IKKα-STAT3-S727 axis: a novel mechanism in DOX-induced cardiomyopathy.

Doxorubicin (DOX) is an effective chemotherapeutic drug, but its use can lead to cardiomyopathy, which is the leading cause of mortality among cancer patients. Macrophages play a role in DOX-induced cardiomyopathy (DCM), but the mechanisms undlerlying this relationship remain unclear. This study aimed to investigate how IKKα regulates macrophage activation and contributes to DCM in a mouse model. Specifically, the role of macrophage IKKα was evaluated in macrophage-specific IKKα knockout mice that received DOX injections. The findings revealed increased expression of IKKα in heart tissues after DOX administration. In mice lacking macrophage IKKα, myocardial injury, ventricular remodeling, inflammation, and proinflammatory macrophage activation worsened in response to DOX administration. Bone marrow transplant studies confirmed that IKKα deficiency exacerbated cardiac dysfunction. Macrophage IKKα knockout also led to mitochondrial damage and metabolic dysfunction in macrophages, thereby resulting in increased cardiomyocyte injury and oxidative stress. Single-cell sequencing analysis revealed that IKKα directly binds to STAT3, leading to the activation of STAT3 phosphorylation at S727. Interestingly, the inhibition of STAT3-S727 phosphorylation suppressed both DCM and cardiomyocyte injury. In conclusion, the IKKα-STAT3-S727 signaling pathway was found to play a crucial role in DOX-induced cardiomyopathy. Targeting this pathway could be a promising therapeutic strategy for treating DOX-related heart failure.

Deficiency of CARMA3 attenuates the development of bleomycin induced pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) has attracted more and more attention due to its irreversibility and high mortality rate. Currently, there is no effective treatment option is available to reverse the disease. Caspase recruitment domain-containing membrane-associated guanylate kinase protein (CARMA3) has been recognized as a proinflammatory molecule involved in many lung diseases, such as Allergic airway inflammation and lung cancer. Bleomycin (Bleo), as an alkaline sugar peptide antibiotics, is often used as a first-line anti-tumor agent. Its toxic effect is to induce pulmonary fibrosis (PF) and its clinical symptoms, so it has been widely used in the construction of pulmonary fibrosis model. METHODS: Wild type mice (WT, n = 20) and CARMA3 knockout mice (CARMA3-KO, n = 20) were generated and injected with bleomycin or saline via trachea. The severity of fibrosis was evaluated by fibrosis markers and lung histological morphology. Furthermore, the amount of alveolar epithelial cells and inflammation in lung tissue were examined. Finally, epithelial-mesenchymal transition was further investigated. RESULTS: We found CARMA3 expression in the mice alveolar epithelial cells. And compared with WT mice, CARMA3-KO mice showed reduced deposition of collagen fibers, inflammation and destruction of alveolar epithelial cells in lung tissue. In addition, after bleomycin induction, the expressions of proinflammatory factors and collagen-related factors in CARMA3-KO mice were much lower than those in WT mice. The epithelial-mesenchymal transformation phenotype was also improved in CARMA3-KO mice compared to WT mice. CONCLUSION: Our Results shows that CARMA3 plays an important role in the pathogenesis of bleomycin-induced pulmonary fibrosis. CARMA3 could alleviate the fibrosis by improving inflammation, deposition of collagen and damage of alveolar epithelial cells, which revealed that CARMA3 may be a potential target for pulmonary fibrosis.

LncRNA AC061961.2 overexpression inhibited endoplasmic reticulum stress induced apoptosis in dilated cardiomyopathy rats and cardiomyocytes via activating wnt/ß-catenin pathway.

