Efficiency and safety of high-power ablation guided by Lesion size index: An ex vivo porcine heart study.

BACKGROUND: Although Lesion size index (LSI) has been reported to highly predict radiofrequency lesion size in vitro, its accuracy in lesion size and steam pop estimation has not been well investigated for every possible scenario. METHODS: Initially, radiofrequency ablations were performed on porcine myocardial slabs at various power, CF, and time settings with blinded LSI. Subsequently, radiofrequency power at 20, 30, 40, 50, and 60 W was applied at CF values of 5, 10, 20, and 30 g to reach target LSIs of 4, 5, 6, and 7. Lesion size and steam pops were recorded for each ablation. RESULTS: Lesion size was positively correlated with LSI regardless of power settings (p < 0.001). The linear correlation coefficients of lesion size and LSI decreased at higher power settings. At high power combined with high CF settings (50 W/20 g), lesion depth and LSI showed an irrelevant correlation (p = 0.7855). High-power ablation shortened ablation time and increased the effect of resistive heating. LSI could predict the risk of steam pops at high-power settings with the optimal threshold of 5.65 (sensitivity, 94.1%; specificity, 46.1%). The ablation depth of the heavy heart was shallower than that of the light heart under similar ablation settings. CONCLUSIONS: LSI could predict radiofrequency lesion size and steam pops at high power settings in vitro, while synchronous high power and high CF should be avoided. Lighter hearts require relatively lower ablation settings to create appropriate ablation depth.

ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury.

Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl2 or elesclomol-CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe-S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.

Cirsiliol regulates mitophagy in colon cancer cells via STAT3 signaling.

BACKGROUND: Mitophagy is a type of selective autophagy for dysfunctional mitochondria and plays a key role in tumorigenesis and cancer progression. However, whether mitophagy plays a role in colon cancer remains unclear. Cirsiliol is a natural product and has been found to exert anti-cancer effects in multiple tumors. The effects of cirsiliol in the tumorigenesis and progression of colon cancer remain unknown. METHODS: CCK8 assay, plate cloning assay, and cell scratch assay were performed to determine cell viability, colony formation, and wound healing abilities of HCT116 and SW480 cells. JC-1 staining, H2DCFDA staining, and Mito-Tracker Red staining were carried out to evaluate mitochondrial membrane potential (Δψm), intracellular reactive oxygen species (ROS) level, and mitochondrial morphology. Molecular docking technology was utilized to predict interaction of cirsiliol and signal transducer and activator of transcription 3 (STAT3). Immunofluorescence staining was used to measure nuclear translocation of STAT3. The protein levels of phosphorylated STAT3 (Y705), total STAT3, and mitophagy proteins were detected by western blot. RESULTS: In this study, we first found that cirsiliol inhibited cell viability, colony formation, and wound healing abilities of HCT116 and SW480 colon cancer cells. Moreover, cirsiliol suppressed Δψm, increased ROS production, and disrupted mitochondrial morphology via inhibiting the levels of mitophagy proteins including PINK1, Parkin, BNIP3, and FUNDC1. Application of mitophagy activator improved the levels of mitophagy-related proteins, and ameliorated Δψm and ROS levels. According to the result of molecular docking, we found that cirsiliol potentially bound to the SH2 domain of STAT3, the key domain for the functional activation of STAT3. Moreover, it was found that cirsiliol inhibited constitutive and IL­6­induced STAT3 phosphorylation and nuclear translocation by western blot and immunofluorescence analysis. Comparing with cirsiliol group, we found that overexpression of STAT3 restored the expressions of mitophagy proteins. CONCLUSIONS: Cirsiliol targets STAT3 to inhibit colon cancer cell proliferation by regulating mitophagy.

Coagulopathy in COVID-19: Focus on vascular thrombotic events.

