Upregulation of Small Ubiquitin-Like Modifier 2 and Protein SUMOylation as a Cardioprotective Mechanism Against Myocardial Ischemia-Reperfusion Injury

Abstract

Background: Small ubiquitin-like modifier (SUMO) proteins modify proteins through SUMOylation as an essential protein post-translational modification (PTM) for regulating redox status, inflammation, and cardiac fibrosis in myocardial infarction. This study aimed to investigate whether natural product puerarin could alleviate myocardial ischemia/reperfusion injury (MI-RI) by targeting protein SUMOylation.Methods: Mouse MI-RI model was induced by ligating the left anterior descending (LAD) coronary artery and subsequently treated with puerarin at the dose of 100 mg/kg. Rat cardiomyocyte H9c2 cells were challenged by hypoxia/reoxygenation and treated with puerarin at concentrations of 10, 20, and 40 μM. The infarction area of mouse hearts was assessed by 2% TTC staining. Cell damage was analyzed for the release of lactate dehydrogenase (LDH) in serum and cell culture medium. Western blot technique was employed to detect the expression of SUMO2, phospho-ERK, pro-inflammatory biomarker COX2, fibrosis index galectin-3, apoptosis-related protein cleaved PARP-1. The activation of the estrogen receptor (ER) pathway was assayed by the dual-luciferase reporter system.Results: The present study validated that puerarin effectively reduced myocardial infarct size and LDH release in the mouse MI-RI model. In the cell culture system, puerarin effectively decreased the release of LDH and the protein level of COX2, galectin-3, and cleaved PARP-1. Mechanistic studies revealed that puerarin increased the expression of SUMO2, SUMOylation of proteins and the activation of ER/ERK pathway in cardiomyocytes. ER, ERK and SUMO2 inhibitors attenuated the cardioprotective effects of puerarin.Conclusion: Puerarin may alleviate myocardial injury by promoting protein SUMOylation through ER/ERK/SUMO2-dependent mechanism.

SUMOylation of Nuclear γ-Actin by SUMO2 supports DNA Damage Repair against Myocardial Ischemia-Reperfusion Injury

“…For animal experiments, the sample size was calculated using the formula: Sample size = 2* SD2 (Zα/2 + Zβ) *2 /d2. It was previously demonstrated that the mean myocardial infarction area was 16.32% for mice model and 6.85% for sham groups while SD is 6.45% [34]. When the level of significance at 5% and power of study at 80% were selected for two tailed unpaired t -test, the sample size = 2* (6.45)2* (1.96 + 0.842) *2 / (9.47)2 = 5.2.…”

“…Natural products ginkgolic acid and astragaloside IV were also evaluated for targeting SUMOylation of proteins in animal models of MI and cell culture systems [32,33]. Along this line, we previously demonstrated that plant-derived C-glycosylated isoflavone puerarin exhibited effective cardioprotective potential in a mouse model of myocardial infarction via enhancing SUMO2-mediated SUMOylation without affecting SUMO1 expression [34]. However, little is known about the protein substrates that are SUMOylated by SUMO2 in myocardial infarction.…”

A four-compound remedy AGILe protected H9c2 cardiomyocytes against oxygen glucose deprivation via targeting the TNF-α/NF-κB pathway: Implications for the therapy of myocardial infarction

“…Mouse Hearts were cut into 1 cm-thick sections and stained with 2,3,5-triphenyl tetrazolium chloride (TTC) (Sigma Aldrich, Saint Louis, MO, United States) as previously described (Zhao et al, 2021). In brief, five pieces of heart sections were immersed in 2% TTC solution and incubated at 37 °C for 20 min.…”

Natural Products Against Renal Fibrosis via Modulation of SUMOylation

“…PPARγ plays a key role in physiological and pathological processes of renal fibrosis. The reduction of PPARγ SUMOylation suppresses the activation of anti-apoptotic and anti-inflammatory cytokines through inhibiting the NF-κB activity (Xie et al, 2018;Zhao et al, 2021b). In lipopolysaccharide (LPS)-induced human renal proximal tubular cells, rosiglitazone (an agonist of PPARγ) decreases chemokines expression via inhibiting NF-κB activation by activating PPARγ SUMOylation (Lu et al, 2013).…”