BackgroundHypertension is prevalent and contributes significantly to cardiovascular risk in patients with systemic lupus erythematosus (SLE). Primary aldosteronism (PA), the most common endocrine cause of hypertension, confers higher cardiovascular risk than essential hypertension and has been linked to autoimmune diseases including SLE. While the prevalence of PA in SLE is unknown, a third of patients in a tertiary lupus clinic have been demonstrated to have clinical indications for PA testing.ObjectivesTo compare SLE phenotypes and outcomes in patients attending the clinic with and without indications for PA testing.MethodsIn this retrospective study, hypertension was defined as blood pressure ≥140/90 on two clinic visits, or a documented diagnosis of hypertension. Baseline demographic and SLE disease characteristics were compared between patients with and without an indication for PA testing as determined according to the 2016 Endocrine Society guidelines, before multivariable regression analyses assessed for associations between having an indication for PA testing with disease phenotypes and outcomes specifically within the subset of patients with hypertension.ResultsOf 322 patients with SLE, 95 patients (30%) had at least one indication for PA testing. These patients were older, had longer SLE disease duration, higher body mass index, higher blood pressure, and more baseline organ damage compared to those without an indication for PA testing. Over the period of clinic attendance (median 6.8 years), these patients had greater accrual of organ damage, higher flare rates, and more frequent proteinuria. Within the subset of hypertensive patients, indications for PA testing were independently associated with reduced baseline renal function (adjusted OR 3.29, 95% CI 1.30-9.47; p = 0.017), higher baseline organ damage (adjusted OR 1.94, 95% CI 1.03-3.73; p = 0.043), and higher prevalence of flare throughout the study period (adjusted OR 2.86, 95% CI 1.04-8.60; p = 0.049) in multivariable modelling.ConclusionSLE patients with an indication for PA testing exhibit a phenotype characterised by impaired renal function, increased organ damage and higher prevalence of flare. Further research is needed to prospectively assess whether the increased burden is attributable to PA, other causes of hypertension, or the severe hypertension.

Ischemic heart disease remains a leading cause of mortality worldwide. Although mesenchymal stem cell (MSC) transplantation offers a promising strategy for myocardial infarction, its therapeutic efficacy is limited by poor cell survival and insufficient regenerative capacity. Traditional Chinese medicine has been widely used to promote blood circulation and treat ischemic diseases. Chuanxiong-Chishao (Ligusticum chuanxiong and Paeoniae Radix Rubra) is a commonly used herb pair for this purpose. This study aimed to investigate whether Chuanxiong-Chishao combined with MSCs could synergistically enhance angiogenesis after myocardial infarction. A rat model of myocardial infarction (MI) was established by permanent ligation of the left anterior descending coronary artery, and the animals were randomly assigned to the sham, model, MSCs, and Chuanxiong-Chishao combined with MSCs (CC-MSCs) groups. MSCs were injected intramyocardially immediately after ligation, and herbal treatment was administered for 28 days. Cardiac function was evaluated by echocardiography, myocardial fibrosis by Masson staining, and angiogenesis by CD31 immunofluorescence. Proteomic profiling was performed using label-free quantitative analysis, and key proteins were validated by Western blot. Compared with MSCs alone, CC-MSCs significantly improved left ventricular ejection fraction, fractional shortening, and cardiac output, reduced infarct size, and enhanced neovascularization in MI rats. Proteomic analysis identified 154 differentially expressed proteins between the model and CC-MSCs groups, and Gene Ontology enrichment analysis indicated significant activation of angiogenesis-related processes. Among these proteins, CDC42, NRP1, and AMOT were markedly altered, which was further confirmed by Western blot analysis. These findings suggest that Chuanxiong-Chishao enhances MSC-mediated angiogenesis and cardiac repair after MI, potentially through modulation of angiogenesis-related protein networks.

Restraint stress is a well-established model for inducing psychological and physiological stress that triggers oxidative damage, inflammation, and apoptosis in cardiac tissue. Wedelolactone, a bioactive coumestan derived from Eclipta alba, possesses known antioxidant and anti-inflammatory properties, but its cardioprotective effects under restraint stress have not been well elucidated. The present study aimed to evaluate the cardioprotective potential of Wedelolactone against restraint stress-induced myocardial injury through biochemical, molecular, and histopathological assessments. Male Wistar rats were divided into four groups: Control, Restraint Stress (RS), RS + wedelolactone (10 mg/kg, orally), and wedelolactone-alone. Electrocardiographic parameters, serum cardiac biomarkers (creatine kinase MB (CK-MB), lactate dehydrogenase, aspartate aminotransferase, cardiac troponin I), oxidative stress markers (malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione), inflammatory mediators (tumor necrosis factor-α, interleukin-6, C-reactive protein, nuclear factor-κB), and apoptotic gene expression (Bax, Bcl-2, caspase-3 and caspase-9) were analyzed. Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway activation was evaluated by western blot, and myocardial histology was assessed using hematoxylin and eosin staining. Restraint stress caused significant increases in oxidative stress, inflammation, and apoptotic gene expression, along with histological evidence of myocyte necrosis and vascular congestion. Wedelolactone treatment markedly normalized cardiac biomarkers, restored antioxidant enzyme levels, reduced inflammatory cytokines, and downregulated pro-apoptotic genes while enhancing Nrf2/HO-1 signaling and anti-apoptotic gene expression. We found that Wedelolactone exhibits potent cardioprotective, antioxidant, anti-inflammatory, and anti-apoptotic properties against restraint stress-induced myocardial damage, primarily through activation of the Nrf2/HO-1 pathway and suppression of nuclear factor-κB signaling.

