Psychological stress contributes to cardiovascular disease (CVD) and sudden cardiac death, yet its molecular basis remains obscure. RNA binding protein RBM24 plays a critical role in cardiac development, rhythm regulation, and cellular stress. Here, we show that psychological stress activates RBM24 S181 phosphorylation through eIF4E2-GSK3 beta signaling, which causally links psychological stress to CVD by promoting APOE translation (apolipoprotein E). Using an Rbm24 S181A KI mouse model, we show that impaired S181 phosphorylation leads to cardiac contractile dysfunction, atrial fibrillation, dyslipidemia, reduced muscle strength, behavioral abnormalities, and sudden death under acute and chronic psychological stressors. The impaired S181 phosphorylation of RBM24 inhibits cardiac translation, including APOE translation. Notably, cardiomyocyte-specific expression of APOE rescues cardiac electrophysiological abnormalities and contractile dysfunction, through preventing ROS stress and mitochondrial dysfunction. Moreover, RBM24-S181 phosphorylation acts as a serum marker for chronic stress in human. These results provide a functional link between RBM24 phosphorylation, eIF4E-regulated APOE translation, and psychological-stress-induced CVD. Mental stress is well known to cause cardiovascular disease. Here, the authors show that an imbalance in RBM24-S181 phosphorylation impairs cardiac translation of APOE, leading to cardiac contractile dysfunction, atrial fibrillation, fibrosis, and sudden death under psychological stress.

Liver injury is closely related to poor outcomes in sepsis patients. Current studies indicate that sepsis is accompanied by metabolic disorders, especially those related to lipid metabolism. It is highly important to explore the mechanism of abnormal liver lipid metabolism during sepsis. As a key regulator of glucose and lipid metabolism, angiopoietin-like 8 (ANGPTL8) is involved in the regulation of multiple chronic metabolic diseases. In the present study, severe liver lipid deposition and lipid peroxidation were observed in the early stages of lipopolysaccharide (LPS) induced liver injury. LPS promotes the expression of ANGPTL8 both in vivo and in vitro. Knockout of ANGPTL8 reduced hepatic lipid accumulation and lipid peroxidation, improved fatty acid oxidation and liver function, and increased the survival rate of septic mice by activating the PGC1α/PPARα pathway. We also found that the expression of ANGPTL8 induced by LPS depends on TNF-α, and that inhibiting the TNF-α pathway reduces LPS-induced hepatic lipid deposition and lipid peroxidation. However, knocking out ANGPTL8 improved the survival rate of septic mice better than inhibiting the TNF-α pathway. Taken together, the results of our study suggest that ANGPTL8 functions as a novel cytokine in LPS-induced liver injury by suppressing the PGC1α/PPARα signaling pathway. Therefore, targeting ANGPTL8 to improve liver lipid metabolism represents an attractive strategy for the management of sepsis patients.

Gestational diabetes mellitus (GDM) presents varied manifestations throughout pregnancy and poses a complex clinical challenge. High-depth cell-free DNA (cfDNA) sequencing analysis holds promise in advancing our understanding of GDM pathogenesis and prediction. In 299 women with GDM and 299 matched healthy pregnant women, distinct cfDNA fragment characteristics associated with GDM are identified throughout pregnancy. Integrating cfDNA profiles with lipidomic and single-cell transcriptomic data elucidates functional changes linked to altered lipid metabolism processes in GDM. Transcription start site (TSS) scores in 50 feature genes are used as the cfDNA signature to distinguish GDM cases from controls effectively. Notably, differential coverage of the islet acinar marker gene PRSS1 emerges as a valuable biomarker for GDM. A specialized neural network model is developed, predicting GDM occurrence and validated across two independent cohorts. This research underscores the high-depth cfDNA early prediction and characterization of GDM, offering insights into its molecular underpinnings and potential clinical applications.

