The transcription factor zinc fingers and homeoboxes 2 alleviates NASH by transcriptional activation of phosphatase and tensin homolog.

BACKGROUND AND AIMS: NASH, which is a common clinical condition predisposing to advanced liver diseases, has become a worldwide epidemic. A large and growing unmet therapeutic need for this condition reflects incomplete understanding of its pathogenesis. In the current study, we identified a transcription factor, zinc fingers and homeoboxes 2 (ZHX2), in hepatocytes as a protective factor against steatohepatitis. APPROACH AND RESULTS: We found that hepatic ZHX2 was significantly suppressed in NASH models and steatotic hepatic cells. Hepatocyte-specific ablation of ZHX2 exacerbated NASH-related phenotypes in mice, including lipid accumulation, enhanced inflammation, and hepatic fibrosis. Conversely, hepatocyte-specific overexpression of ZHX2 significantly alleviated the progression of NASH in an experimental setting. Integrated analysis of transcriptomic profiling and chromatin immunoprecipitation sequencing data demonstrated that the phosphatase and tensin homolog (PTEN) was a target gene of ZHX2 in hepatocyte. ZHX2 bound to the promoter of PTEN gene and subsequently promoted the transcription of PTEN, which mediated the beneficial role of ZHX2 against NASH. CONCLUSIONS: The current findings demonstrate a protective role of ZHX2 against NASH progression by transcriptionally activating PTEN. These findings shed light on the therapeutic potential of targeting ZHX2 for treating NASH and related metabolic disorders.

The nuclear receptor co-repressor 1 is a novel cardioprotective factor against acute myocardial ischemia-reperfusion injury.

Acute myocardial ischemia/reperfusion (MI/R) is a major determinant of prognosis in myocardial infarction patients, while effective therapies are currently lacking. Nuclear receptor co-repressor 1 (NCoR1) is emerging as a critical regulator of cell survival and death signaling in mammals. However, the role of NCoR1 in the pathogenesis of acute MI/R injury remains unknown. Here, we observed that NCoR1 was highly expressed in the mouse heart and significantly downregulated after acute MI/R injury. Cardiomyocyte-specific NCoR1 deletion led to significantly increased infarct size and exacerbated cardiac dysfunction compared to wild-type littermates. Moreover, cardiomyocyte-specific NCoR1 deficiency exacerbated MI/R-induced mitochondrial dysfunction and apoptotic pathway activation. Transcriptomic profiling results indicated that cardiomyocyte-specific NCoR1 deficiency pivotally promoted activation of inflammatory pathways. Through integrated omics analysis, signal transducer and activator of transcription 1 (STAT1) was identified as a downstream target trans-repressed by NCoR1. STAT1 activation played a key mediating role in the detrimental effects of NCoR1 deficiency in MI/R injury. Collectively, our findings provided the first evidence that cardiomyocyte-expressed NCoR1 functioned as a crucial cardioprotective factor against acute MI/R injury by targeting the STAT1 pathway in heart.

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Metabolic Dysfunctions in Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis (HS), insulin resistance (IR), and inflammation, poses a high risk of cardiometabolic disorders. Ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme, is pivotally involved in regulating multiple inflammatory pathways; however, the role of USP4 in NAFLD is unknown. Here, we report that USP4 expression was dramatically down-regulated in livers from NAFLD patients and different NAFLD mouse models induced by high-fat diet (HFD) or genetic deficiency (ob/ob) as well as in palmitate-treated hepatocytes. Hepatocyte-specific USP4 depletion exacerbated HS, IR, and inflammatory response in HFD-induced NAFLD mice. Conversely, hepatic USP4 overexpression notably alleviated the pathological alterations in two different NAFLD models. Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-ß activated kinase 1 (TAK1), leading to a suppression of the activation of downstream nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) cascades, which, in turn, reversed the disruption of insulin receptor substrate/protein kinase B/glycogen synthase kinase 3 beta (IRS-AKT-GSK3ß) signaling. In addition, USP4-TAK1 interaction and subsequent TAK1 deubiquitination were required for amelioration of metabolic dysfunctions. Conclusion: Collectively, the present study provides evidence that USP4 functions as a pivotal suppressor in NAFLD and related metabolic disorders. (Hepatology 2018; 00:000-000).

Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor RORα signaling.