Down-regulated lncRNA AC061961.2 in dilated cardiomyopathy (DCM) patients was previous reported. Whether AC061961.2 has regulatory effect on DCM still need exploration. Here, we tried to investigate the effect of AC061961.2 on DCM. After DCM model rat was established through injecting Adriamycin, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were measured by echocardiography. Histopathological changes and apoptosis were detected by hematoxylin-eosin, Masson staining, and TUNEL. After cardiomyocytes were isolated and identified by immunofluorescence, DCM cell model was established by injecting adriamycin. After transfected with overexpressed-AC061961.2 plasmids, cell apoptosis was detected by flow cytometry. The expressions of AC061961.2, ß-catenin, Axin2, c-Myc, CRP78, CHOP, Caspase-3, Bcl-2, and Bax in cardiomyocytes and heart tissues were detected by RT-qPCR or western blot. LVEDD and LVESD were increased while LVEF and LVFS were decreased in DCM rats. The histopathological of heart tissues showed a typical sign of DCM. Apoptosis were increased in heart tissues of DCM rats. In DCM rats, the expressions of AC061961.2, ß-catenin, Axin2, c-Myc, and Bcl-2 were decreased, the expressions of CRP78, CHOP, Caspase-3, and Bax were increased. After the overexpression of AC061961.2, levels of ß-catenin, Axin2, c-Myc, and Bcl-2 were increased, while levels of CRP78, CHOP, Caspase-3, and Bax were decreased, compared with that in DCM cardiomyocytes. LncRNA AC061961.2 overexpression inhibited endoplasmic reticulum stress induced apoptosis in DCM rats and cardiomyocytes via activating Wnt/ß-catenin pathway.

Stomatin-Like Protein-2: A Potential Target to Treat Mitochondrial Cardiomyopathy.

Stomatin-like protein-2 (SLP-2) is a mitochondrial-associated protein that is abundant in cardiomyocytes. Many reports have shown that SLP-2 plays an important role in mitochondria. The treatment of mitochondrial cardiomyopathy (MCM) needs further improvement, so the relationship between SLP-2 and MCM is worth exploring. This study reviewed some protective mechanisms of SLP-2 on mitochondria. Published studies have shown that SLP-2 protects mitochondria by stabilising the function of optic atrophy 1 (OPA1), promoting mitofusin (Mfn) 2 expression, interacting with prohibitins and cardiolipin, forming SLP-2-PARL-YME1L (SPY) complex, and stabilising respiratory chain complexes, suggesting that SLP-2 is a new potential target for the treatment of MCM. However, the specific mechanism of SLP-2 needs to be confirmed by further research.

[Clinical outcomes of radial artery as the second arterial conduit in coronary artery bypass].

Objective: To examine the clinical experience and outcomes of coronary artery bypass grafting (CABG) using radial artery as the second arterial graft. Methods: Totally 585 patients in whom both left internal thoracic artery and radial artery as arterial conduits were used in CABG in Department of Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University from April 2008 to August 2019 were consecutively enrolled. There were 436 males and 149 females, aging (63±10) years (range: 36 to 86 years). There were 40.7% (238/585) of patients had diabetes and 75.6% (442/585) of them had multivessel disease (two-vessel or three-vessel diseases). From January 2017, transit time flow measurement was performed on every patient. Demographic and perioperative data were retrospectively collected, as well as follow-up data for patients who underwent CABG from January 2014 to August 2019. Analysis were made on their early and late outcomes. Results: 81.9%(479/585) Most patients in this cohort (81.9%) received on-pump CABG and 11 patients had intraoperative intro-aortic balloon counterpulsation (prior to CABG) support. Forty-three patients had concomitant valve procedures. The number of distal anastomosis was 3.6±0.9 (range: 2 to 6) and number of arterial distal anastomosis was 2.1±0.3. Radial artery was anastomosed to left obtuse marginal artery in 95.8% (560/585) patients. All target vessels for radial artery conduit had significant proximal stenosis (>70%) and 72.5% (424/585) of target vessels had proximal stenosis which was >90%. Intraoperative transit-time flow measurement of 151 cases showed that radial artery conduits had a flow of (29.8±10.2) ml/minutes (range: 10 to 150 ml/min), and pulsatility index of 2.5±1.4 (range: 0.7 to 5.0). There was no operative death. Two in-hospital death occurred more than 30 days after index surgery. There was no perioperative myocardial infarction. There were 188 patients who received CABG from January 2014 to August 2019 followed-up for a median duration of 3.2 years. There were two noncardiac death. No patient had myocardial infarction or to receive myocardial revascularization. Conclusions: Radial artery as the second arterial conduit is a safe and effective strategy for CABG. Good selection of target vessel and intraoperative transit-time flow measurement may help achieve good patency, as well as the short and mid-term outcome.

