Identification of potential crucial cuproptosis-related genes in myocardial ischemia-reperfusion injury through the bioinformatic analysis.

BACKGROUND: Cuproptosis is known to regulate diverse physiological functions in many diseases, but its role in regulating Myocardial Ischemia-Reperfusion Injury (MI/RI) remains unclear. METHODS: For this purpose, the MI/RI microarray datasets GSE61592 were downloaded from the Gene Expression Omnibus (GEO) database, and the Differently Expressed Genes (DEGs) in MI/RI were identified using R software. Moreover, the MI/RI mice model was established to confirm further the diagnostic value of Pyruvate Dehydrogenase B (Pdhb), Dihydrolipoamide S-acetyltransferase (Dlat), and Pyruvate dehydrogenase E1 subunit alpha 1 (Pdhα1). RESULTS: The analysis of microarray datasets GSE61592 revealed that 798 genes were upregulated and 768 were downregulated in the myocardial tissue of the ischemia-reperfusion injury mice. Furthermore, Dlat, Pdhb, Pdhα1, and cuproptosis-related genes belonged to the downregulated genes. The receiver operating characteristics curve analysis results indicated that the Dlat, Pdhb, and Pdhα1 levels were downregulated in MI/RI and were found to be potential biomarkers for MI/RI diagnosis and prognosis. Similarly, analysis of Dlat, Pdhb, and Pdhα1 levels in the MI/RI mice revealed Pdhb being the key diagnostic marker. CONCLUSIONS: This study demonstrated the prognostic value of cuproptosis-related genes (Dlat, Pdhb, and Pdhα1), especially Pdhb, MI/RI, providing new insight into the MI/RI treatment.

K-clip™, a Novel Transcatheter Treatment in Patients with Severely Tricuspid Regurgitation.

Patients who suffer from severe tricuspid regurgitation (TR) and who are at high surgical risk have no standard care therapy. Therefore, minimally invasive and safer methods are sought. K-clip™, the first ultrasound-positioned interventional tricuspid annuloplasty instrument intended for percutaneous transcatheter repair. We report a patient with severe functional TR and high surgical risk who underwent K-clip™ tricuspid annuloplasty under echocardiography and fluoroscopy guidance.

Insight into tricuspid transcatheter edge-to-edge repair: no longer the forgotten valve.

INTRODUCTION: Tricuspid regurgitation (TR) is one of the most prevalent types of valvular heart disease linked to poor prognosis in patients with heart failure and is usually ignored. TR has received considerable attention due to the progressive advancements in transcatheter therapies in recent years. AREAS COVERED: With relatively solid data and rapid technological advancements, tricuspid transcatheter edge-to-edge repair (T-TEER) is the most frequently employed in a series of tricuspid transcatheter interventional treatments for TR. However, the efficacy and technical benefits of T-TEER are limited because of the unique anatomical characteristics and pathological mechanisms of the tricuspid valve. The aim of this review is to summarize reported data on current status of T-TEER and to provide an expert opinion regarding the challenges it is now experiencing and future development direction and approach. EXPERT OPINION: T-TEER is a significant treatment for TR, but its effectiveness and technical promotion are limited due to the tricuspid valve unique anatomical characteristics and pathological mechanisms. The selection criteria for suitable patients, the choice of when to intervene, device innovation, the advancement of ultrasound technology, and the volume of evidence in evidence-based medicine all indicate that the disorder of TR will eventually be better treated and understood.

Acute Coronary Artery Occlusion during Transcatheter Aortic Valve Replacement in a Patient with an Anomalous Left Circumflex Coronary Artery.