Exercise-induced physiological hypertrophy provides protection against cardiovascular disease, whereas disease-induced pathological hypertrophy leads to heart failure. Emerging evidence suggests pleiotropic roles of melatonin in cardiac disease; however, the effects of melatonin on physiological vs pathological cardiac hypertrophy remain unknown. Using swimming-induced physiological hypertrophy and pressure overload-induced pathological hypertrophy models, we found that melatonin treatment significantly improved pathological hypertrophic responses accompanied by alleviated oxidative stress in myocardium but did not affect physiological cardiac hypertrophy and oxidative stress levels. As an important mediator of melatonin, the retinoid-related orphan nuclear receptor-α (RORα) was significantly decreased in human and murine pathological hypertrophic cardiomyocytes, but not in swimming-induced physiological hypertrophic murine hearts. In vivo and in vitro loss-of-function experiments indicated that RORα deficiency significantly aggravated pathological cardiac hypertrophy, and notably weakened the anti-hypertrophic effects of melatonin. Mechanistically, RORα mediated the cardioprotection of melatonin in pathological hypertrophy mainly by transactivation of manganese-dependent superoxide dismutase (MnSOD) via binding to the RORα response element located in the promoter region of the MnSOD gene. Furthermore, MnSOD overexpression reversed the pro-hypertrophic effects of RORα deficiency, while MnSOD silencing abolished the anti-hypertrophic effects of RORα overexpression in pathological cardiac hypertrophy. Collectively, our findings provide the first evidence that melatonin exerts an anti-hypertrophic effect on pathological but not physiological cardiac hypertrophy via alleviating oxidative stress through transactivation of the antioxidant enzyme MnSOD in a RORα-dependent manner.

Effects of farnesoid-X-receptor SUMOylation mutation on myocardial ischemia/reperfusion injury in mice.

Myocardial ischemia/reperfusion (MI/R) injury induces excessive cellular apoptosis and contributes significantly to final infarct size. We previously demonstrated that a nuclear receptor, Farnesoid X receptor (FXR), plays a crucial role in mediating myocardial apoptosis. The FXR functions are regulated by post translational modifications (PTM). However, whether the proapoptotic effect of FXR in MI/R injury is regulated by PTM remains unclear. Here, we aimed to study the effect of SUMOylation, a PTM involved in the pathogenesis of MI/R injury per se, on the proapoptotic effect of FXR in MI/R injury. We observed that FXR could be SUMOylated in heart tissues, and FXR SUMOylation levels were downregulated in ischemia reperfused myocardium. By overexpression of SUMOylation-defective FXR mutant, it was demonstrated that decreased SUMOylation augmented the detrimental effect of FXR, via activation of mitochondrial apoptosis pathway and autophagy dysfunction in MI/R injury. Further mechanistic studies suggested that decreased SUMOylation levels increased the transcription activity of FXR, and the subsequently upregulated FXR target gene SHP mediated the proapoptotic effects of FXR. Taken together, we provided the first evidence that the cardiac effects of FXR could be regulated by SUMOylation, and that manipulating FXR SUMOylation levels may hold therapeutic promise for constraining MI/R injury.

Nuclear receptor retinoid-related orphan receptor α deficiency exacerbates high-fat diet-induced cardiac dysfunction despite improving metabolic abnormality.

Retinoid-related orphan receptor α (RORα), a member of the metabolic nuclear receptor superfamily, plays a vital regulatory role in circadian rhythm and metabolism. Here, we investigated the role of RORα in high-fat diet (HFD)-induced cardiac impairments and the underlying mechanisms involved. RORα-deficient stagger mice (sg/sg) and wild type (WT) littermates were fed with either standard diet or HFD. At 20weeks after HFD treatment, RORα deficiency resulted in significantly decreased body weight gain, improved dyslipidemia and ameliorated insulin resistance (evaluated by blood biochemical and glucose/insulin tolerance tests) compared with WT control. However, compared with HFD-treated WT mice, HFD-treated sg/sg mice exhibited significantly augmented myocardial hypertrophy, cardiac fibrosis (wheat germ agglutinin, masson trichrome and sirius red staining) and cardiac dysfunction (echocardiography and hemodynamics). Mechanistically, RORα deficiency impaired mitochondrial biogenesis and function. Additionally, RORα deficiency resulted in inhibition of the AMPK-PGC1α signaling pathway. In contrast, cardiomyocyte-specific RORα overexpression ameliorated myocardial hypertrophy, fibrosis and dysfunction by restoring AMPK-PGC1α signaling, and subsequently normalizing mitochondrial biogenesis. These findings demonstrated for the first time that nuclear receptor RORα deficiency aggravated HFD-induced myocardial dysfunction at least in part by impairing mitochondrial biogenesis in association with disrupting AMPK-PGC1α signaling. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren and Megan Yingmei Zhang.