Downregulation of AC061961.2, LING01-AS1, and RP11-13E1.5 is associated with dilated cardiomyopathy progression.

This study aimed to explore long noncoding RNAs (lncRNAs) implicated in dilated cardiomyopathy (DCM). Ten samples of failing hearts collected from the left ventricles of patients with DCM undergoing heart transplants, and ten control samples obtained from normal heart donors were included in this study. After sequencing, differentially expressed genes (DEGs) and lncRNAs between DCM and controls were screened, followed with functional enrichment analysis and weighted gene coexpression network analysis (WGCNA). Five key lncNRAs were validated through real-time polymerase chain reaction (PCR). Total 1,398 DEGs were identified, including 267 lncRNAs. WGCNA identified seven modules that were significantly correlated with DCM. The top 50 genes in the three modules (black, dark-green, and green-yellow) were significantly correlated with DCM disease state. Four core enrichment lncRNAs, such as AC061961.2, LING01-AS1, and RP11-557H15.4, in the green-yellow module were associated with neurotransmitter secretion. Five core enrichment lncRNAs, such as KB-1299A7.2 and RP11-13E1.5, in the black module were associated with the functions of blood circulation and heart contraction. AC061961.2, LING01-AS1, and RP11-13E1.5 were confirmed to be downregulated in DCM tissues by real-time PCR. The current study suggests that downregulation of AC061961.2, LING01-AS1, and RP11-13E1.5 may be associated with DCM progression, which may serve as key diagnostic biomarkers and therapeutic targets for DCM.

Stomatin-like protein-2 relieve myocardial ischemia/reperfusion injury by adenosine 5'-monophosphate-activated protein kinase signal pathway.

Previous studies have shown that stomatin-like protein-2 (SLP-2) could regulate mitochondrial biogenesis and function. The study was designed to explore the contribution of SLP-2 to the myocardial ischemia and reperfusion (I/R) injury. Anesthetized rats were treated with SLP-2 and subjected to ischemia for 30 minutes before 3 hours of reperfusion. An oxygen-glucose deprivation/reoxygenation model of I/R was established in H9C2 cells. In vivo, SLP-2 significantly improved cardiac function recovery of myocardial I/R injury rats by increasing fractional shortening and ejection fraction. SLP-2 pretreatment alleviated infarct area and myocardial apoptosis, which was paralleled by decreasing the level of cleaved caspase-3 and the ratio of Bax/Bcl-2, increasing the content of superoxide dismutase and reducing oxidative stress damage in serum. In addition, SLP-2 increased the level of ATP and stabilized mitochondrial potential (Ψm). The present in vitro study revealed that overexpression with SLP-2 reduced H9C2 cells apoptosis, accompanied by an increased level of ATP, the ratio of mitochondrial DNA/nuclear DNA, activities of complex II and V, and decreased the production of mitochondrial reactive oxygen species. Simultaneously, SLP-2 activated the adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway in myocardial I/R injury rats and H9C2 cells. This study revealed that SLP-2 mediates the cardioprotective effect against I/R injury by regulating AMPK signaling pathway.

Regulatory role of IKKɑ in myocardial ischemia/reperfusion injury by the determination of M1 versus M2 polarization of macrophages.