SARS-CoV-2 causes a phenotype of pneumonia with diverse manifestation, which is termed as coronavirus disease 2019 (COVID-19). An impressive high transmission rate allows COVID-19 conferring enormous challenge for clinicians worldwide, and developing to a pandemic level. Combined with a series of complications, a part of COVID-19 patients progress into severe cases, which critically contributes to the risk of fatality. To date, coagulopathy has been found as a prominent feature of COVID-19 and severe coagulation dysfunction may be associated with poor prognosis. Coagulopathy in COVID-19 may predispose patients to hypercoagulability-related disorders including thrombosis and even fatal vascular events. Inflammatory storm, uncontrolled inflammation-mediated endothelial injury and renin angiotensin system (RAS) dysregulation are the potential mechanisms. Ongoing efforts made to develop promising therapies provide several potential strategies for hypercoagulability in COVID-19. In this review, we introduce the clinical features of coagulation and the increased vascular thrombotic risk conferred by coagulopathy according to present reports about COVID-19. The potential underlying mechanisms and emerging therapeutic avenues are discussed, emphasizing an urgent need for effective interventions.

Inhibition of Interleukin-6/glycoprotein 130 signalling by Bazedoxifene ameliorates cardiac remodelling in pressure overload mice.

The role of IL-6 signalling in hypertensive heart disease and its sequelae is controversial. Our group demonstrated that Bazedoxifene suppressed IL-6/gp130 signalling in cancer cells but its effect on myocardial pathology induced by pressure overload is still unknown. We explored whether Bazedoxifene could confer benefits in wild-type C57BL/6J mice suffering from transverse aortic constriction (TAC) and the potential mechanisms in H9c2 myoblasts. Mice were randomized into three groups (Sham, TAC, TAC+Bazedoxifene, n = 10). Morphological and histological observations suggested TAC aggravated myocardial remodelling while long-term intake of Bazedoxifene (5 mg/kg, intragastric) attenuated pressure overload-induced pathology. Echocardiographic results indicated Bazedoxifene rescued cardiac function in part. We found Bazedoxifene decreased the mRNA expression of IL-6, MMP2, Col1A1, Col3A1 and periostin in murine hearts after 8-week surgery. By Western blot detection, we found Bazedoxifene exhibited an inhibition of STAT3 activation in mice three hours and 8 weeks after TAC. Acute TAC stress (3 hours) led to down-regulated ratio of LC3-Ⅱ/LC3-Ⅰ, while in mice after long-term (8 weeks) TAC this ratio becomes higher than that in Sham mice. Bazedoxifene inverted the autophagic alteration induced by TAC at both two time-points. In H9c2 myoblasts, Bazedoxifene suppressed the IL-6-induced STAT3 activation. Moreover, IL-6 reduced the ratio of LC3-Ⅱ/LC3-Ⅰ, promoted P62 expression but Bazedoxifene reversed both changes in H9c2 cells. Our data suggested Bazedoxifene inhibited IL-6/gp130 signalling and protected against cardiac remodelling together with function deterioration in TAC mice.

Bazedoxifene exhibits growth suppressive activity by targeting interleukin-6/glycoprotein 130/signal transducer and activator of transcription 3 signaling in hepatocellular carcinoma.

The interleukin (IL)-6/glycoprotein (GP)130/signal transducer and activator of transcription (STAT)3 pathway is emerging as a target for the treatment of hepatocellular carcinoma. IL-6 binds to IL-6R, forming a binary complex, which further combines with GP130 to transduce extracellular signaling by activating STAT3. Therefore, blocking the interaction between IL-6 and GP130 may inhibit the IL-6/GP130/STAT3 signaling pathway and its biological effects. It has been reported that bazedoxifene acetate (BAZ), a selective estrogen receptor modulator approved by the US Food and Drug Administration, could inhibit IL-6/GP130 protein-protein interactions. Western blot, immunofluorescence staining, wound healing and colony formation assays were used to detect the effect of BAZ on liver cancer cells. Cell viability was evaluated by MTT assay. Apoptosis of cells was determined using the Annexin V-FITC detection kit. Mouse xenograft tumor models were utilized to evaluate the effect of BAZ in vivo. Our data showed that BAZ inhibited STAT3 phosphorylation (P-STAT3) and expression of STAT3 downstream genes, inducing apoptosis in liver cancer cells. BAZ inhibited P-STAT3 induced by IL-6, but not by leukemia inhibitory factor. BAZ inhibited P-STAT1 and P-STAT6 less significantly as elicited by interferon-α, interferon-γ and IL-4. In addition, pretreatment of BAZ impeded the translocation of STAT3 to nuclei induced by IL-6. BAZ inhibited cell viability, wound healing and colony formation in vitro. Furthermore, tumor growth in HEPG2 mouse xenografts were significantly inhibited by daily intragastric gavage of BAZ. Our results suggest that BAZ inhibited the growth of hepatocellular carcinoma in vitro and in vivo, indicating another potential strategy for HCC prevention and therapy.

