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Purpose: Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor-1 (P-Rex1), as one of the members of Rac-GEFs, has been proven to play a critical role in cancer progression and metastasis. Nonetheless, its role in cardiac fibrosis remains elusive. In the present study, we aimed to investigate whether and how the P-Rex1 mediates AngII-induced cardiac fibrosis. Method: A cardiac fibrosis mouse model was established by chronic AngII perfusion. The heart structure, function, pathological changes of myocardial tissues, oxidative stress, and cardiac fibrotic protein expression were determined in an AngII induced mouse model. To provide a molecular mechanism for P-Rex1 involvement in cardiac fibrosis, a specific inhibitor or siRNA was used to block P-Rex1, and target the relationship between Rac1-GTPase and its downstream effector. Results: Blocking P-Rex1 showed down-regulation of its downstream effectors such as the profibrotic transcriptional regulator Paks, ERK1/2, and ROS generation. Intervention treatment with P-Rex1 inhibitor 1A-116 ameliorated AngII-induced abnormalities in heart structure and function. Moreover, pharmacological inhibition of the P-Rex1/Rac1 axis showed a protective effect in AngII-induced cardiac fibrosis through the down-regulation of collagen1, CTGF, and α-SMA expression. Conclusion: Our findings demonstrated for the first time that P-Rex1 was an essential signaling mediator in CFs activation and subsequent cardiac fibrosis, and 1A-116 could be a potential pharmacological development drug. [ABSTRACT FROM AUTHOR]

Triglyceride glycemic-body mass index (TyG-BMI) is a simple and reliable surrogate for insulin resistance (IR). However, it is still unclear if TyG-BMI has any predictive value in patients having percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). The purpose of this study was to examine the TyG-BMI index's prognostic significance and predictive power in patients with STEMI. The study comprised a total of 2648 consecutive STEMI patients who underwent PCI. The primary endpoint was the occurrence of major adverse cardiovascular events (MACE), defined as the combination of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and coronary revascularization. The TyG-BMI index was formulated as ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2] × BMI. 193 patients in all experienced MACE over a median follow-up of 14.7 months. There was a statistically significant difference between the Kaplan–Meier survival curves for the TyG-BMI index tertiles (log-rank test, p = 0.019) for the cumulative incidence of MACE. The adjusted HRs for the incidence of MACE in the middle and highest quartiles of the TyG-BMI index compared with the lowest quartile were 1.37 (95% CI 0.92, 2.03) and 1.53 (95% CI 1.02, 2.29), respectively, in the fully adjusted Cox regression model. At six months, one year, and three years, the TyG-BMI area under the curve (AUC) for predicting MACE was 0.691, 0.666, and 0.637, respectively. Additionally, adding the TyG-BMI index to the risk prediction model enhanced outcome prediction. In STEMI patients undergoing PCI, TyG-BMI was independently linked to MACE. TyG-BMI could be a simple and solid way to assess MACE risk and prognosis. [ABSTRACT FROM AUTHOR]

Background. Acute ST-segment elevation myocardial infarction (STEMI) is a serious cardiovascular disease that poses a great threat to the life and health of patients. Therefore, early diagnosis is important for STEMI patient treatment and prognosis. The purpose of this study was to investigate the value of serum YKL-40 and TNF-α in the diagnosis of STEMI. Methods. From October 2020 to February 2022, 120 patients with STEMI were admitted to the Chest Pain Center of the Second People's Hospital of Hefei, and 81 patients with negative coronary angiography were selected as the control group. Serum YKL-40 and TNF-α concentrations were measured by sandwich ELISA. Pearson correlation was used to analyze the correlation between serum YKL-40, TNF-α, and serum troponin I (cTnI) in STEMI patients; multivariate logistic regression analysis was used to screen independent risk factors for STEMI. Three diagnostic models were constructed: cTnI univariate model (model A), combined serum YKL-40 and TNF-α model other than cTnI (model B), and combined cTnI and serum YKL-40 and TNF-α model (model C). We assessed the clinical usefulness of the diagnostic model by comparing AUC with decision curve analysis (DCA). Results. Serum YKL-40 and TNF-α in the STEMI group were significantly higher than those in the control group (P < 0.001). On Pearson correlation analysis, there was a significant positive correlation between serum YKL-40, TNF-α, and cTnI levels in STEMI patients. Multivariate logistic regression analysis showed that serum YKL-40 and TNF-α were independent risk factors for the development of STEMI. The results of ROC analysis showed that the area under the curve (AUC) of serum YKL-40 for predicting the occurrence of STEMI was 0.704. The AUC of serum TNF-α for predicting the occurrence of STEMI was 0.852. The AUC of cTnI as a traditional model, model A, for predicting the occurrence of STEMI was 0.875. Model B predicted STEMI with an AUC of 0.851. The addition of serum YKL-40 and serum TNF-α to the traditional diagnostic model composed of cTnI constituted a new diagnostic model; that is, the AUC of model C for predicting the occurrence of STEMI was 0.930. Model C had a better net benefit between a threshold probability of 70–95% for DCA. Conclusion. In this study, we demonstrate the utility of serum YKL-40 and TNF-α as diagnostic markers for STEMI and the clinical utility of diagnostic models by combining serum YKL-40 and TNF-α with cTnI. [ABSTRACT FROM AUTHOR]