The IκB kinase (IKK) complex plays a well-documented role in cancer and immune system. This function has been widely attributed to its role as the master regulator of the NF-κB family. Particularly, IKKɑ, a member of IKK complex, is reported to have various regulating effects in inflammatory and malignant diseases. However, its role as well as its mechanism of function in macrophages following myocardial ischemia and reperfusion (I/R) injury remains unexplored. In vivo, sham or I/R operations were performed on macrophage-specific IKKɑ knockout (mIKKɑ-/-) mice and their IKKɑflox/flox littermates. We ligated the left anterior descending (LAD) coronary artery of I/R groups simulating ischemia for 30 min, followed by a reperfusion period of 3 days and 7 days, respectively. The hearts of mIKKɑ-/- mice exhibited significantly increased inflammation and macrophage aggregation as compared to their IKKɑflox/flox littermates. Moreover, in the mIKKɑ-/- group subjected to I/R macrophages had a tendency to polarize to M1 phenotype. In vitro, we stimulated RAW264.7 cells with Lipopolysaccharides (LPS) after infection by the lentivirus, either knocking-down or overexpressing IKKɑ. We discovered that a deficiency of IKKɑ in RAW264.7 caused increased expression of pro-inflammatory markers compared to normal RAW264.7 after LPS stimulation. Inversely, pro-inflammatory factors were inhibited with IKKɑ overexpression. Mechanistically, IKKɑ directly combined with RelB to regulate macrophage polarization. Furthermore, IKKɑ regulated MEK1/2-ERK1/2 and downstream p65 signaling cascades after LPS stimulation. Overall, our data reveals that IKKɑ is a novel mediator protecting against the development of myocardial I/R injury via negative regulation of macrophage polarization to M1 phenotype. Thus, IKKɑ may serve as a valuable therapeutic target for the treatment of myocardial I/R injury.

Targeted Metagenome Based Analyses Show Gut Microbial Diversity of Inflammatory Bowel Disease patients.

Inflammatory bowel disease (IBD) is a multifactorial disease including both genetic and environmental factors. We compared the diversity of intestinal microbesamong a cohort of IBD patients to study the microbial ecological effects on IBD. Fecal samples from patients were sequenced with next generation sequence technology at 16S rDNA region. With statistical tools, microbial community was investigated at different level. The gut microbial diversity of Crohn's disease (CD) patients and colonic polyp (CP) patients significantly different from each other. However, the character of ulcerative colitis (UC) patients has of both CD and CP features. The microbial community from IBD patients can be very different (CD patient) or somewhat similar (UC patients) to non-IBD patients. Microbial diversity can be an important etiological factor for IBD clinical phenotype.

Comparison of surgical and conservative treatment outcomes for type a aortic intramural hematoma.

OBJECTIVE: This study aimed to compare hospital and long-term clinical outcomes associated with various treatment methods for Stanford A type aortic intramural hematoma (IMH) to provide a reference for clinical decision-making. METHODS: In this single-center cohort study, we retrospectively analyzed 73 patients with Type A IMH treated at our center from August 1, 2018 to August 1, 2021. Among these patients, 26 were treated conservatively, and 47 underwent surgical intervention. We next compared this IMH cohort with 154 patients with acute type A aortic dissection (AD) who were treated surgically during the same study period. RESULTS: Computed tomography angiography revealed that the diameter of the ascending aorta of IMH patients treated with surgery was higher than IMH patients treated with conservative therapy (44.92 ± 7.58 mm vs. 51.22 ± 11.85 mm, P < 0.05), while there was no significant difference in other clinical parameters. The in-hospital mortality of patients with IMH who underwent surgical treatment was lower than those undergoing conservative treatment (0% vs. 11.5%, P < 0.05). The long-term mortality of the conservative IMH group was higher than the surgical IMH group (26.1% vs. 8.5%, P < 0.05). There was no significant difference in the surgical parameters and postoperative complications between AD and IMH surgery patients. The proportion of circulatory arrest time in the lower body (19.98 ± 9.39 min vs. 17.51 ± 3.97 min) and arch involvement (98 (63.6%) vs. 22 (46.8%)) in the IMH surgery group was lower than in the AD surgery group (P < 0.05). CONCLUSIONS: Compared with conservative treatment, surgical treatment of IMH significantly improves the survival rate of patients. Thus, surgical intervention should be considered the primary treatment option if feasible. Furthermore, The safety of IMH surgery can be guaranteed just like AD. But we still need in the future evidence on bigger samples.

Targeting translocator protein protects against myocardial ischemia/reperfusion injury by alleviating mitochondrial dysfunction.