Inhibition of IL-6/STAT3 signaling in human cancer cells using Evista.

Persistent activation of IL-6/STAT3 signaling pathway has been frequently detected in human cancer including breast cancer, colon cancer and multiple myeloma. IL-6/STAT3 can be a promising target for cancer prevent and treatment. However, few STAT3 inhibitors with high efficiency, specificity and safety is available for present clinical cancer therapy. Evista (Raloxifene·HCl) is known as selective estrogen receptor modulator which has been used for the prevention and treatment of osteoporosis and was approved for reducing the risk of invasive breast cancer. Our previous study found that Raloxifene inhibited IL-6/GP130 interaction, resulting in blockade of STAT3 phosphorylation. In our present study, we examined the effect on IL-6/GP130/STAT3 signaling pathway and cancer cell viability with Evista. We first demonstrated Evista inhibited constitutive activation of STAT3 in breast cancer cell line MDB-MB-231, colon cancer cell line HCT116 and multiple myeloma cancer cell line U266. Evista also inhibited phosphorylation of STAT3 induced by IL-6 in MCF-7, HT29 and MM.1S cancer cell lines. Induction of apoptosis was exerted in MDA-MB-231, HCT116 and U266 as evidenced by increased caspase-3 cleavage. However, Evista did not inhibit STAT1, STAT2, STAT4 or STAT6 phosphorylation elicited by IFN-α, IFN-γ and IL-4, nor phosphorylation of STAT3 induced by LIF in MCF-7 cell lines. Evista attenuated STAT3 phosphorylation, decreased STAT3 transcriptional activity but much less in pGL3 and AP1 transcriptional luciferase activity, and decreased cell viability in vitro. These results suggest that it may be possible for Evista to emerge as a chemoprevention agent for breast cancer and other cancers such as colon cancer or multiple myeoloma by targeting IL-6/STAT3 signaling.

Ability of ambulatory ECG-based T-wave alternans to modify risk assessment of cardiac events: a systematic review.

BACKGROUND: Exercise-based spectral T-wave alternans (TWA) has been proposed as a noninvasive tool-identifying patients at risk of sudden cardiac death (SCD) and cardiac mortality. Prior studies have indicated that ambulatory electrocardiogram (AECG)-based TWA is an important alternative platform to exercise for risk stratification of cardiac events. This study sought to review data regarding 24-hour AECG-based TWA and to discuss its potential role in risk stratification of fatal cardiac events across a series of patient risk profiles. METHODS: Prospective clinical studies of the predictive value of AECG-based TWA obtained with daily activity published between January 1990 and November 2014 were retrieved. Major endpoints included composite endpoint of SCD, cardiac mortality, and severe arrhythmic events. RESULTS: Data were accumulated from 5 studies involving a total of 1,588 patients, including 317 positive and 1,271 negative TWA results. Compared with the negative group, positive group showed increased rates of SCD (hazard ratio [HR]: 7.49, 95% confidence interval [CI]: 2.65 to 21.15), cardiac mortality (HR: 4.75, 95% CI: 0.42 to 53.55), and composite endpoint (SCD, cardiac mortality, and severe arrhythmic events, HR: 5.94, 95% CI: 1.80 to 19.63). For the 4 studies evaluating TWA measured using the modified moving average method, the HR associated with a positive versus negative TWA result was 9.51 (95% CI: 4.99 to 18.11) for the composite endpoint. CONCLUSIONS: The positive group of AECG-based TWA has a nearly six-fold risk of severe outcomes compared with the negative group. Therefore, AECG-based TWA provides an accurate means of predicting fatal cardiac events.