Novel protective role of the circadian nuclear receptor retinoic acid-related orphan receptor-α in diabetic cardiomyopathy.

Diabetic cardiomyopathy is a major complication that significantly contributes to morbidity and mortality in diabetics with few therapies. Moreover, antidiabetic drugs reported inconsistent or even adverse cardiovascular effects, suggesting that it is important to exploit novel therapeutic targets against diabetic cardiomyopathy. Here, we observed that the nuclear melatonin receptor, the retinoic acid-related orphan receptor-α (RORα), was downregulated in diabetic hearts. By utilizing a mouse line with RORα disruption, we demonstrated that RORα deficiency led to significantly augmented diastolic dysfunction and cardiac remodeling induced by diabetes. Microscopic and molecular analyses further indicated that the detrimental effects of RORα deficiency were associated with aggravated myocardial apoptosis, autophagy dysfunction, and oxidative stress by disrupting antioxidant gene expression. By contrast, restoration of cardiac RORα levels in transgenic mice significantly improved cardiac functional and structural parameters at 8 weeks after diabetes induction. Consistent with genetic manipulation, pharmacological activation of RORα by melatonin and SR1078 (a synthetic agonist) showed beneficial effects against diabetic cardiomyopathy, while the RORα inhibitor SR3335 significantly exacerbated cardiac impairments in diabetic mice. Collectively, these findings suggest that cardiac-targeted manipulation of nuclear melatonin receptor RORα may hold promise for delaying diabetic cardiomyopathy development.

The nuclear melatonin receptor RORα is a novel endogenous defender against myocardial ischemia/reperfusion injury.

Circadian rhythm disruption or decrease in levels of circadian hormones such as melatonin increases ischemic heart disease risk. The nuclear melatonin receptors RORs are pivotally involved in circadian rhythm regulation and melatonin effects mediation. However, the functional roles of RORs in the heart have never been investigated and were therefore the subject of this study on myocardial ischemia/reperfusion (MI/R) injury pathogenesis. RORα and RORγ subtypes were detected in the adult mouse heart, and RORα but not RORγ was downregulated after MI/R. To determine the pathological consequence of MI/R-induced reduction of RORα, we subjected RORα-deficient staggerer mice and wild-type (WT) littermates to MI/R injury, resulting in significantly increased myocardial infarct size, myocardial apoptosis and exacerbated contractile dysfunction in the former. Mechanistically, RORα deficiency promoted MI/R-induced endoplasmic reticulum stress, mitochondrial impairments, and autophagy dysfunction. Moreover, RORα deficiency augmented MI/R-induced oxidative/nitrative stress. Given the emerging evidence of RORα as an essential melatonin effects mediator, we further investigated the RORα roles in melatonin-exerted cardioprotection, in particular against MI/R injury, which was significantly attenuated in RORα-deficient mice, but negligibly affected by cardiac-specific silencing of RORγ. Finally, to determine cell type-specific effects of RORα, we generated mice with cardiomyocyte-specific RORα overexpression and they were less vulnerable to MI/R injury. In summary, our study provides the first direct evidence that the nuclear melatonin receptor RORα is a novel endogenous protective receptor against MI/R injury and an important mediator of melatonin-exerted cardioprotection; melatonin-RORα axis signaling thus appears important in protection against ischemic heart injury.

Early resolution of ST-segment elevation after reperfusion therapy for acute myocardial infarction: Its relation to echocardiography-determined left ventricular global and regional function and deformation.