Ischemic heart disease (IHD) remains a leading cause of mortalities worldwide, necessitating timely reperfusion to reduce acute mortality. Paradoxically, reperfusion can induce myocardial ischemia/reperfusion (I/R) injury, which is primarily characterized by mitochondrial dysfunction. Translocator protein (TSPO) participates in multiple cellular events; however, its role in IHD, especially in the process of myocardial I/R injury, has not been well determined. The aim of the present study was to investigate the functional role of TSPO in myocardial I/R injury and dissect the concomitant cellular events involved. This study utilized small interfering RNA (siRNA) technology to knock down TSPO expression. The I/R process was simulated using an anoxia/reoxygenation (A/R) model. The role of TSPO in H9c2 cardiomyocytes was assessed using various techniques, such as Western blotting, Flow cytometry, Reverse transcription-quantitative PCR (RT-qPCR), Immunofluorescence, Co-immunoprecipitation (co-IP) and similar methods. It was found that A/R markedly upregulated the expression of TSPO in cardiomyocytes. Inhibition of TSPO improved myocardial cell apoptosis and damage following A/R stimulation. Additionally, targeting TSPO alleviated mitochondrial damage, reduced mitochondrial ROS release and enhanced ATP synthesis following A/R stimulation. It was further confirmed that A/R stimulation induced a significant increase in the expression of pivotal markers [phosporylated-PKR-like ER kinase (PERK)/PERK, activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1] involved in the adaptive unfolded protein response, which is accompanied by downstream signaling during endoplasmic reticulum (ER) stress. Notably, TSPO knockdown increased the expression of the aforementioned markers and, subsequently, TSPO was confirmed to interact with ATF6, suggesting that TSPO might play a role in ER stress during myocardial I/R injury. Finally, inhibition of TSPO upregulated mitophagy, as indicated by further decreases in P62 and increases in Parkin and PINK1 levels following A/R stimulation. Together, the results suggest that TSPO plays a multifaceted role in myocardial I/R injury. Understanding TSPO-induced cellular responses could inform targeted therapeutic strategies for patients with IHD.

CARMA3 Deficiency Aggravates Angiotensin II-Induced Abdominal Aortic Aneurysm Development Interacting Between Endoplasmic Reticulum and Mitochondria.

BACKGROUND: Abdominal aortic aneurysm (AAA) is life threatening and associated with vascular walls' chronic inflammation. However, a detailed understanding of the underlying mechanisms is yet to be elucidated. CARMA3 assembles the CARMA3-BCL10-MALT1 (CBM) complex in inflammatory diseases and is proven to mediate angiotensin II (Ang II) response to inflammatory signals by modulating DNA damage-induced cell pyroptosis. In addition, interaction between endoplasmic reticulum (ER) stress and mitochondrial damage is one of the main causes of cell pyroptosis. METHODS: Male wild type (WT) or CARMA3-/- mice aged 8 to 10 weeks were subcutaneously implanted with osmotic minipumps, delivering saline or Ang II at the rate of 1 µg/kg/min for 1, 2, and 4 weeks. RESULTS: We discovered that CARMA3 knockout promoted formation of AAA and prominently increased diameter and severity of the mice abdominal aorta infused with Ang II. Moreover, a significant increase in the excretion of inflammatory cytokines, expression levels of matrix metalloproteinases (MMPs) and cell death was found in the aneurysmal aortic wall of CARMA3-/- mice infused with Ang II compared with WT mice. Further studies found that the degree of ER stress and mitochondrial damage in the abdominal aorta of CARMA3-/- mice was more severe than that in WT mice. Mechanistically, CARMA3 deficiency exacerbates the interaction between ER stress and mitochondrial damage by activating the p38MAPK pathway, ultimately contributing to the pyroptosis of vascular smooth muscle cells (VSMCs). CONCLUSIONS: CARMA3 appears to play a key role in AAA formation and might be a potential target for therapeutic interventions of AAA.

Stomatin-like protein 2 deficiency exacerbates adverse cardiac remodeling.