Background: Acute coronary artery occlusion (CAO) during transcatheter aortic valve replacement (TAVR) is a rare but life-threatening complication during the procedure; there were a few case reports about an anomalous LCX during perioperative period. We report a case of successful coronary protection using the chimney stenting technique in a patient with a severely calcified aortic valve and an anomalous LCX. Case Summary. A 75-year-old man was found an anomalous left circumflex coronary artery (LCX) originating from the right coronary cusp with severely calcified aortic valve stenosis requiring TAVR. When a self-expanding aortic valve was deployed, we found flow compromise in the right coronary system and circumflex to TIMI-0 flow. By using the chimney stenting technique, we rapidly planted 2 stents from the proximal CX branch to the sinotubular junction and the coronary flow was maintained. Conclusion: Chimney stenting protection as a bailout technique is safe and feasible and should be considered in patients deemed to be at high risk of coronary flow compromise, especially with an anomalous LCX.

N6-methyladenosine methyltransferase plays a role in hypoxic preconditioning partially through the interaction with lncRNA H19.

N6-methyladenosine (m6A), a methylation in the N6 position of adenosine especially in the mRNA, exerts diverse physiological and pathological functions. However, the precise role of m6A methylation in hypoxic preconditioning (HPC) is still unknown. Here, we observed that HPC treatment protected H9c2 cells against H2O2-induced injury, upregulated the m6A level in the total RNA and the expression of methyltransferase like 3 (METTL3), methyltransferase like 14 (METTL14), and long noncoding RNA (lncRNA) H19. Either knockdown of METTL3 or METTL14 notably reversed the HPC-induced enhancement of cell viability, anti-apoptosis ability, and H19 expression. Methylated RNA immunoprecipitation (IP) indicated that knockdown of METTL3 or METTL14 decreased m6A level in the lncRNA H19. Gain-of-function assay demonstrated that H19 overexpression could partially rescue the decreased protection mediated by METTL3 or METTL14 knockdown in HPC-treated H9c2 cells. RNA binding protein immunoprecipitation (RIP) assay showed that METTL3 and METTL14 could directly bind with H19. Our study identified a novel pattern of posttranscriptional regulation in HPC treatment. Since METTL3, METTL14, and lncRNA H19 were involved in HPC protection, they could be considered as potential biomarkers and therapeutic targets in HPC-derived cardiac rehabilitation and therapeutic approaches.

Bradykinin protects cardiac c-kit positive cells from high-glucose-induced senescence through B2 receptor signaling pathway.

Cardiac c-kit positive cells are cardiac-derived cells that exist within the heart and have a great many protective effects. The senescence of cardiac c-kit positive cells probably leads to cell dysfunction. Bradykinin plays a key role in cell protection. However, whether bradykinin prevents cardiac c-kit positive cells from high-glucose-induced senescence is unknown. Here, we found that glucose treatment causes the premature senescence of cardiac c-kit positive cells. Bradykinin B2 receptor (B2R) expression was declined by glucose-induced senescence. Bradykinin treatment inhibited senescence and reduced intracellular oxygen radicals according to senescence-associated ß-galactosidase staining and 2',7'-dichlorodihydrofluorescein diacetate staining. Moreover, the mitochondrial membrane potential was damaged, as measured by JC-1 staining. The mitochondrial membrane potential was preserved under bradykinin treatment. The concentration of superoxide was decreased, and the concentration of intracellular adenosine triphosphate was increased after bradykinin treatment. Western blot showed that bradykinin leads to AKT and mammalian target of rapamycin (mTOR) phosphorylation and decreased levels of P53 and P16 when compared with glucose treatment alone. Antagonists of B2R, phosphoinositide 3-kinase (PI3K), mTOR, and B2R small interfering RNA prevented the protective effect of bradykinin. P53 antagonist also inhibited the glucose-induced senescence of cardiac c-kit positive cells. In conclusion, bradykinin prevents the glucose-induced premature senescence of cardiac c-kit positive cells through the B2R/PI3K/AKT/mTOR/P53 signal pathways.

Triglyceride to high-density lipoprotein cholesterol ratio as a risk factor of repeat revascularization among patients with acute coronary syndrome after first-time percutaneous coronary intervention.

