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Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality. The current study aims to explore the role of Cullin-associated and neddylation-dissociated protein 1 (CAND1) in the development of NAFLD and the underlying mechanisms. CAND1 is reduced in the liver of NAFLD male patients and high fat diet (HFD)-fed male mice. CAND1 alleviates palmitate (PA) induced lipid accumulation in vitro. Hepatocyte-specific knockout of CAND1 exacerbates HFD-induced liver injury in HFD-fed male mice, while hepatocyte-specific knockin of CAND1 ameliorates these pathological changes. Mechanistically, deficiency of CAND1 enhances the assembly of Cullin1, F-box only protein 42 (FBXO42) and acetyl-CoA acyltransferase 2 (ACAA2) complexes, and thus promotes the ubiquitinated degradation of ACAA2. ACAA2 overexpression abolishes the exacerbated effects of CAND1 deficiency on NAFLD. Additionally, androgen receptor binds to the −187 to −2000 promoter region of CAND1. Collectively, CAND1 mitigates NAFLD by inhibiting Cullin1/FBXO42 mediated ACAA2 degradation. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality, and there is no specific drug to treat it. Here, the authors show that the AR-CAND1-ACAA2 axis regulates the development of NAFLD, and enhancing the function of CAND1 is a promising strategy for the development of a therapeutic agent for NAFLD. [ABSTRACT FROM AUTHOR]

Myocardial ischemia/reperfusion (MI/R) injury is a pathological process that seriously affects the health of patients with coronary artery disease. Long non-coding RNAs (lncRNAs) represents a new class of regulators of diverse biological processes and disease conditions, the study aims to discover the pivotal lncRNA in MI/R injury. The microarray screening identifies a down-regulated heart-enriched lncRNA-CIRPIL (Cardiac ischemia reperfusion associated p53 interacting lncRNA, lncCIRPIL) from the hearts of I/R mice. LncCIRPIL inhibits apoptosis of cultured cardiomyocytes exposed to anoxia/reoxygenation (A/R). Cardiac-specific transgenic overexpression of lncCIRPIL alleviates I/R injury in mice, while knockout of lncCIRPIL exacerbates cardiac I/R injury. LncCIRPIL locates in the cytoplasm and physically interacts with p53, which leads to the cytoplasmic sequestration and the acceleration of ubiquitin-mediated degradation of p53 triggered by E3 ligases CHIP, COP1 and MDM2. p53 overexpression abrogates the protective effects of lncCIRPIL. Notably, the human fragment of conserved lncCIRPIL mimics the protective effects of the full-length lncCIRPIL on cultured human AC16 cells. Collectively, lncCIRPIL exerts its cardioprotective action via sequestering p53 in the cytoplasm and facilitating its ubiquitin-mediated degradation. The study highlights a unique mechanism in p53 signal pathway and broadens our understanding of the molecular mechanisms of MI/R injury. Overexpression of long non-coding RNA, lncCIRPIL protects the heart from ischemia/reperfusion (I/R) injury. LncCIRPIL binds and sequesters p53 in the cytoplasm to exert the cardioprotective action. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a common complication in diabetic patients. The molecular mechanisms of DCM remain to be fully elucidated. The intronic long noncoding RNA of DACH1 (lncDACH1) has been demonstrated to be closely associated with heart failure and cardiac regeneration. In this study, we investigated the role of lncDACH1 in DCM and the underlying molecular mechanisms. The expression of lncDACH1 was increased in DCM hearts and in high glucose-treated cardiomyocytes. Knockout of lncDACH1 reduced mitochondrial oxidative stress, cell apoptosis, cardiac fibrosis and hypertrophy, and improved cardiac function in DCM mice. Overexpression of lncDACH1 exacerbated mitochondria-derived reactive oxygen species (ROS) level and apoptosis, decreased activity of manganese superoxide dismutase (Mn-SOD); while silencing of lncDACH1 attenuated ROS production, mitochondrial dysfunction, cell apoptosis, and increased the activity of Mn-SOD in cardiomyocytes treated with high glucose. LncDACH1 directly bound to sirtuin3 (SIRT3) and facilitated its degradation