INTRODUCTION
B-type natriuretic peptide (BNP) is widely used to diagnose and assess heart failure prognosis. However, its effects on pathological cardiomyocyte hypertrophy and the underlying mechanisms remain largely unexplored.
Methods
Here, we report the use of isoproterenol (ISO)-induced cardiomyocyte hypertrophy models with varying doses of BNP to investigate the potential targets and molecular mechanisms of BNP in rat cardiomyocyte hypertrophy.
Results
Phenotypic measurement confirmed that BNP treatment significantly attenuated ISOinduced cardiomyocyte hypertrophy. Transcriptomic profiling of cardiomyocytes identified key markers and pathways associated with hypertrophy and BNP intervention, revealing that BNP could broadly reverse ISO-induced molecular perturbations. Trajectory analysis and network module analysis further highlighted MyD88 and Pik3r3 as candidate regulatory nodes associated with BNP intervention. BNP treatment potentially downregulates these genes, which is accompanied by reduced activity of inflammatory and growth-related signaling networks. These changes are associated with pathways involved in sarcomeric protein synthesis, immune-inflammatory responses, myocardial fibrosis, mitochondrial homeostasis, and oxidative stress, suggesting a potential role for BNP in attenuating cardiomyocyte hypertrophy.
Discussion
These findings suggest that BNP may exert protective effects against cardiomyocyte hypertrophy through coordinated modulation of multiple signaling pathways. MyD88- and Pik3r3- associated networks emerged as potential molecular mechanisms underlying BNP-mediated responses and may represent promising targets for future investigation.
Conclusion
This study provides transcriptomic evidence that BNP may attenuate cardiomyocyte hypertrophy and identifies MyD88- and Pik3r3-associated signaling networks as potential molecular mediators of this response. These findings suggest possible mechanisms underlying the protective effects of BNP and provide a foundation for future functional validation studies in hypertrophic heart disease.
Background Diabetes markedly increases the risk of heart failure, yet the molecular signals connecting metabolic stress, myocardial fibrosis, and impaired cardiac repair remain incompletely understood. Methods We integrated bulk transcriptomic data from postischemic hearts (GSE26887), fibrosis‐related genes from the CTD database, protein–protein interaction (PPI) analysis, and pathway enrichment (GO, KEGG, GSEA, and GSVA) to identify candidate mediators in diabetic versus nondiabetic heart failure. Single‐cell RNA‐sequencing datasets were analyzed with Seurat to map the cellular distribution of key genes. Pan‐cancer analyses using TCGA cohorts were performed to evaluate prognostic, immune, and tumor mutation burden (TMB) correlations. Mechanistic validation was conducted in human cardiac progenitor cells (CPCs) exposed to normoglycemia or high glucose with S100A9 knockdown or overexpression, recombinant S100A8/A9, and a neutralizing S100A9 antibody. Cell viability (CCK‐8); qPCR panels for fibrosis, inflammation, and metabolic genes; ROS production (DCF‐DA and MitoSOX); and mitochondrial respiration were quantified. Results Differential expression and PPI network analyses identified S100A8 as a fibrosis‐related hub specifically enriched in diabetic heart failure. Single‐cell mapping revealed predominant S100A8 expression in CPCs rather than mature cardiomyocytes. Pathway analyses linked S100A8 to collagen fibril organization, ECM–receptor interaction, oxidative phosphorylation, and fatty acid β‐oxidation. Functionally, high glucose upregulated S100A8/S100A9 and profibrotic and proinflammatory genes in CPCs, increased total and mitochondrial ROS, and reduced basal, ATP‐linked, and maximal respiration and spare capacity. S100A9 knockdown partially restored CPC proliferation, redox balance, and mitochondrial function, whereas S100A9 overexpression or recombinant S100A8/A9 further exacerbated oxidative stress and bioenergetic failure; S100A9 neutralization attenuated these effects. Pan‐cancer analyses showed that high S100A8 expression was associated with adverse prognosis, altered immune infiltration, and increased TMB in several TCGA cohorts. Conclusions S100A8/S100A9 emerges as a central mediator linking hyperglycemia‐induced oxidative stress, metabolic inflexibility, and fibrotic reprogramming of CPCs, thereby promoting diabetic heart failure. S100A8/S100A9 may serve as a biomarker and therapeutic target at the interface of immunometabolism, cardiac regeneration, and cardio‐oncology.