Inhibitory effects of roscovitine on proliferation and migration of vascular smooth muscle cells in vitro.

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are the major cause of in-stent restenosis (ISR). Intervention proliferation and migration of VSMCs is an important strategy for antirestenotic therapy. Roscovitine, a second-generation cyclin-dependent kinase inhibitor, can inhibit cell cycle of multiple cell types. We studied the effects of roscovitine on cell cycle distribution, proliferation and migration of VSMCs in vitro by flow cytometry, BrdU incorporation and wound healing assay, respectively. Our results showed that roscovitine increased the proportion of G0/G1 phase cells after 12 h (69.57±3.65 vs. 92.50±1.68, P=0.000), 24 h (80.87±2.24 vs. 90.25±0.79, P=0.000) and 48 h (88.08±3.86 vs. 88.87±2.43, P=0.427) as compared with control group. Roscovitine inhibited proliferation and migration of VSMCs in a concentration-dependent way. With the increase of concentration, roscovitine showed increased capacity for growth and migration inhibition. Roscovitine (30 µmol/L) led to an almost complete VSMCs growth and migration arrest. Combined with its low toxicity and selective inhibition to ISR-VSMCs, roscovitine may be a potential drug in the treatment of vascular stenosis diseases and particularly useful in the prevention and treatment of ISR.

Modulation of ER-mitochondria tethering complex VAPB-PTPIP51: Novel therapeutic targets for aging-associated diseases.

Aging is a gradual and irreversible natural process. With aging, the body experiences a functional decline, and the effects amplify the vulnerability to a range of age-related diseases, including neurodegenerative, cardiovascular, and metabolic diseases. Within the aging process, the morphology and function of mitochondria and the endoplasmic reticulum (ER) undergo alterations, particularly in the structure connecting these organelles known as mitochondria-associated membranes (MAMs). MAMs serve as vital intracellular signaling hubs, facilitating communication between the ER and mitochondria when regulating various cellular events, including calcium homeostasis, lipid metabolism, mitochondrial function, and apoptosis. The formation of MAMs is partly dependent on the interaction between the vesicle-associated membrane protein-associated protein-B (VAPB) and protein tyrosine phosphatase-interacting protein-51 (PTPIP51). Accumulating evidence has begun to elucidate the pivotal role of the VAPB-PTPIP51 tether in the initiation and progression of age-related diseases. In this study, we delineate the intricate structure and multifunctional role of the VAPB-PTPIP51 tether and discuss its profound implications in aging-associated diseases. Moreover, we provide a comprehensive overview of potential therapeutic interventions and pharmacological agents targeting the VAPB-PTPIP51-mediated MAMs, thereby offering a glimmer of hope in mitigating aging processes and treating age-related disorders.

The role of STAT3/VAV3 in glucolipid metabolism during the development of HFD-induced MAFLD.

Metabolic-associated fatty liver disease (MAFLD) is a globally prevalent chronic hepatic disease. Previous studies have indicated that the activation of the signal transducer and activator of transcription3 (STAT3) plays a vital role in MAFLD progression at the very beginning. However, the specific association between STAT3 and abnormal hepatic metabolism remains unclear. In this study, activated inflammation was observed to induce abnormal glucolipid metabolic disorders in the hepatic tissues of high-fat diet (HFD)-fed ApoE-/- mice. Furthermore, we found that the activation of STAT3 induced by HFD might function as a transcriptional factor to suppress the expression of VAV3, which might participate in intracellular glucolipid metabolism and the regulation of glucose transporter 4 (GLUT4) storage vesicle traffic in the development of MAFLD both in vitro and in vivo. We verified that VAV3 deficiency could retard the GLUT4 membrane translocation and impair the glucose homeostasis. Additionally, VAV3 participates in cholesterol metabolism in hepatocytes, eventually resulting in the accumulation of intracellular cholesterol. Moreover, rAAV8-TBG-VAV3 was conducted to restore the expression of VAV3 in HFD-fed ApoE-/- mice. VAV3 overexpression was observed to improve glucose homeostasis as well as attenuate hepatic cholesterol accumulation in vivo. In conclusion, the STAT3/VAV3 signaling pathway might play a significant role in MAFLD by regulating glucose and cholesterol metabolism, and VAV3 might be a potential therapeutic strategy which could consequently ameliorate MAFLD.

