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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]

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]