Myocardial fibrosis, oxidative stress, and autophagy both play key roles in the progression of adverse cardiac remodeling. Stomatin-like protein 2 (SLP-2) is closely related to mitochondrial function, but little is known about its role and mechanism in cardiac remodeling. We developed doxorubicin (Dox), angiotensin (Ang) II, and myocardial ischemia-reperfusion (I/R) injury induced cardiac remodeling model and Dox treated H9C2 cell injury model using SLP-2 knockout (SLP-2-/-) mice and H9C2 cells with low SLP-2 expression. We first examined cardiac functional and structural changes as well as levels of oxidative stress, apoptosis and autophagy. We found that SLP-2 deficiency leads to decreased cardiac function and promotes myocardial fibrosis. After Dox and Ang II treatment, SLP-2 deficiency further aggravated myocardial fibrosis, increased myocardial oxidative stress and apoptosis, and activated autophagy by inhibiting PI3K-Akt-mTOR signaling pathway, ultimately exacerbating adverse cardiac remodeling. Similarly, SLP-2 deficiency further exacerbates adverse cardiac remodeling after myocardial I/R injury. Moreover, we extracted cardiomyocyte mitochondria for proteomic analysis, suggesting that SLP-2 deficiency may be involved in myocardial I/R injury induced adverse cardiac remodeling by influencing ubiquitination of intramitochondrial proteins. In addition, the oxidative stress, apoptosis and autophagy levels of H9C2 cells with low SLP-2 expression were further enhanced, and the PI3K-Akt-mTOR signaling pathway was further inhibited under Dox stimulation. Our results suggest that SLP-2 deficiency promotes myocardial fibrosis, disrupts normal mitochondrial function, overactivates autophagy via PI3K-Akt-mTOR signaling pathway, affects the level of ubiquitination, leads to irreversible myocardial damage, and ultimately exacerbates adverse cardiac remodeling.

Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages.

Pulmonary hypertension (PH) is a devastating disease characterized by irreversible pulmonary vascular remodeling (PVR) that causes right ventricular failure and death. The early alternative activation of macrophages is a critical event in the development of PVR and PH, but the underlying mechanisms remain elusive. Previously we have shown that N6-methyladenosine (m6A) modifications of RNA contribute to phenotypic switching of pulmonary artery smooth muscle cells and PH. In the current study, we identify Ythdf2, an m6A reader, as an important regulator of pulmonary inflammation and redox regulation in PH. In a mouse model of PH, the protein expression of Ythdf2 was increased in alveolar macrophages (AMs) during the early stages of hypoxia. Mice with a myeloid specific knockout of Ythdf2 (Ythdf2Lyz2 Cre) were protected from PH with attenuated right ventricular hypertrophy and PVR compared to control mice and this was accompanied by decreased macrophage polarization and oxidative stress. In the absence of Ythdf2, heme oxygenase 1 (Hmox1) mRNA and protein expression were significantly elevated in hypoxic AMs. Mechanistically, Ythdf2 promoted the degradation of Hmox1 mRNA in a m6A dependent manner. Furthermore, an inhibitor of Hmox1 promoted macrophage alternative activation, and reversed the protection from PH seen in Ythdf2Lyz2 Cre mice under hypoxic exposure. Together, our data reveal a novel mechanism linking m6A RNA modification with changes in macrophage phenotype, inflammation and oxidative stress in PH, and identify Hmox1 as a downstream target of Ythdf2, suggesting that Ythdf2 may be a therapeutic target in PH.

Osteopontin is required for angiotensin II-induced migration of vascular smooth muscle cells.

Migration and proliferation of vascular smooth muscle cells (VSMCs) play a prominent role in the development of atherosclerotic plaques and restenosis lesions. Angiotensin II (Ang-II) is typically associated with excessive proliferation and migration of VSMCs and vascular remodeling. High levels of osteopontin (OPN) mRNA and protein were reported in human atherosclerotic plaque from the aorta, carotid and coronary arteries. However whether OPN plays a role in VSMCs migration induced by Ang-II is unknown. Here we show that, in primary cultured rat VSMCs, Ang-II exhibits chemotactic effect on cultured VSMCs and induces OPN expression dose-dependently. With a lentiviral shRNA specifically targeting OPN and transwell migration assay, we find that blockade of OPN with shRNA inhibits Ang-II-induced MMP9 upregulation and VSMCs migration. Our results demonstrated that OPN is required for Ang-II to induce VSMCs migration and suggested OPN as a potential target in preventing atherosclerotic development.

I-κB kinase-ε deficiency improves doxorubicin-induced dilated cardiomyopathy by inhibiting the NF-κB pathway.