KN-93, A CaMKII inhibitor, suppresses ventricular arrhythmia induced by LQT2 without decreasing TDR.

Abnormal enhanced transmural dispersion of repolarization (TDR) plays an important role in the maintaining of the severe ventricular arrhythmias such as torsades de pointes (TDP) which can be induced in long-QT (LQT) syndrome. Taking advantage of an in vitro rabbit model of LQT2, we detected the effects of KN-93, a CaM-dependent kinase (CaMK) II inhibitor on repolarization heterogeneity of ventricular myocardium. Using the monophasic action potential recording technique, the action potentials of epicardium and endocardium were recorded in rabbit cardiac wedge infused with hypokalemic, hypomagnesaemic Tyrode's solution. At a basic length (BCL) of 2000 ms, LQT2 model was successfully mimicked with the perfusion of 0.5 µmol/L E-4031, QT intervals and the interval from the peak of T wave to the end of T wave (Tp-e) were prolonged, and Tp-e/QT increased. Besides, TDR was increased and the occurrence rate of arrhythmias like EAD, R-on-T extrasystole, and TDP increased under the above condition. Pretreatment with KN-93 (0.5 µmol/L) could inhibit EAD, R-on-T extrasystole, and TDP induced by E-4031 without affecting QT interval, Tp-e, and Tp-e/QT. This study demonstrated KN-93, a CaMKII inhibitor, can inhibit EADs which are the triggers of TDP, resulting in the suppression of TDP induced by LQT2 without affecting TDR.

Clinical characteristics of primary atrial tumor and their diagnostic value: A retrospective study of 10 years.

Background: Primary atrial tumors are relatively rare and predominantly benign. However, some atrial tumors may be malignant and are associated with poor outcome. Currently, it is hard to determine the malignance of atrial tumors by preoperative clinical presentation or by echocardiography. We aimed to report the difference in the clinical characteristics of patients with benign and malignant atrial tumor. Methods: This was a single-center retrospective study. A total of 194 patients with primary atrial tumor admitted to our center between 2012 and 2021 were included. The clinical characteristics of patients with benign and malignant tumor were compared. Results: Benign and malignant tumor accounted for 93% (n = 180) and 7% (n = 14) of the total patients, respectively. Malignant atrial tumor tended to occur in younger patients (P < 0.05), was more likely to be located at the right atrium (P < 0.05), and tended to attach to the atrial wall or valve instead of the atrial septum. Fever symptoms were more common in patients with malignant tumors than in patients with benign tumors (P < 0.05). Compared to benign tumor, patients with malignant atrial tumor also demonstrated higher rates of fever, lower rates of increasing fibrinogen, increased blood glucose (P < 0.05), significantly longer prothrombin time, and lower prothrombin activity (P < 0.05). Patients with malignant primary atrial tumor had higher mortality rate, tumor metastasis rate, and tumor recurrence rate than patients with benign primary atrial tumor (P < 0.05). Conclusion: We compared the clinical characteristics of patients with benign and malignant atrial tumor. These findings provide valuable information to preoperatively determine the malignance of atrial tumor and thus guide surgical treatment.

sGC agonist BAY1021189 promotes thoracic aortic dissection formation by accelerating vascular smooth muscle cell phenotype switch.