AIMS: To evaluate the relationships between ST-segment resolution (STR) and echocardiography-determined left ventricular (LV) global and regional function and deformation in the sub-acute phase of STEMI. METHODS AND RESULTS: STR, defined as either complete (≥70%) or incomplete (<70%), was evaluated 60minutes after primary percutaneous coronary intervention (PCI) of 84 STEMI patients. Conventional two-dimensional (2D) echocardiography and 2D speckle-tracking echocardiography (STE) were performed at 3-7days after reperfusion. LV deformation [including the infarction-related regional longitudinal (RLS), circumferential (RCS), and radial (RRS) strains, and global longitudinal (GLS), circumferential (GCS), and radial (GRS) strains] was measured by 2D STE. LV segmental function was assessed by wall motion score index (WMSI). Patients in incomplete vs. complete STR groups had higher WMSI (p<0.001); decreased peak amplitude of RLS (p<0.001), RCS (p=0.008), RRS (p=0.002); and decreased peak amplitude of GLS (p<0.001), GCS (p<0.001), GRS (p=0.003). RLS (r=0.27, p=0.015) and GLS (r=0.33, p=0.003) were best correlates of STR at the regional and global level, respectively. CONCLUSIONS: STR correlated with global and regional LV function and deformation in patients with sub-acute phase of STEMI after PCI. RLS and GLS were the strongest correlates of STR at the regional and global levels, respectively.

The Role of CD147 in Pathological Cardiac Hypertrophy Is Regulated by Glycosylation.

CD147, also known as EMMPRIN or basigin, is a transmembrane glycoprotein receptor that activates matrix metalloproteinases and promotes inflammation. CD147 function is regulated by posttranslational modifications of which glycosylation has attracted the most attention. In this study, we demonstrated that glycosylated CD147 was the dominant form in heart tissue, and its levels were markedly elevated in response to transverse aortic constriction (TAC). Adeno-associated virus 9-mediated, cardiac-specific overexpression of wild-type CD147 in mice significantly promoted pressure overload-induced pathological cardiac remodeling accompanied by augmented oxidative stress and ferroptosis. By contrast, mutations of CD147 glycosylation sites notably weakened these detrimental effects of CD147. Mechanistically, CD147 exacerbated TAC-induced pathological cardiac remodeling via direct binding with the adaptor molecule TRAF2 and subsequent activation of TAK1 signalling, which was dependent on glycosylation of CD147. Collectively, our findings provide the first evidence that CD147 promoted pathological cardiac remodeling and dysfunction in a glycosylation-dependent manner through binding the adaptor protein TRAF2 and activating the downstream TRAF2-TAK1 signalling pathway. Thus, glycosylation of CD147 may be a potent interventional target for heart failure treatment.

Disruption of Circadian Rhythms by Shift Work Exacerbates Reperfusion Injury in Myocardial Infarction.

BACKGROUND: Shift work is associated with increased risk of acute myocardial infarction (AMI) and worsened prognosis. However, the mechanisms linking shift work and worsened prognosis in AMI remain unclear. OBJECTIVES: This study sought to investigate the impact of shift work on reperfusion injury, a major determinant of clinical outcomes in AMI. METHODS: Study patient data were obtained from the database of the EARLY-MYO-CMR (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI) registry, which was a prospective, multicenter registry of patients with ST-segment elevation myocardial infarction (STEMI) undergoing cardiac magnetic resonance (CMR) imaging after reperfusion therapy. The primary endpoint was CMR-defined post-reperfusion infarct size. A secondary clinical endpoint was the composite of major adverse cardiac events (MACE) during follow-up. Potential mechanisms were explored with the use of preclinical animal AMI models. RESULTS: Of 706 patients enrolled in the EARLY-MYO-CMR registry, 412 patients with STEMI were ultimately included. Shift work was associated with increased CMR-defined infarct size (ß = 5.94%; 95% CI: 2.94-8.94; P < 0.0001). During a median follow-up of 5.0 years, shift work was associated with increased risks of MACE (adjusted HR: 1.92; 95% CI: 1.12-3.29; P = 0.017). Consistent with clinical findings, shift work simulation in mice and sheep significantly augmented reperfusion injury in AMI. Mechanism studies identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that played a crucial role in mediating the detrimental effects of shift work on myocardial injury. CONCLUSIONS: The current study provided novel findings that shift work increases myocardial infarction reperfusion injury. It identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that might play a crucial role in mediating this process. (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI [EARLY-MYO-CMR] registry; NCT03768453).

The circadian nuclear receptor RORα negatively regulates cerebral ischemia-reperfusion injury and mediates the neuroprotective effects of melatonin.