BACKGROUND: It is clinically important to identify high-risk patients with acute coronary syndrome (ACS) who may require repeat revascularization. This retrospective study identified risk factors for repeat revascularization among ACS patients after first-time successful percutaneous coronary interventions (PCIs). The predictive value of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio for repeat revascularization was also evaluated. METHODS: We enrolled consecutive ACS patients who had coronary angiography performed during the period from 6 to 12 months after a first-time successful PCI. The primary outcome of the study was to identify the risk factors of repeat revascularization. The subjects were stratified based on repeat PCI events. After comparing various clinical characteristics, univariate and multivariate Cox proportional hazard model analyses were adopted to evaluate the effects of risk factors on repeat revascularization. RESULTS: The patients (n=271) were divided into the event (+) group (n=101) and the event (-) group (n=170). In the event (+) group, target lesion revascularization (TLR) accounted for 20.79% and target vessel revascularization (TVR) accounted for 50.49% of the patients. In contrast, 52.47% of the patients required de novo vessel revascularization (DVR). After adjustment for confounding factors, the TG/HDL-C ratio [hazard ratio (HR) =1.206, 95% confidence interval (CI): 1.016-1.431, P=0.032 for each higher TG/HDL-C ratio unit] and the Gensini score (HR =1.012, 95% CI: 1.005-1.018, P<0.001 for each higher Gensini score unit) were independent risk factors for a repeat PCI. Subgroup analyses showed that higher TG/HDL-C ratios were associated with a significantly higher risk of repeat PCIs in the male, hypertensive, and diabetes mellitus subgroups. CONCLUSIONS: The TG/HDL-C ratio and Gensini score could serve as risk factors for repeat revascularization in ACS patients after a first-time successful PCI.

Metformin Modulates High Glucose-Incubated Human Umbilical Vein Endothelial Cells Proliferation and Apoptosis Through AMPK/CREB/BDNF Pathway.

Cardiovascular disease (CVD) is a leading cause of mortality and morbidity among patients with diabetes. Endothelial dysfunction is an early physiological event in CVD. Metformin, a common oral antihyperglycemic agent, has been demonstrated to directly affect endothelial cell function. Brain-derived neurotrophic factor (BDNF), originally discovered in the brain as a neurotrophin, has also been reported to play a protective role in the cardiovascular system. In our study, we demonstrated that high glucose (HG) reduced cell proliferation and induced cell apoptosis via changes in BDNF expression and that metformin reversed the effects of HG injury by upregulating BDNF expression. Furthermore, we found that cyclic AMP response element binding (CREB) phosphorylation was reduced in HG-treated human umbilical vein endothelial cells (HUVECs), and this effect was reversed by the metformin treatment. However, the metformin effect on BDNF levels in HG-incubated HUVECs was blocked by a CREB inhibitor, which indicated that BDNF expression is regulated by metformin through CREB activation. In addition, we found that adenosine monophosphate-activated protein kinase (AMPK) activation is involved in CREB/BDNF regulation in HG-incubated HUVECs treated with metformin and that an AMPK inhibitor impaired the protective effects of metformin on HG-treated HUVECs. In conclusion, this study demonstrated that metformin affects cell proliferation and apoptosis via the AMPK/CREB/BDNF pathway in HG-incubated HUVECs.

Insulin-like growth factor-1-mediated regulation of miR-193a expression promotes the migration and proliferation of c-kit-positive mouse cardiac stem cells.