Dilated cardiomyopathy (DCM) can lead to heart expansion and severe heart failure, but its specific pathogenesis is still elusive. In many cardiovascular diseases, I-κB kinase-ε (IKKε) has been recognized as a pro-inflammatory molecule. In this study, wild-type mice (WT, n = 14) and IKKε knockout mice (IKKε-KO, n = 14) were intraperitoneally injected with a cumulative dose of 25 mg/kg with Dox or Saline five times in 30 days. Finally, the experimental mice were divided into WT + Saline group、WT + DOX group、IKKε-KO + Saline group and IKKε-KO + Dox group. Echocardiography was performed to assess cardiac structure and function. Moreover, the mechanism was validated by immunohistochemistry and western blotting. Our results demonstrated that compared to WT + Dox mice, IKKε-KO + Dox mice exhibited attenuation of dilated cardiomyopathy-related morphological changes and alleviation of heart failure. Additionally, compared to the WT mice after Dox-injected, the expression of fibrosis and proinflammatory were decreased in IKKε-KO mice, and the expression of cardiac gap junction proteins was much higher in IKKε-KO mice. Further testing found that pyroptosis and apoptosis in the myocardium were also ameliorated in IKKε-KO mice compared to WT mice after Dox was injected. Mechanistically, our results showed that deficiency of IKKε might inhibit the phosphorylation of IκBα, p65, RelB, and p100 in mouse heart tissues after Dox stimulation. In summary, our research suggests that IKKε might play an essential role in the development of Dox-induced dilated cardiomyopathy and may be a potential target for the treatment of dilated cardiomyopathy in the future.

[Surgical treatment of post-infarction left ventricular aneurysm: clinical analysis].

OBJECTIVE: To explore the clinical experiences, efficacies and postoperative left ventricular remodeling changes of surgical ventricular reconstruction in the treatment of post-infarction left ventricular aneurysm. METHODS: The investigators reviewed retrospectively the clinical data, operative approaches and follow-up outcomes of consecutive 194 patients with post-infarction left ventricular aneurysm, who underwent surgical ventricular reconstruction between January 1997 and December 2009. There were 54 cases in the linear group and 137 cases in the endoventricular patch plasty group. The changes of ventricular remodeling were measured by peri-operative and follow-up echocardiography. RESULTS: All patients underwent surgery with a mean cardiopulmonary bypass duration of (103 ± 35) min and aortic cross clamp duration of (62 ± 26) min. There were 8 per-operative deaths with a mortality rate of 2.2%. Angina pectoris of other cases disappeared and heart function greatly improved. After operation, the ventricular remodeling results showed that in the linear group, there was not significant difference in the changes of ventricular remodeling of post-op 2 weeks, 6 months, 1 year and 5 years versus pre-operation. However, in the endoventricular patch group, the changes of ventricular remodeling of post-op 2 weeks and follow-up 6 months versus pre-operation were significantly reduced (P < 0.05). End-systolic volume (LVESV) reduced from (129 ± 27) ml to (65 ± 8) ml and end-systolic volume index (LVESVI) decreased from (104 ± 14) ml/m(2) to (44 ± 6) ml/m(2) and the subgroup of LVEF < 35% was the most significant in the changes of LVESV and LVESVI. But LVEF improved significantly at post-operation and follow-up (from preoperation 42% ± 11% to 52% ± 7% during follow-up). CONCLUSIONS: For patients with infarction left ventricular aneurysm, left ventricular reconstruction is quite effective. The choice of operative approaches is determined by the size and range of ventricular aneurysm. Both string suture and endoventricular patch plasty technique can yield similarly satisfactory surgical outcomes. After operation, ventricular volume significantly decreases and cardiac function greatly improves.

[Clinical application of extracorporeal membrane oxygenation for severe heart failure during peri-operative period of end-stage cardiopathy].

