific conditions that trigger SUMOylation and deSUMOylation remain unclear.
Since the discovery of the first SUMO protein, the SUMO conjugation pathway has attracted ample attention due to its different roles in various cellular events. Recent advances in SUMO research have highlighted its roles in heart development, function, and disease. SUMOylation has been shown to occur in many cell types of the heart, such as cardiomyocytes, fibroblasts [14,15], endothelial cells [16,17], smooth muscle cells [18], etc. However, the differences and commonalities of SUMOylation in these cells are still unclear. SUMOylation and some other post-translational modifications (PTM) can also regulate cardiac proteasome function and alter cellular protein homeostasis [19,20]. Previous studies of SUMOylation in cardiovascular disease were principally focused on heart failure. However, few studies have been conducted on SUMOylation in MI/R injury.
Current research suggests that SUMOylation of some proteins could alleviate or exacerbate myocardial damage by inhibiting or promoting the pathological mechanisms of MI/R injury. There is a series of metabolic disorders that occur during MI/R, including dysfunction of a number of proteins. As a type of PTM, SUMOylation or deSUMOylation may partly enhance the protein expression, thereby affecting the mechanisms of MI/R injury through performing their functions. By determining the exact effects of protein SUMOylation on MI/R injury, the damage can be attenuated by promoting or inhibiting SUMOylation. Therefore, SUMOylation in MI/R may provide an effective method to relieve myocardial injury and enhance the curative effects of recanalization.
In this review, we will refer to six key proteins associated with SUMOylation, which have been suggested to play remarkable roles during MI/R injury, as well as describe the following protein characteristics: (1) physiological functions; (2) pathological protein changes during MI/R; (3) influence of altering protein SUMOylation status on MI/R injury and their relevant mechanisms.
Section snippets
SUMOylation of SERCA2a alleviates calcium overload
Calcium overload is one of the most essential mechanisms in MI/R injury. Sarcoplasmic reticulum (SR) Ca2+ ATPase pump (SERCA2a), which is highly expressed in the heart, is a critical ATPase that controls Ca2+ reuptake and replenishment to SR in excitation-contraction coupling. In the period of ischemia and reperfusion, various factors cause the elevation of cytoplasmic Ca2+ levels (Fig. 2). The high concentration of Ca2+ in the cytosol activates several proteases and other proteins that lead to
SUMOylation of HDAC in epigenetic changes
It was confirmed that MI/R could cause epigenetic changes and tissue damage [31]. Epigenetic refers to the regulation of heritable gene expression without DNA sequence changes, including DNA methylation, histone modification, and noncoding RNAs. Histone modifications include acetylation, methylation, ubiquitination, phosphorylation, and crotonylation [32]. A histone octamer contains four different histone proteins (H2A, H2B, H3, and H4) with 146 pairs of DNA wrapped around to form a nucleosome,
SUMOylation of Drp1 in mitochondrial fission
Mitochondria are important organelles for energy production, buffering calcium, ROS generation, and sequestering molecules such as cytochrome c [54]. Mitochondria are composed of the outer and inner membranes. The outer membrane encapsulates the inner membrane, while the inner membrane is the site where most of the electron transport proteins occur [55]. Mitochondria change their morphology constantly through fission and fusion in response to alterations in their intracellular environment in
SUMOylation in HIF-mediated hypoxia-signaling cascade
During myocardial ischemia, the cardiomyocyte energy supply decreases, the metabolism becomes abnormal, and homeostasis is broken. These factors lead to cell dysfunction and even death. Hypoxia-inducible factor (HIF) plays an essential role in cellular and systemic oxygen homeostasis by inducing the transcription of hundreds of hypoxia-responsive genes. These genes are involved in many cell functional events, including angiogenesis, vasomotor control, vascular reactivity and remodeling,
Phosphorylated eEF2 is SUMOylated and induces cardiomyocyte apoptosis
Apoptosis is a basic mechanism of cell death during MI/R injury. It is a programmed cell death mediated by multiple apoptotic mediators. It was confirmed that DNA damage caused by various factors is an important reason for apoptosis [79]. Here, we will describe one of the mechanisms associated with SUMOylation that causes DNA damage.
Eukaryotic elongation factor 2 (eEF2) is one of the protein factors involved in polypeptide chain elongation in protein translation. It was confirmed that eEF2
Conclusion
In this review, we summarized recent studies investigating the effects of SUMOylation of six key proteins on MI/R injury. The modifications by SUMO affect the expression and function of proteins in MI/R and attenuate or exacerbate the myocardium injury via different mechanisms. SEARCA2a SUMOylation relieves Ca2+ overload in MI/R and reduces myocardial injury. SUMOylation promotes degradation of HDAC4 and reduces the production of ROS. Sirt1 mainly exists in the nucleus of cardiomyocytes in the
Author contributions
Jingwen Chen and Yuanyuan Luo contributed equally to this paper. Jingwen Chen and Yuanyuan Luo wrote the manuscript and made the figures. Shuai Wang collected the literature. Dongye Li and Hong Zhu conceived the review and critically revised the manuscript.
Funding
This review did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This work was supported by the National Natural Science Foundation of China (81570326).
Declaration of Competing Interest
The authors report no conflict of interest.
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These authors contributed equally to this work.