Thoracic aortic dissection (TAD) is common but lethal cardiovascular disease with high mortality. This study aimed to expound whether and how sGC-PRKG1 signaling pathway might promote the formation of TAD. Our work identified two modules with high relevance to TAD using WGCNA method. Combined with previous studies, we focused on the participation of endothelial NOS (eNOS) in the progression of TAD. Through immunohistochemistry, immunofluorescence and western blot we verified that eNOS expression was elevated in the tissues of patients and mice with aortic dissection, and the phosphorylation Ser1177 of eNOS was activated. In a BAPN-induced TAD mouse model, sGC-PRKG1 signaling pathway promotes TAD formation by inducing vascular smooth muscle cells (VSMCs) phenotype transition, which was demonstrated as a decrease in markers of the contractile phenotype of VSMCs such as αSMA, SM22α, and Calponin. These results were also verified by experiments in vitro. To explore the further mechanism, we conducted immunohistochemistry, western blot and quantitative RT-PCR (qPCR), the results of which indicated that sGC-PRKG1 signaling pathway was activated when TAD occurred. In conclusion, our current study revealed that sGC-PRKG1 signaling pathway could promote TAD formation by accelerating VSMCs phenotype switch.

Notopterol Ameliorates Hyperuricemia-Induced Cardiac Dysfunction in Mice.

Notopterol is a naturally occurring furanocoumarin compound found in the root of Notopterygium incisum. Hyperuricemia involves the activation of chronic inflammation and leads to cardiac damage. Whether notopterol has cardioprotective potential in hyperuricemia mice remains elusive. The hyperuricemic mouse model was constructed by administration of potassium oxonate and adenine every other day for six weeks. Notopterol (20 mg/kg) and allopurinol (10 mg/kg) were given daily as treatment, respectively. The results showed that hyperuricemia dampened heart function and reduced exercise capacity. Notopterol treatment improved exercise capacity and alleviated cardiac dysfunction in hyperuricemic mice. P2X7R and pyroptosis signals were activated both in hyperuricemic mice and in uric acid-stimulated H9c2 cells. Additionally, it was verified that inhibition of P2X7R alleviated pyroptosis and inflammatory signals in uric acid-treated H9c2 cells. Notopterol administration significantly suppressed expression levels of pyroptosis associated proteins and P2X7R in vivo and in vitro. P2X7R overexpression abolished the inhibition effect of notopterol on pyroptosis. Collectively, our findings suggested that P2X7R played a critical role in uric acid-induced NLRP3 inflammatory signals. Notopterol inhibited pyroptosis via inhibiting the P2X7R/NLRP3 signaling pathway under uric acid stimulation. Notopterol might represent a potential therapeutic strategy against pyroptosis and improve cardiac function in hyperuricemic mice.

STAT3 signaling promotes cardiac injury by upregulating NCOA4-mediated ferritinophagy and ferroptosis in high-fat-diet fed mice.

High-fat diet (HFD) intake provokes obesity and cardiac anomalies. Recent studies have found that ferroptosis plays a role in HFD-induced cardiac injury, but the underlying mechanism is largely unclear. Ferritinophagy is an important part of ferroptosis that is regulated by nuclear receptor coactivator 4 (NCOA4). However, the relationship between ferritinophagy and HFD-induced cardiac damage has not been explored. In this study, we found that oleic acid/palmitic acid (OA/PA) increased the level of ferroptotic events including iron and ROS accumulation, upregulation of PTGS2 mRNA and protein levels, reduced SOD and GSH levels, and significant mitochondrial damage in H9C2 cells, which could be reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Intriguingly, we found that the autophagy inhibitor 3-methyladenine mitigated OA/PA-induced ferritin downregulation, iron overload and ferroptosis. OA/PA increased the protein level of NCOA4. Knockdown of NCOA4 by SiRNA partly reversed the reduction in ferritin, mitigated iron overload and lipid peroxidation, and subsequently alleviated OA/PA-induced cell death, indicating that NCOA4-mediated ferritinophagy was required for OA/PA-induced ferroptosis. Furthermore, we demonstrated that NCOA4 was regulated by IL-6/STAT3 signaling. Inhibition or knockdown of STAT3 effectively reduced NCOA4 levels to protect H9C2 cells from ferritinophagy-mediated ferroptosis, whereas STAT3 overexpression by plasmid appeared to increase NCOA4 expression and contribute to classical ferroptotic events. Consistently, phosphorylated STAT3 upregulation, ferritinophagy activation, and ferroptosis induction also occurred in HFD-fed mice and were responsible for HFD-induced cardiac injury. In addition, we found evidence that piperlongumine, a natural compound, effectively reduced phosphorylated STAT3 levels to protect cardiomyocytes from ferritinophagy-mediated ferroptosis both in vitro and in vivo. Based on these findings, we concluded that ferritinophagy-mediated ferroptosis was one of the critical mechanisms contributing to HFD-induced cardiac injury. The STAT3/NCOA4/FTH1 axis might be a novel therapeutic target for the treatment of HFD-induced cardiac injury.