Background: Idiopathic ventricular tachycardia (VT) occurs in structurally normal hearts and accounts for a significant number of all types of VT. The genome-wide association study is the most effective strategy for identifying novel genetic variants for common diseases. However, no genome-wide association study has been reported for idiopathic VT. Methods: We conducted the first genome-wide association study for idiopathic VT in the Chinese Han population using a discovery population with 246 cases and 648 controls and a replication population with 222 cases and >4072 controls. Candidate VT genes were functionally characterized in zebrafish. Real-time RT-PCR analysis was used to determine the effects of candidate genes on expression of ion channels and regulators. Patch-clamping was used to record L-type calcium current from neonatal rat cardiomyocytes with overexpression of candidate genes. Results: We identified 4 significant loci represented by rs78960694 (minor allele frequency [MAF]=5.02% in cases and 1.84% in controls; P=4.30×10−12, odds ratio [OR]=3.91) and rs2229095 (MAF=3.25% in cases and 1.63% in controls; P=1.02×10−7, OR=3.44) near and in CCR7, respectively, rs68126098 in NELL1 (MAF=40.98% in cases and 32.07% in controls; P=2.40×10−8, OR=1.53), rs2390325 between PKN2 and LMO4 (MAF=21.19% in cases and 15.12% in controls; P=1.92×10−7, OR=1.62), and rs270065 in CSMD1 (MAF=33.63% in cases and 40.25% in controls; P=9.51×10−7, OR=0.69). Note that the associations of idiopathic VT for CCR7 variant rs78960694 and NELL1 variant rs68126098 reach genome-wide significance (P<5.00×10−8). Overexpression of either PKN2 or CCR7 increased the heart rate in zebrafish, and enhanced expression of CACNA1C, RYR2, or NOS1AP in zebrafish embryos, HEK293, and AC16 cardiomyocytes. Overexpression of either PKN2 or CCR7 significantly increased L-type Ca2+ current density. Conclusions: The first genome-wide association study identifies 4 novel loci and 2 risk genes (PKN2 and CCR7) for idiopathic VT. These findings identify new molecular determinants for cardiac calcium homeostasis and rhythm maintenance and provide novel targets for diagnosis and treatment for idiopathic VT.

Cholesterol is a precursor to steroid hormones and can be obtained from serum LDL or de novo synthesis in steroidogenic cells. Before luteinizing hormone (LH) surge-induced ovulation, follicles remain avascular, and cholesterol required for progesterone production in granulosa cells (GCs) is derived from de novo biosynthesis. Previous studies have verified that the intrafollicular TGF-β1 plays inhibitory roles in GCs luteinization, vascularization, and progesterone production. Nevertheless, the regulatory function of TGF-β1 on de novo cholesterol synthesis in granulosa-lutein (GL) cells remains largely unknown. We aim to investigate this aspect in this study using in vivo cultured human GL cells. Our results suggested that TGF-β1 significantly suppresses intracellular cholesterol levels and down-regulates the expression of the final step enzyme, DHCR24, that catalyzes de novo cholesterol synthesis. We used specific inhibitors and siRNA-mediated knockdown approaches demonstrate that TGF-β1 suppression of DHCR24 expression in GL cells is mediated by the GSK-3β/EZH2/H3K27me3 signaling pathway. Further ChIP assays revealed that elevated H3K27me3 levels in the promoter region of DHCR24 play a vital role in TGF-β1-induced DHCR24 down-regulation, and RNA-sequencing results confirmed these findings. Notably, our study provides a novel insight into the molecular mechanisms by which TGF-β1 suppresses de novo cholesterol biosynthesis in GL cells.