Disruptions of the circadian rhythm and reduced circulating levels of the circadian hormone melatonin predispose to ischemic stroke. Although the nuclear receptor RORα is considered as a circadian rhythm regulator and a mediator of certain melatonin effects, its potential role in cerebral ischemia-reperfusion (CI/R) injury and in the neuroprotective effects of melatonin remain undefined. Here, we observed that CI/R injury in RORα-deficient mice was associated with greater cerebral infarct size, brain edema, and cerebral apoptosis compared with wild-type model. In contrast, transgenic mice with brain-specific overexpression of RORα versus non-transgenic controls exerted significantly reduced infarct volume, brain edema and apoptotic response induced by CI/R. Mechanistically, RORα deficiency was found to exacerbate apoptosis pathways mediated by endoplasmic-reticulum stress and mitochondria and aggravate oxidative/nitrative stress after CI/R. Further studies revealed that RORα deficiency intensified the activation of nuclear factor-κB signaling induced by CI/R. Given the emerging evidence of RORα as an essential melatonin activity mediator, we further investigated the RORα roles in melatonin-exerted neuroprotection against acute ischemic stroke. Melatonin treatment significantly decreased infarct volume and cerebral apoptosis; mitigated endoplasmic reticulum stress and mitochondrial dysfunction; and inhibited CI/R injury-induced oxidative/nitrative stress and nuclear factor-κB activation, which was eradicated in RORα-deficient mice. Collectively, current findings suggest that RORα is a novel endogenous neuroprotective receptor, and a pivotal mediator of melatonin's suppressive effects against CI/R injury.

The desumoylating enzyme sentrin-specific protease 3 contributes to myocardial ischemia reperfusion injury.

Sentrin-specific protease 3 (SENP3), a member of the desumoylating enzyme family, is known as a redox sensor and could regulate multiple cellular signaling pathways. However, its implication in myocardial ischemia reperfusion (MIR) injury is unclear. Here, we observed that SENP3 was expressed and upregulated in the mouse heart depending on reactive oxygen species (ROS) production in response to MIR injury. By utilizing siRNA-mediated cardiac specific gene silencing, SENP3 knockdown was demonstrated to significantly reduce MIR-induced infarct size and improve cardiac function. Mechanistic studies indicated that SENP3 silencing ameliorated myocardial apoptosis mainly via suppression of endoplasmic reticulum (ER) stress and mitochondrial-mediated apoptosis pathways. By contrast, adenovirus-mediated cardiac SENP3 overexpression significantly exaggerated MIR injury. Further molecular analysis revealed that SENP3 promoted mitochondrial translocation of dynamin-related protein 1 (Drp1) in reperfused myocardium. In addition, mitochondrial division inhibitor-1 (Mdivi-1), a pharmacological inhibitor of Drp1, significantly attenuated the exaggerated mitochondrial abnormality and cardiac injury by SENP3 overexpression after MIR injury. Taken together, we provide the first direct evidence that SENP3 upregulation pivotally contributes to MIR injury in a Drp1-dependent manner, and suggest that SENP3 suppression may hold therapeutic promise for constraining MIR injury.

Novel Protective Role for Ubiquitin-Specific Protease 18 in Pathological Cardiac Remodeling.

Ubiquitin-specific protease 18 (USP18), a USP family member, is involved in antiviral activity and cancer inhibition. Although USP18 is expressed in heart, the role of USP18 in the heart and in cardiac diseases remains unknown. Here, we show that USP18 expression is elevated in both human dilated hearts and hypertrophic murine models. Cardiomyocyte-specific overexpression of USP18 in mice significantly blunted cardiac remodeling as evidenced by mitigated myocardial hypertrophy, fibrosis, ventricular dilation, and preserved ejection function, whereas USP18-deficient mice displayed exacerbated cardiac remodeling under the same pathological stimuli. Similar results were observed for in vitro angiotensin II-induced neonatal rat cardiomyocyte hypertrophy. The antihypertrophic effects of USP18 under hypertrophic stimuli were associated with the blockage of the transforming growth factor-ß-activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling cascade. Blocking transforming growth factor-ß-activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling with a pharmacological inhibitor (5Z-7-oxozeaenol) greatly reversed the detrimental effects observed in USP18-knockout mice subjected to aortic banding. Our data indicate that USP18 inhibits cardiac hypertrophy and postpones cardiac dysfunction during the remodeling process, which is dependent on its modulation of the transforming growth factor-ß-activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling axis. Thus, USP18 is a potent therapeutic target for heart failure treatment.

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy.