IL-6/gp130/STAT3 signaling contributed to the activation of the PERK arm of the unfolded protein response in response to chronic ß-adrenergic stimulation.

Prolonged activation of the PERK branch of the unfolded protein response (UPR) promotes cardiomyocytes apoptosis in response to chronic ß-adrenergic stimulation. STAT3 plays a critical role in ß-adrenergic functions in the heart. However, whether STAT3 contributed to ß-adrenoceptor-mediated PERK activation and how ß-adrenergic signaling activates STAT3 remains unclear. This study aimed to investigate whether STAT3-Y705 phosphorylation contributed to the PERK arm activation in cardiomyocytes and if IL-6/gp130 signaling was involved in the chronic ß-AR-stimulation-induced STAT3 and PERK arm activation. We found that the PERK phosphorylation was positively associated with STAT3 activation. Wild-type STAT3 plasmids transfection activated the PERK/eIF2α/ATF4/CHOP pathway in cardiomyocytes while dominant negative Y705F STAT3 plasmids caused no obvious effect on PERK signaling. Stimulation with isoproterenol produced a significant increase in the level of IL-6 in the cardiomyocyte's supernatants, while IL-6 silence inhibited PERK phosphorylation but failed to attenuate STAT3 activation in response to isoproterenol stimulation. Gp130 silence attenuated isoproterenol-induced STAT3 activation and PERK phosphorylation. Inhibiting IL-6/gp130 pathway by bazedoxifene and inhibiting STAT3 by stattic both reversed isoproterenol-induced STAT3-Y705 phosphorylation, ROS production, PERK activation, IRE1α activation, and cardiomyocytes apoptosis in vitro. Bazedoxifene (5 mg/kg/day by oral gavage once a day) exhibited similar effect as carvedilol (10 mg/kg/day by oral gavage once a day) on attenuating chronic isoproterenol (30 mg/kg by abdominal injection once a day, 7 days) induced cardiac systolic dysfunction, cardiac hypertrophy and fibrosis in C57BL/6 mice. Meanwhile, bazedoxifene attenuates isoproterenol-induced STAT3-Y705 phosphorylation, PERK/eIF2α/ATF4/CHOP activation, IRE1α activation, and cardiomyocytes apoptosis to a similar extend as carvedilol in the cardiac tissue of mice. Our results showed that chronic ß-adrenoceptor-mediated stimulation activated the STAT3 and PERK arm of the UPR at least partially via IL-6/gp130 pathway. Bazedoxifene has great potential to be used as an alternative to conventional ß-blockers to attenuate ß-adrenoceptor-mediated maladaptive UPR.

Endothelial Dysfunction and Diabetic Cardiomyopathy.