by ubiquitination, therefore promoting mitochondrial oxidative injury and cell apoptosis in mouse hearts. In addition, SIRT3 silencing abrogated the protective effects of lncDACH1 deficiency in cardiomyocytes. In summary, lncDACH1 aggravates DCM by promoting mitochondrial oxidative stress and cell apoptosis via increasing ubiquitination-mediated SIRT3 degradation in mouse hearts. Inhibition of lncDACH1 represents a novel therapeutic strategy for the intervention of diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) account for a large proportion of genomic transcripts and are critical regulators in various cardiac diseases. Though lncRNAs have been reported to participate in the process of diverse cardiac diseases, the contribution of lncRNAs in cardiac fibrosis remains to be fully elucidated. Here, we identified a novel anti-fibrotic lncRNA, SAIL (scaffold attachment factor B interacting lncRNA). SAIL was reduced in cardiac fibrotic tissue and activated cardiac fibroblasts. Gain- and loss-of-function studies showed that knockdown of SAIL promoted proliferation and collagen production of cardiac fibroblasts with or without TGF-β1 (transforming growth factor beta1) treatment, while overexpression of SAIL did the opposite. In mouse cardiac fibrosis induced by myocardial infarction, knockdown of SAIL exacerbated, whereas overexpression of SAIL alleviated cardiac fibrosis. Mechanically, SAIL inhibited the fibrotic process by directly binding with SAFB via 23 conserved nucleotide sequences, which in turn blocked the access of SAFB to RNA pol II (RNA polymerase II) and reduced the transcription of fibrosis-related genes. Intriguingly, the human conserved fragment of SAIL (hSAIL) significantly suppressed the proliferation and collagen production of human cardiac fibroblasts. Our findings demonstrate that SAIL regulates cardiac fibrosis by regulating SAFB-mediated transcription of fibrotic related genes. Both SAIL and SAFB hold the potential to become novel therapeutic targets for cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Ventricular arrhythmia is the most common cause of sudden cardiac death in patients with myocardial infarction (MI). Fibroblast growth factor 21 (FGF21) has been shown to play an important role in cardiovascular and metabolic diseases. However, the effects of FGF21 on ventricular arrhythmias following MI have not been addressed yet. The present study was conducted to investigate the pharmacological action of FGF21 on ventricular arrhythmias after MI. Adult male mice were administrated with or without recombinant human basic FGF21 (rhbFGF21), and the susceptibility to arrhythmias was assessed by programmed electrical stimulation and optical mapping techniques. Here, we found that rhbFGF21 administration reduced the occurrence of ventricular tachycardia (VT), improved epicardial conduction velocity and shorted action potential duration at 90% (APD90) in infarcted mouse hearts. Mechanistically, FGF21 may improve cardiac electrophysiological remodeling as characterized by the decrease of INa and IK1 current density in border zone of infarcted mouse hearts. Consistently, in vitro study also demonstrated that FGF21 may rescue oxidant stress-induced dysfunction of INa and IK1 currents in cultured ventricular myocytes. We further found that oxidant stress-induced down-regulation of early growth response protein 1 (EGR1) contributed to INa and IK1 reduction in post-infarcted hearts, and FGF21 may recruit EGR1 into the SCN5A and KCNJ2 promoter regions to up-regulate NaV1.5 and Kir2.1 expression at transcriptional level. Moreover, miR-143 was identified as upstream of EGR1 and mediated FGF21-induced EGR1 up-regulation in cardiomyocytes. Collectively, rhbFGF21 administration effectively suppressed ventricular arrhythmias in post-infarcted hearts by regulating miR-143-EGR1-NaV1.5/Kir2.1 axis, which provides novel therapeutic strategies for ischemic arrhythmias in clinics. [ABSTRACT FROM AUTHOR]

