Deficiency of Interleukin-36 Receptor Protected Cardiomyocytes from Ischemia-Reperfusion Injury in Cardiopulmonary Bypass

Abstract

Background: Interleukin-36 has been demonstrated to be involved in inflammatory responses. Inflammatory responses due to ischemia-reperfusion injury following cardiopulmonary bypass (CPB) can cause heart dysfunction or damage. Material/Methods: The CPB models were constructed in IL-36R-/-, IL-36RN-/-, and wild-type SD rats. Ultrasonic cardiography and ELISA were used to evaluate the cardiac function and measuring myocardial biomarker levels in different groups. TUNEL assay was used to evaluate apoptosis. Western blot assays and RT-PCR were performed to measure the expression of chemokines and secondary inflammatory cytokines in the heart. Oxidative stress in tissue and cultured cells was assessed using a DCFH-DA fluorescence probe and quantification of superoxide dismutase activity. Results: Improved systolic function and decreased serum levels of myocardial damage biomarkers were found in IL-36R-/-rats compared to WT rats, while worse cardiac function and cardiomyocyte IR injury were observed in IL-36RN-/-rats compared to WT rats. TUNEL staining and Western blot analyses found that cardiomyocyte apoptosis and inflammation were significantly lower in the hearts of IL-36R-/-rats compared with that of WT rats. Oxidative stress was significantly lower in IL-36R-/-rats compared to WT rats. iNOS expression was significantly reduced, while eNOS expression was increased in the hearts of IL-36R-/-rats. Silencing of IL-36R expression in vitro activated SIRT1/FOXO1/p53 signaling in cardiomyocytes. Conclusions: IL-36R deficiency in cardiomyocytes repressed infiltration of bone marrow-derived inflammatory cells and oxidative stress dependent on SIRT1-FOXO1 signaling, thus protecting cardiomyocytes and improving cardiac function in CPB model rats.

Targeting IL-36 improves age-related coronary microcirculatory dysfunction and attenuates myocardial ischemia/reperfusion injury in mice

“…Importantly, this decrease was evident in both adult and more damaged aged hearts. Our data support the recent observation of reduced oxidative stress, measured using spectrophotometry of superoxide dismutase and malondialdehyde activity, in IL-36R–knockout rats undergoing cardiopulmonary bypass ( 51 ). However, we further detail that the antioxidant effects of IL-36Ra occur specifically on both coronary endothelial cells and cardiomyocytes.…”

“…However, our finding that IL-36Ra not only was vasculoprotective but also, importantly, remained beneficial in the setting of an age-related heightened inflammation in the coronary microvessels makes it a candidate worth pursuing clinically in elderly patients undergoing PCI for MI. In support of this is the recent work by Luo and colleagues, who demonstrated experimentally that deficiency of IL-36R protected cardiomyocytes in the setting of cardiopulmonary bypass ( 51 ).…”

The Serum Levels of IL-36 in Patients with Coronary Artery Disease and Their Correlation with the Serum Levels of IL-32, IL-6, TNF-α, and Oxidative Stress

“…Another study by Mutlu-Turkoglu et al [45] demonstrated that MDA level was increased and FRAP level was decreased in the CAD group compared to the control group. The results of a study by Luo et al [46] confirmed that IL-36R deficiency in cardiomyocytes repressed infiltration of bone marrow-derived inflammatory cells and oxidative stress, thus protecting cardiomyocytes and improving cardiac function in the cardiopulmonary bypass model rats. In conclusion, our study demonstrated that the higher serum levels of IL-36 and its association with the serum levels of TNF-α, IL-32, and IL-6 may play a key role in the CAD pathogenesis, leading to an increased risk of clogged arteries and oxidative stress.…”

Cardiomyocyte depolarization triggers NOS-dependent NO transient after calcium release, reducing the subsequent calcium transient

“…Our results support previous reports demonstrating that cardiomyocytes express nNOS [ 90 ], specifically in the sarcoplasmic reticulum [ 18 , 109 ] and at the sarcoplasm membrane [ 104 ]. eNOS is detectable in spatial microdomains of plasma membrane, such as caveolae and lipid rafts and at the sarcoplasmic membrane [ 25 , 59 , 115 ], and iNOS is normally expressed under physiological conditions in the cardiomyocyte cytoplasm, perinuclear space, Golgi complex, contractile fibers, but not in the sarcoplasmic reticulum [ 4 , 5 , 10 – 12 , 57 , 90 ]. The second approach was using pharmacological agents at the IC 50 and thus specifically inhibiting only one NOS isoform.…”

“…Alternatively, NO also modifies protein activity by reacting with specific sulfur moieties from cysteine residues, forming S -nitrosylations (SNOs) [ 69 , 93 , 110 ]. The cardiac production of NO is mediated by one of three NO synthase isoforms expressed under normal conditions: neuronal (nNOS), inducible (iNOS) or endothelial (eNOS) [ 10 , 30 , 57 , 69 , 88 , 105 , 109 , 110 ]. The three isoforms are expressed differentially and heterogeneously, varying in intensity and location between ventricles and in each muscle layer of the ventricle [ 12 , 13 ].…”