OBJECTIVE: To summarize the clinical effect and experience of extracorporeal membrane oxygenation (ECMO) support for severe heart failure during peri-operative period of end-stage cardiopathy. METHODS: From June 2007 to July 2010, 6 patients with severe heart failure during peri-operative period of end-stage cardiopathy received ECMO support. The changes in the hemodynamics and outcome of the patients during the use of ECMO were investigated. RESULTS: The duration of ECMO assistance ranged from 23 to 168 hours with a mean of 78 hours. The hemodynamics after using ECMO was much improved than before ECMO [mean arterial pressure (mm Hg, 1 mm Hg=0.133 kPa): 78.13±8.01 vs. 47.75±5.21, central venous pressure ( mm Hg ): 11.03±3.21 vs. 19.36±4.51, cardiac output (L/min): 4.93±1.01 vs. 3.50±0.81, cardiac index (L×min(-1)×m(-2)): 2.71±0.51 vs. 1.91±0.40, pulmonary artery wedge pressure ( mm Hg ): 12.72±6.52 vs. 20.22±6.91, venous oxygen saturation: 0.66±0.13 vs. 0.54±0.07], and the amount of using inotropic drug was significantly reduced compared with that before ECMO [dopamine (µg×kg(-1)×min(-1)): 5.05±0.85 vs. 14.20±5.05, epinephrine (µg×kg(-1) ×min(-1)): 0.05±0.01 vs. 0.24±0.04, all P<0.05]. All patients were successfully weaned from ECMO. After weaning, 3 patients recovered and discharged, and the hospital discharge rate was 50%, while 3 patients died of multiple organ failure (MOF). Major complication was bleeding, disseminated intravascular coagulation, infection, embolism. CONCLUSION: ECMO is an important extracorporeal method to support life. ECMO is an effective measure of treatment for end-stage cardiopathy patients with peri-operative severe heart failure. It is important to properly select patients for ECMO.

High expression levels and localization of Sox5 in dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a disease that can lead to heart expansion and severe heart failure, but the specific pathogenesis remains unclear. Sox5 is a member of the Sox family with a key role in cardiac function. However, the role of Sox5 in DCM remains unclear. In the present study, wild­type mice were intraperitoneally injected with doxorubicin (Dox) to induce DCM, and heart specimens from human patients with DCM were used to investigate the preliminary role of Sox5 in DCM. The present study demonstrated that, compared with control human hearts, the hearts of patients with DCM exhibited high expression levels of Sox5 and activation of the wnt/ß­catenin pathway. This result was consistent with Dox­induced DCM in mice. Furthermore, in Dox­treated mice, apoptosis was activated during the development of DCM. Inflammation and collagen deposition also increased in DCM mice. The results of the present study indicate that Sox5 may be associated with the development of DCM. Sox5 may be a novel potential factor that regulates DCM.

A Novel Molecular Mechanism of IKKε-Mediated Akt/mTOR Inhibition in the Cardiomyocyte Autophagy after Myocardial Infarction.

Autophagy of cardiomyocytes after myocardial infarction (MI) is an important factor affecting the prognosis of MI. Excessive autophagy can lead to massive death of cardiomyocytes, which will seriously affect cardiac function. IKKε plays a crucial role in the occurrence of autophagy, but the functional role in MI remains largely unknown. To evaluate the impact of IKKε on the autophagy of cardiomyocytes after MI, MI was induced by surgical left anterior descending coronary artery ligation in IKKε knockout (KO) mice and wild-type (WT) mice. Starvation of H9c2 cells with IKKε siRNA and rescued with IKKε overexpressed afterwards to test the mechanism of IKKε in autophagy in vitro. Our results demonstrated that the expression of IKKε was upregulated in mice myocardial tissues which were consistent with cardiomyocyte autophagy after MI. Significantly, the IKKε KO mice showed increased infarct size, decreased viable cardiomyocytes, and exacerbated cardiac dysfunction when compared with the wild-type mice. Western blot and electron micrography analysis also revealed that loss of IKKε induces excessive cardiomyocyte autophagy and reduced the expression of p-Akt and p-mTOR. Similar results were observed in IKKε siRNA H9c2 cells in vitro which were under starvation injury. Notably, the levels of p-Akt and p-mTOR can restore in IKKε rescued cells. In conclusion, our results indicated that IKKε protects cardiomyocyte survival by reduced autophagy following MI via regulation of the Akt/mTOR signaling pathway. Thus, our study suggests that IKKε might represent a potential therapeutic target for the treatment of MI.