The cardiovascular complications contribute to a majority of diabetes associated morbidity and mortality, accounting for 44% of death in those patients with type 1 diabetes mellitus (DM) and 52% of deaths in type 2 DM. Diabetes elicits cardiovascular dysfunction through 2 major mechanisms: ischemic and non-ischemic. Non-ischemic injury is usually under-recognized although common in DM patients, and also a pathogenic factor of heart failure in those diabetic individuals complicated with ischemic heart disease. Diabetic cardiomyopathy (DCM) is defined as a heart disease in which the myocardium is structurally and functionally abnormal in the absence of coronary artery disease, hypertensive, valvular, or congenital heart disorders in diabetic patients, theoretically caused by non-ischemic injury solely. Current therapeutic strategies targeting DCM mainly address the increased blood glucose levels, however, the effects on heart function are disappointed. Accumulating data indicate endothelial dysfunction plays a critical role in the initiation and development of DCM. Hyperglycemia, hyperinsulinemia, and insulin resistance cause the damages of endothelial function, including barrier dysfunction, impaired nitric oxide (NO) activity, excessive reactive oxygen species (ROS) production, oxidative stress, and inflammatory dysregulation. In turn, endothelial dysfunction promotes impaired myocardial metabolism, intracellular Ca2+ mishandling, endoplasmic reticulum (ER) stress, mitochondrial defect, accumulation of advanced glycation end products, and extracellular matrix (ECM) deposit, leads to cardiac stiffness, fibrosis, and remodeling, eventually results in cardiac diastolic dysfunction, systolic dysfunction, and heart failure. While endothelial dysfunction is closely related to cardiac dysfunction and heart failure seen in DCM, clinical strategies for restoring endothelial function are still missing. This review summarizes the timely findings related to the effects of endothelial dysfunction on the disorder of myocardium as well as cardiac function, provides mechanical insights in pathogenesis and pathophysiology of DCM developing, and highlights potential therapeutic targets.

Mitochondria-endoplasmic reticulum contacts in sepsis-induced myocardial dysfunction.

Mitochondrial and endoplasmic reticulum (ER) are important intracellular organelles. The sites that mitochondrial and ER are closely related in structure and function are called Mitochondria-ER contacts (MERCs). MERCs are involved in a variety of biological processes, including calcium signaling, lipid synthesis and transport, autophagy, mitochondrial dynamics, ER stress, and inflammation. Sepsis-induced myocardial dysfunction (SIMD) is a vital organ damage caused by sepsis, which is closely associated with mitochondrial and ER dysfunction. Growing evidence strongly supports the role of MERCs in the pathogenesis of SIMD. In this review, we summarize the biological functions of MERCs and the roles of MERCs proteins in SIMD.

Endocardial Radiofrequency Ablation vs. Septal Myectomy in Patients With Hypertrophic Obstructive Cardiomyopathy: A Systematic Review and Meta-Analysis.

Background: Septal myectomy (SM) has been the gold standard therapy for most patients with hypertrophic obstructive cardiomyopathy (HOCM). Endocardial radiofrequency ablation of septal hypertrophy (ERASH) is a novel treatment for septal reduction. We aimed to assess the efficacy and safety between two treatment strategies. Methods: We searched PubMed, Web of Science, Cochrane Library, and Embase databases to identify relevant studies published up to March 2021. Random-effect models were used to calculate standardized mean difference (SMD) and 95% confidence intervals (CIs) for resting left ventricular outflow tract gradient (LVOTG) and septal thickness. Results: Twenty-five studies are included in this review, eighteen studies for SM and seven studies for ERASH. During follow-up, there were significant reductions of the mean resting LVOTG in adults (SM groups: SMD = -3.03, 95% CI [-3.62 to -2.44]; ERASH groups: SMD = -1.95, 95% CI [-2.45 to -1.45]) and children (SM groups: SMD = -2.67, 95% CI [-3.21 to -2.12]; ERASH groups: SMD= -2.37, 95% CI [-3.02 to -1.73]) after the septal reduction therapies. For adults, SM groups contributed to more obvious reduction than ERASH groups in interventricular septal thickness (SM groups: SMD = -1.82, 95% CI [-2.29 to -1.34]; ERASH groups: SMD = -0.43, 95% CI [-1.00 to 0.13]). The improvement of the New York Heart Association class was similar in the two groups (SM groups: 46.4%; ERASH groups: 46.7%). The periprocedural mortality in SM and ERASH were 1.1 and 1.8%, respectively. Conclusions: This systematic review suggests that SM is superior to ERASH in the treatment of HOCM. But for the patients who are at risk for open cardiac surgeries or prefer a less invasive approach, ERASH might be an optional approach.