BACKGROUND
The role of Klotho in heart failure (HF) and its underlying metabolic mechanisms remain unclear. This study investigated how Klotho deficiency affects extracellular matrix (ECM) homeostasis and metabolic regulation in post-myocardial infarction HF (MI-HF), with a focus on aldehyde dehydrogenase 1 family member L1 (ALDH1L1).
METHODS
Wild-type (WT), Klotho haploinsufficient (Klotho+/-), MI-HF, and Klotho+/--MI-HF mouse models were used. Transcriptomic and proteomic analyses were performed.
RESULTS
Compared with WT, Klotho+/- mice showed 84 differentially expressed genes (DEGs) and 311 differentially expressed proteins (DEPs) enriched in ECM-related pathways. MI-HF mice exhibited similar ECM enrichment. Importantly, comparison between Klotho+/--MI-HF and MI-HF identified 201 DEPs. Proteomic KEGG enrichment analysis revealed significant enrichment of ALDH1L1-related one‑carbon metabolism and NADPH regeneration pathways, along with significant downregulation of ALDH1L1 in Klotho-deficient HF mic.
CONCLUSION
Klotho deficiency is associated with exacerbated post-myocardial infarction heart failure, accompanied by significant alterations in ECM homeostasis-related molecules and ALDH1L1-mediated one‑carbon metabolism and NADPH regeneration pathways. These findings suggest that the Klotho/ALDH1L1 axis may represent a potential therapeutic target for post-myocardial infarction heart failure.
Bing Zhao, Chun Xiao· Experimental Gerontology· 0 citations
BACKGROUND
Pulmonary hypertension (PH) is a life-threatening blood vessel disorder marked by remodeling of the pulmonary arteries. A key feature of this process is the uncontrolled growth of pulmonary artery smooth muscle cells (PASMCs). Although changes in fatty acid metabolism are thought to drive this abnormal cell growth, the exact molecular mechanisms behind it are still not fully understood.
OBJECTIVE
This study aimed to identify key regulators of fatty acid metabolism in PH using multi-omics data and lab experiments, and to explore how they contribute to PASMC overgrowth, with the goal of uncovering new treatment targets.
METHODS
We analyzed PH-related transcriptome data (GSE113439) and protein interaction networks to pinpoint central fatty acid metabolism genes. Functional enrichment, immune cell infiltration, and single-cell RNA sequencing (GSE210248) were used to explore the role of a key gene, ACSL4. We then screened FDA-approved drugs for potential ACSL4 inhibitors using molecular docking and dynamics simulations. Finally, in a rat model of PH induced by chronic low oxygen and in primary PASMCs, we tested how blocking ACSL4 (with the inhibitor PRGL493 or siRNA) affected cell growth and the pathways involved.
RESULTS
ACSL4 stood out as a central player in fatty acid metabolism in PH. Its high expression was linked to changes in the immune environment and early disease stages. Functional analysis showed that ACSL4 and its related networks are involved in lipid metabolism, PPAR signaling, and ferroptosis. Virtual screening and molecular dynamics pointed to three FDA-approved drugs that bind tightly and steadily to ACSL4. In lab and animal studies, ACSL4 levels went up in lung tissue and PASMCs exposed to low oxygen, along with shifts in fatty acid profiles and increased PASMC growth. Blocking or silencing ACSL4 eased this overgrowth by helping restore normal VGLL4/YAP levels and reversing the suppression of the Hippo pathway.
CONCLUSION
This study uncovers a novel mechanism by which ACSL4 fuels PASMC growth in PH through reshaping fatty acid metabolism and targeting the VGLL4/YAP signaling axis. Although the role of ACSL4 in pulmonary hypertension has been previously reported, its function via the VGLL4/YAP axis is a novel finding. These findings highlight a key pathway in PH progression and point to ACSL4 as a possible target for new treatments.