Dear Editor, Hypertension affects one billion people in the world.1 Half of the Chinese population aged from 35 to 75 years is also affected with hypertension.2 Genetic factors contribute to hypertension. Different ethnic populations share some common genetic factors; however, populationspecific genetic factors also play important roles in common complex diseases in different ethnic populations. Most genome wide association study (GWAS) for blood pressure have been reported in European ancestry populations; thus, much more GWAS are needed for hypertension in non-European ancestry populations, including the Chinese population. We designed a three-phase GWAS as reported previously3 to identify novel genomic variants conferring risk to hypertension in the Chinese Han population. The overall study design is shown in Figure 1A. Genotyping, imputation, and principal component analyses were conducted in phase 1 GWAS samples with 353 cases with hypertension and 332 controls without hypertension (Figure S1). After quality control, 3,956,088 single nucleotide polymorphisms (SNPs) were analyzed for their association with hypertension with adjustment of age, age2, gender, and the first three principal components (Figure S2). A total of 17,435 SNPs showing p value of <5.0 × 10–3 were selected for the phase 2 in silico replication study using GWAS summary data from the NHAPC cohort (1592 cases and 1302 controls).4 One hundred thirty-six SNPs clustering into 15 independent loci (Table S2) showed nominal association with hypertension (p < 5 × 10–3). Sixteen leading SNPs representing 15 loci were selected for replication in the phase 3 population containing 3274 cases and 2734 controls. Fourteen SNPs at 13 loci were genotyped successfully (two of 16 SNPs failed in genotyping). Two SNPs, including rs10847208 in the last exon of a long noncoding RNA (lncRNA) gene LINC00944 on 12q24.32 and rs2064453 in the promoter of GGT7

Background: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand in cancer, inflammation, and infection and negatively regulate inflammation and the immune response. Heart failure (HF) is a complex clinical syndrome wherein inflammation induction and incomplete resolution can potentially contribute to HF development and progression. However, the role of MDSCs in HF remains unclear. Methods: The percentage of MDSCs in patients with HF and in mice with pressure overload–induced HF using isoproterenol infusion or transverse aortic constriction (TAC) was detected by flow cytometry. The effects of MDSCs on isoproterenol- or TAC-induced HF were observed on depleting MDSCs with 5-fluorouracil (50 mg/kg) or gemcitabine (120 mg/kg), transferring purified MDSCs, or enhancing endogenous MDSCs with rapamycin (2 mg·kg −1 ·d −1 ). Hypertrophic markers and inflammatory factors were detected by ELISA, real-time polymerase chain reaction, or Western blot. Cardiac functions were determined by echocardiography and hemodynamic analysis. Results: The percentage of human leukocyte antigen-D–related (HLA-DR) − CD33 + CD11b + MDSCs in the blood of patients with HF was significantly increased and positively correlated with disease severity and increased plasma levels of cytokines, including interleukin-6, interleukin-10, and transforming growth factor–β. Furthermore, MDSCs derived from patients with HF inhibited T-cell proliferation and interferon-γ secretion. Similar results were observed in TAC- and isoproterenol-induced HF in mice. Pharmaceutical depletion of MDSCs significantly exacerbated isoproterenol- and TAC-induced pathological cardiac remodeling and inflammation, whereas adoptive transfer of MDSCs prominently rescued isoproterenol- and TAC-induced HF. Consistently, administration of rapamycin significantly increased endogenous MDSCs by suppressing their differentiation and improved isoproterenol- and TAC-induced HF, but MDSC depletion mostly blocked beneficial rapamycin-mediated effects. Mechanistically, MDSC-secreted molecules suppressed isoproterenol-induced hypertrophy and proinflammatory gene expression in cardiomyocytes in a coculture system. Neutralization of interleukin-10 blunted both monocytic MDSC- and granulocytic MDSC–mediated anti-inflammatory and antihypertrophic effects, but treatment with a nitric oxide inhibitor only partially blocked the antihypertrophic effect of monocytic MDSCs. Conclusions: Our findings revealed a cardioprotective role of MDSCs in HF by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through interleukin-10 and nitric oxide. Pharmacological targeting of MDSCs by rapamycin constitutes a promising therapeutic strategy for HF.