Dysregulation of the ubiquitin proteasome system components ubiquitin ligases and proteasome plays an important role in the pathogenesis of cardiac hypertrophy. However, little is known about the role of another ubiquitin proteasome system component, the deubiquitinating enzymes, in cardiac hypertrophy. Here, we revealed a crucial role of ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme prominently expressed in the heart, in attenuating pathological cardiac hypertrophy and dysfunction. USP4 levels were consistently decreased in human failing hearts and in murine hypertrophied hearts. Adenovirus-mediated gain- and loss-of-function approaches indicated that deficiency of endogenous USP4 promoted myocyte hypertrophy induced by angiotensin II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of angiotensin II. To corroborate the role of USP4 in vivo, we generated USP4 global knockout mice and mice with cardiac-specific overexpression of USP4. Consistent with the in vitro study, USP4 depletion exacerbated the hypertrophic phenotype and cardiac dysfunction in mice subjected to pressure overload, whereas USP4 transgenic mice presented ameliorated pathological cardiac hypertrophy compared with their control littermates. Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor ß-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo. These findings provide the first evidence for the involvement of USP4 in cardiac hypertrophy, and shed light on the therapeutic potential of targeting USP4 in the treatment of cardiac hypertrophy.

YiXin-Shu, a ShengMai-San-based traditional Chinese medicine formula, attenuates myocardial ischemia/reperfusion injury by suppressing mitochondrial mediated apoptosis and upregulating liver-X-receptor α.

Positive evidence from clinical trials has fueled growing acceptance of traditional Chinese medicine (TCM) for the treatment of cardiac diseases; however, little is known about the underlying mechanisms. Here, we investigated the nature and underlying mechanisms of the effects of YiXin-Shu (YXS), an antioxidant-enriched TCM formula, on myocardial ischemia/reperfusion (MI/R) injury. YXS pretreatment significantly reduced infarct size and improved viable myocardium metabolism and cardiac function in hypercholesterolemic mice. Mechanistically, YXS attenuated myocardial apoptosis by inhibiting the mitochondrial mediated apoptosis pathway (as reflected by inhibition of mitochondrial swelling, cytochrome c release and caspase-9 activity, and normalization of Bcl-2 and Bax levels) without altering the death receptor and endoplasmic reticulum-stress death pathways. Moreover, YXS reduced oxidative/nitrative stress (as reflected by decreased superoxide and nitrotyrosine content and normalized pro- and anti-oxidant enzyme levels). Interestingly, YXS upregulated endogenous nuclear receptors including LXRα, PPARα, PPARß and ERα, and in-vivo knockdown of cardiac-specific LXRα significantly blunted the cardio-protective effects of YXS. Collectively, these data show that YXS is effective in mitigating MI/R injury by suppressing mitochondrial mediated apoptosis and oxidative stress and by upregulating LXRα, thereby providing a rationale for future clinical trials and clinical applications.

Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy.

Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure.

Association between tissue characteristics of coronary plaque and distal embolization after coronary intervention in acute coronary syndrome patients: insights from a meta-analysis of virtual histology-intravascular ultrasound studies.

BACKGROUND AND OBJECTIVES: The predictive value of plaque characteristics assessed by virtual histology-intravascular ultrasound (VH-IVUS) including fibrous tissue (FT), fibrofatty (FF), necrotic core (NC) and dense calcium (DC) in identifying distal embolization after percutaneous coronary intervention (PCI) is still controversial. We performed a systematic review and meta-analysis to summarize the association of pre-PCI plaque composition and post-PCI distal embolization in acute coronary syndrome patients. METHODS: Studies were identified in PubMed, OVID, EMBASE, the Cochrane Library, the Current Controlled Trials Register, reviews, and reference lists of relevant articles. A meta-analysis using both fixed and random effects models with assessment of study heterogeneity and publication bias was performed. RESULTS: Of the 388 articles screened, 10 studies with a total of 872 subjects (199 with distal embolization and 673 with normal flow) met the eligibility of our study. Compared with normal flow groups, significant higher absolute volume of NC [weighted mean differences (WMD): 5.79 mm3, 95% CI: 3.02 to 8.55 mm3; p<0.001] and DC (WMD: 2.55 mm3, 95% CI: 0.22 to 4.88 mm3; p = 0.03) were found in acute coronary syndrome patients with distal embolization. Further subgroup analysis demonstrated that the predictive value of tissue characteristics in determining distal embolization was correlated to clinical scenario of the patients, definition of distal embolization, and whether the percutaneous aspiration thrombectomy was applied. CONCLUSION: Our study that pooled current evidence showed that plaque components were closely related to the distal embolization after PCI, especially the absolute volume of NC and DC, supporting further studies with larger sample size and high-methodological quality.