Wei Chen, Yi-Ting Dong, Qiong Shi et al.· Vascular pharmacology· 0 citations
The results nominate testable macrophage regulatory and signaling hypotheses for HFpEF but do not establish drug-specific reversal or cross-model conservation.
Dingkun Wang, Wenyao Cai, Ruonan Wang et al.· Omics· 0 citations
Hypertension-induced cardiac fibrosis is a major risk factor for heart failure; although disrupted mitochondrial homeostasis has been confirmed to serve a critical role in the pathological process, its upstream regulatory factors remain incompletely understood. In the current study, RNA sequencing and bioinformatics analyses identified POU domain class 2 transcription factor 1 (POU2F1) as a hub transcriptional regulator in the fibrotic cardiac tissues of spontaneously hypertensive rats (SHRs). The expression levels of POU2F1 were associated with the severity of myocardial fibrosis, and cardiac expression of PTEN-induced kinase 1 (PINK1) and Parkin in SHRs. Complementing these in vivo observations, angiotensin II stimulation significantly upregulated POU2F1 expression in cardiac fibroblasts (CFs) in vitro. Furthermore, POU2F1 expression exhibited a positive correlation with fibroblast activation, as indicated by α-smooth muscle actin fluorescence intensity. Mechanistically, POU2F1 knockdown attenuated CF activation, improved mitochondrial structure and energy metabolism, and restored PINK1/Parkin-mediated mitophagy balance in vivo and in vitro. Conversely, POU2F1 overexpression was associated with enhanced PINK1/Parkin-mediated mitophagy signaling. Crucially, through chromatin immunoprecipitation-quantitative PCR, electrophoretic mobility shift assay and dual-luciferase reporter assay, it was demonstrated that POU2F1 can directly bind to the PINK1 promoter to activate its transcription. In conclusion, the present study identified a novel role for POU2F1 in hypertensive cardiac fibrosis, demonstrating that it exacerbates disease progression by disrupting mitochondrial homeostasis through transcriptional activation of PINK1, accompanied by alterations consistent with enhanced PINK1/Parkin-mediated mitophagy.
Yongbo Ma, Xiaozhe Chen, Zixian Liu et al.· Molecular Medicine Reports· 0 citations
Pathological cardiac hypertrophy is maladaptive cardiac remodeling induced by chronic adverse stimuli. In this study, the E3 ubiquitin ligase RNF128 was identified as a suppressor of pathological cardiac dysfunction with therapeutic value. Methods: The expression of Ring Finger protein 128 (RNF128) in pathological cardiac hypertrophy was characterized via public database analysis, scRNA-seq (single-cell RNA sequencing), and further validated in clinical myocardial samples and mouse disease models. The regulatory function of RNF128 in the progression of cardiac hypertrophy was verified in vivo by cardiomyocyte-specific RNF128 knockout mice and cTnT-AAV9-mediated RNF128 overexpression. Ang II (angiotensin II)-stimulated NMCMs (neonatal mouse cardiomyocytes) were used for in vitro validation. Moreover, the downstream target of RNF128 was identified through integrated analysis of scRNA-seq, interactome profiling and quantitative proteomics, followed by a panel of molecular assays. Results: Pathological cardiac hypertrophy reduced RNF128 expression in both human and murine samples. RNF128 deficiency aggravated cardiac dysfunction and pathological remodeling, while its overexpression protected cardiac function. Mechanistically, RNF128 directly interacted with SERCA2a, and catalyzed K63-linked polyubiquitination of SERCA2a at residue K476 (lysine 476), thereby impaired SERCA2a recognition by SQSTM1/p62. Consequently, RNF128 inhibited autophagy-lysosome-mediated degradation of SERCA2a. Conclusions: The findings of this study highlight RNF128 as a novel therapeutic target for heart failure, linking ubiquitination-dependent protein regulation to calcium handling in cardiomyocytes.