Hyperactivity of the sympathetic nervous system is a major driver of cardiac remodeling, exerting its effects through both α-, and β-adrenoceptors (α-, β-ARs). As the relative contribution of subtype α1-AR to cardiac stress responses remains poorly investigated, we subjected mice to either subcutaneous perfusion with the β-AR agonist isoprenaline (ISO, 30 mg/kg × day) or to a combination of ISO and the stable α1-AR agonist phenylephrine (ISO/PE, 30 mg/kg × day each). Telemetry analysis revealed similar hemodynamic responses under both ISO and ISO/PE treatment i.e., permanently increased heart rates and only transient decreases in mean blood pressure during the first 24 h. Echocardiography and single cell analysis after 1 week of exposure showed that ISO/PE-, but not ISO-treated animals established α1-AR-mediated inotropic responsiveness to acute adrenergic stimulation. Morphologically, additional PE perfusion limited concentric cardiomyocyte growth and enhanced cardiac collagen deposition during 7 days of treatment. Time-course analysis demonstrated a diverging development in transcriptional patterns at day 4 of treatment i.e., increased expression of selected marker genes Xirp2, Nppa, Tgfb1, Col1a1, Postn under chronic ISO/PE treatment which was either less pronounced or absent in the ISO group. Transcriptome analyses at day 4 via RNA sequencing demonstrated that additional PE treatment caused a marked upregulation of genes allocated to extracellular matrix and fiber organization along with a more pronounced downregulation of genes involved in metabolic processes, muscle adaptation and cardiac electrophysiology. Consistently, transcriptome changes under ISO/PE challenge more effectively recapitulated early transcriptional alterations in pressure overload-induced experimental heart failure and in human hypertrophic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Objective: Little is known regarding the functional role of microRNA-193-3p (miR-193-3p) in sepsis. Hence, the aim of the present study was to investigate the effect of miR-193-3p on myocardial injury in mice with sepsis and its mechanism through the regulation of signal transducers and activators of transcription 3 (STAT3).Methods: The mice model of sepsis was established by cecal ligation and puncture (CLP), septic mice were injected with miR-193-3p agomir, miR-193-3p antagomir or siRNA-STAT3. The expression of miR-193-3p, STAT3 and HMGB1 in the myocardial tissue of septic mice were detected. Cardiac ultrasound, hemodynamics, myocardial injury markers, inflammatory factors and cardiomyocyte apoptosis in septic mice were measured.Results: MiR-193-3p expression was reduced while STAT3 expression was increased in septic mice. Down-regulated STAT3 or up-regulated miR-193-3p improved cardiac function, attenuated myocardial injury, inflammation and cardiomyocyte apoptosis in septic mice. Knockdown STAT3 reversed the role of inhibited miR-193-3p for mice with sepsis. miR-193-3p targeted STAT3, thereby inhibiting HMGB1 expression.Conclusion: This study provides evidence that miR-193-3p targets STAT3 expression to reduce HMGB1 expression, thereby reducing septic myocardial damage. MiR-193-3p might be a potential candidate marker and therapeutic target for sepsis. [ABSTRACT FROM AUTHOR]

Background: Non‐small cell lung cancer (NSCLC) occupies the majority of lung cancer cases and is notorious for the awful prognosis. LIM domains‐containing 1 (LIMD1) is suggested as a tumor suppressor in lung cancer, but its mechanism in NSCLC remains elusive. Present study aimed to uncover the mechanism of LIMD1 in NSCLC. Methods: qRT‐PCR was performed to analyze the level of LIMD1. The functions of LIMD1 in NSCLC cells were evaluated by CCK‐8, EdU, and caspase‐3 activity assays. RIP and pull‐down assays were applied to determine the interaction of LIMD1 with heterogeneous nuclear ribonucleoprotein U (hnRNP U) and LIMD1‐AS1. Results: LIMD1 was downregulated in NSCLC samples and cells. Functionally, LIMD1 hindered proliferation and drove apoptosis in NSCLC cells. Moreover, long noncoding RNA (lncRNA) LIMD1 antisense RNA 1 (LIMD1‐AS1) was downregulated in NSCLC samples and cell lines. LIMD1‐AS1 knockdown abrogated NSCLC cell growth in vitro and in vivo. Mechanistically, LIMD1‐AS1 stabilized LIMD1 mRNA through interacting with hnRNP U. Rescue experiments suggested that LIMD1‐AS1 repressed NSCLC progression through LIMD1. Conclusions: LIMD1‐AS1 suppressed NSCLC progression through stabilizing LIMD1 mRNA via hnRNP U, providing new thoughts for the improvement of molecular‐targeted therapy for NSCLC. [ABSTRACT FROM AUTHOR]