Abnormal pulmonary arterial smooth muscle cells (PASMCs) proliferation is an important pathological process in hypoxic pulmonary arterial hypertension. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation-apoptosis balance. However, the molecular mechanism is still unknown. We used hypoxic animal models, cell biology, and molecular biology to determine the effect of mitofusin 1 (Mfn1) on hypoxia-mediated PASMCs mitochondrial homeostasis. We found that Mfn1 expression was increased in hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and smooth muscle cell proliferation as well as hypoxia-stimulated cell-cycle transition from the G/G phase to S phase. Subsequently, we studied the role of microRNAs in mitochondrial function associated with PASMC proliferation under hypoxic conditions. The promotive effect of Mfn1 on pulmonary vascular remodeling was alleviated in the presence of miR-125a agomir, and miR-125a antagomir mimicked the hypoxic damage effects to mitochondrial homeostasis. Moreover, in vivo and in vitro treatment with miR-125a agomir protected the pulmonary vessels from mitochondrial dysfunction and abnormal remodeling. In the present study, we determined that mitochondrial homeostasis, particularly Mfn1, played an important role in PASMCs proliferation. MiR-125a, an important underlying factor, which inhibited Mfn1 expression and decreased PASMCs disordered growth during hypoxia. These results provide a theoretical basis for the prevention and treatment of pulmonary vascular remodeling. Key messages: [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) have emerged as a new class of gene expression regulators playing key roles in many biological and pathophysiological processes. Here, we identify cardiac conduction regulatory RNA (CCRR) as an antiarrhythmic lncRNA. CCRR is downregulated in a mouse model of heart failure (HF) and in patients with HF, and this downregulation slows cardiac conduction and enhances arrhythmogenicity. Moreover, CCRR silencing induces arrhythmias in healthy mice. CCRR overexpression eliminates these detrimental alterations. HF or CCRR knockdown causes destruction of intercalated discs and gap junctions to slow longitudinal cardiac conduction. CCRR overexpression improves cardiac conduction by blocking endocytic trafficking of connexin43 (Cx43) to prevent its degradation via binding to Cx43-interacting protein CIP85, whereas CCRR silence does the opposite. We identified the functional domain of CCRR, which can reproduce the functional roles and pertinent molecular events of full-length CCRR. Our study suggests CCRR replacement a potential therapeutic approach for pathological arrhythmias. Long noncoding RNAs have been shown to play a role in cardiovascular disease. Here, the authors identify a lncRNA named CCRR, whose downregulation in failing hearts causes cardiac conduction disturbances by altering the endocytic trafficking of Cx43. [ABSTRACT FROM AUTHOR]

A long non-coding RNA (lncRNA), named myocardial infarction associated transcript (MIAT), has been documented to confer risk of myocardial infarction (MI). The aim of this study is to elucidate the pathophysiological role of MIAT in regulation of cardiac fibrosis. In a mouse model of MI, we found that MIAT was remarkably up-regulated, which was accompanied by cardiac interstitial fibrosis. MIAT up-regulation in MI was accompanied by deregulation of some fibrosis-related regulators: down-regulation of miR-24 and up-regulation of Furin and TGF-β1. Most notably, knockdown of endogenous MIAT by its siRNA reduced cardiac fibrosis and improved cardiac function and restored the deregulated expression of the fibrosis-related regulators. In cardiac fibroblasts treated with serum or angiotensin II, similar up-regulation of MIAT and down-regulation of miR-24 were consistently observed. These changes promoted fibroblasts proliferation and collagen accumulation, whereas knockdown of MIAT by siRNA or overexpression of miR-24 with its mimic abrogated the fibrogenesis. Our study therefore has identified MIAT as the first pro-fibrotic lncRNA in heart and unraveled the role of MIAT in the pathogenesis of MI. These findings also promise that normalization of MIAT level may prove to be a therapeutic option for the treatment of MI-induced cardiac fibrosis and the associated cardiac dysfunction. [ABSTRACT FROM AUTHOR]