BACKGROUND: C-kit-positive cardiac stem cells (CSCs) have been shown to be a promising candidate treatment for myocardial infarction and heart failure. Insulin-like growth factor (IGF)-1 is an anabolic growth hormone that regulates cellular proliferation, differentiation, senescence, and death in various tissues. Although IGF-1 promotes the migration and proliferation of c-kit-positive mouse CSCs, the underlying mechanism remains unclear. METHODS: Cells were isolated from adult mouse hearts, and c-kit-positive CSCs were separated using magnetic beads. The cells were cultured with or without IGF-1, and c-kit expression was measured by Western blotting. IGF-1 induced CSC proliferation and migration, as measured through Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. The miR-193a expression was measured by quantitative real-time PCR (qPCR) assays. RESULTS: IGF-1 enhanced c-kit expression in c-kit-positive CSCs. The activities of the phosphoinositol 3-kinase (PI3K)/AKT signaling pathway and DNA methyltransferases (DNMTs) were enhanced, and their respective inhibitors LY294002 and 5-azacytidine (5-AZA) blunted c-kit expression. Based on the results of quantitative real-time PCR (qPCR) assays, the expression of miR-193a, which is embedded in a CpG island, was down-regulated in the IGF-1-stimulated group and negatively correlated with c-kit expression, whereas c-kit-positive CSCs infected with lentivirus carrying micro-RNA193a displayed reduced c-kit expression, migration and proliferation. CONCLUSIONS: IGF-1 upregulated c-kit expression in c-kit-positive CSCs resulting in enhanced CSC proliferation and migration by activating the PI3K/AKT/DNMT signaling pathway to epigenetically silence miR-193a, which negatively modifies the c-kit expression level.

Hypoxic Preconditioning Inhibits Hypoxia-induced Apoptosis of Cardiac Progenitor Cells via the PI3K/Akt-DNMT1-p53 Pathway.

Research has demonstrated that hypoxic preconditioning (HP) can enhance the survival and proliferation of cardiac progenitor cells (CPCs); however, the underlying mechanisms are not fully understood. Here, we report that HP of c-kit (+) CPCs inhibits p53 via the PI3K/Akt-DNMT1 pathway. First, CPCs were isolated from the hearts of C57BL/6 mice and further purified by magnetic-activated cell sorting. Next, these cells were cultured under either normoxia (H0) or HP for 6 hours (H6) followed by oxygen-serum deprivation for 24 hours (24h). Flow cytometric analysis and MTT assays revealed that hypoxia-preconditioned CPCs exhibited an increased survival rate. Western blot and quantitative real-time PCR assays showed that p53 was obviously inhibited, while DNMT1 and DNMT3ß were both significantly up-regulated by HP. Bisulphite sequencing analysis indicated that DNMT1 and DNMT3ß did not cause p53 promoter hypermethylation. A reporter gene assay and chromatin immunoprecipitation analysis further demonstrated that DNMT1 bound to the promoter locus of p53 in hypoxia-preconditioned CPCs. Together, these observations suggest that HP of CPCs could lead to p53 inhibition by up-regulating DNMT1 and DNMT3ß, which does not result in p53 promoter hypermethylation, and that DNMT1 might directly repress p53, at least in part, by binding to the p53 promoter locus.

[Optimal time for the administration of rhGH in severely burned patients--analysis of the dynamic changes of IGF axis and blood sugar].

OBJECTIVE: To investigate the effects of recombinant human growth hormone (rhGH) on the changes in serum insulin-like growth factor-I (IGF-I), IGF binding protein 3 (IGFBP-3) and blood sugar in severely burned patients, so as to validate the optimal time of rhGH administration. METHODS: Forty severely burned patients were enrolled in the study and were randomly divided into control (C), treatment 1 (rhGH given from 7 - 9 PBD, T1) and treatment 2 (rhGH from 10 - 14 PBD, T2) groups. The dynamic changes in serum IGF-I, IGFBP-3 and blood sugar on the 1, 3, 5, 7, 10, 14 and 21 PBDs in all 3 groups of burn patients were determined, analyzed and compared with one another. RESULTS: The serum IGF-I, IGFBP-3 and blood sugar levels in T1 and T2 groups were higher than those in C group after the use of rhGH, especially the IGFBP-3 and blood sugar (P < 0.05). There was no difference of all the indices between T1 and T2 groups. CONCLUSION: It might be optimal to give rhGH to severely burned patients during 7-9 PBDs.