Atherosclerosis (AS) is closely related to the pathogenesis and abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). To explore the value of hsa_circ_0044097 in the clinical management of AS and to elucidate its role and mechanism in the injury of VSMCs induced by in vitro oxidized low-density lipoprotein (ox-LDL). The mRNA expressions of hsa_circ_0044097 and miR-3918 were determined using RT-qPCR, and transfection verification was also conducted. The content of IL-6 and TNF-α was determined using an ELISA kit. CCK-8 and transwell assays were performed to determine the proliferation and migration of HASMC cells. The dual luciferase reporter assay and Spearman correlation analysis were performed to verify the relationship between hsa_circ_0044097 and miR-3918. The clinical value of hsa_circ_0044097 was evaluated using the ROC curve, K-M survival analysis and Cox analysis. Hsa_circ_0044097 level was decreased in AS patients' serum and HASMCs stimulated by ox-LDL. Hsa_circ_0044097 could serve as an indicator for the diagnosis of AS and for predicting the occurrence of MACE in AS patients. Overexpression of hsa_circ_0044097 inhibited the levels of inflammatory factors, cell proliferation and migration. MiR-3918 was targeted by hsa_circ_0044097, and overexpression of miR-3918 reversed the inhibitory effect of the upregulation of hsa_circ_0044097 on the proliferation and migration of VSMCs. Hsa_circ_0044097 may be a biomarker for diagnosing AS and predicting the occurrence of MACE. Hsa_circ_0044097 influences the progression of AS.

The management of type 2 diabetes (T2D) has recently witnessed a paradigm shift extending beyond blood glucose regulation towards cardiovascular and renal health targeted by cardiovascular outcome trials (CVOTs) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Preclinical studies suggest a potential role for GLP-1RAs and SGLT2i in the treatment of diabetic neuropathy and neuropathic pain. However, to date largely only small-size phase II shorter-term randomized controlled trials (RCTs) of heterogeneous designs and quality have been performed, without clear evidence of favorable effect of both GLP-1RAs and SGLT2i on clinical and neurophysiological neuropathic outcomes. Moreover, responses to GLP1-RA and SGLT2i treatments in real‑world clinical practice appear heterogeneous, with relatively high rates of non-responders and discontinuation. Several possible risks associated with GLP-1RAs and SGLT2i treatment in real-world practice have been identified requiring increased attention by physicians, their professional societies, and patients alike. Unfortunately, the opportunity has been missed to use simple tools for the detection and monitoring of diabetic sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) in the multiple published large-scale pivotal CVOTs. Diabetic neuropathy is linked to considerable patient burden and mortality, and there remains an unmet need for the disease modifying effects of novel pharmacotherapies derived from the pathogenetic concepts of diabetic neuropathy. In the future, when designing and conducting RCTs more emphasis should be placed on considering neuropathy as a serious and potentially life-threatening complication.

Cardiac remodeling is driven by progressive extracellular matrix stiffening and cardiomyocyte loss. Cardiomyocyte death arising from the progression of fibrosis and ferroptosis, which are regulated by interconnected pathogenic pathways such as lysyl oxidase-like (LOXL), Yes-associated protein (YAP) transcriptional coactivator with PDZ-binding motif (TAZ), and transforming growth factor-beta, leads to cardiac remodeling. However, existing treatments are insufficient to restore heart health. There is mounting evidence that maintaining a healthy balance of metals, particularly copper and iron, can protect the heart from metal-induced cell death, cardiac structural remodeling, and extracellular matrix stiffening. This review examines a therapeutic targeting strategy that emphasises the significance of the Cu-LOXL2-Fe-ferroptosis circuit, a mechanometabolic loop that reinforces the extracellular matrix and oxidative cell death. In this dual-chelation approach, copper modulation inhibits LOXL2-driven extracellular matrix stiffening and profibrotic signaling, while iron chelation suppresses iron-dependent lipid peroxidation and ferroptotic cardiomyocyte death. This combined approach provides a more effective treatment window, interrupting the vicious cycle of tissue damage and cardiomyocyte death. There is preliminary evidence that metal chelators may be able to mitigate ferroptosis and fibrosis, which could lead to possible outcomes.

Ischemic stroke is a major cause of death and disability, and current therapies only partly limit secondary brain injury driven by apoptosis and oxidative stress. Mitochondria dependent cell death is a key contributor, but the upstream regulatory networks and cell type specific effectors remain unclear.

Single cell RNA sequencing, bulk RNA sequencing and miRNA profiling from mouse middle cerebral artery occlusion models were integrated to identify mitochondrial apoptosis related pathways and key regulators. Cell type composition and differentially expressed genes were analyzed by scRNA-seq, intersected bulk datasets were used to define shared apoptosis related genes, and miRNA target prediction nominated candidate miRNA-mRNA pairs. Hypoxia treated BV2 microglia and bEnd.3 endothelial cells were used for functional validation by qPCR, western blotting, flow cytometry, LDH release, CCK-8 and dual luciferase assays.

scRNA-seq identified twelve brain cell populations and showed that endothelial cells, monocytes, astrocytes and microglia display the most prominent changes after ischemia, with Gene Ontology enrichment repeatedly highlighting "apoptotic mitochondrial changes" (GO:0008637). Intersecting two bulk RNA-seq cohorts recovered the same pathway and four candidates (Hk2, Pycard, Fas and Plaur), with Plaur most strongly dysregulated in endothelial and myeloid cells. miRNA profiling and multi database prediction highlighted miR-21a-3p as a putative upstream regulator of Plaur. In vitro, hypoxia increased Plaur and decreased miR-21a-3p. Plaur silencing reduced apoptosis, reactive oxygen species and LDH release and improved viability, while miR-21a-3p overexpression lowered Plaur and attenuated hypoxia induced injury; inhibition of miR-21a-3p had opposite effects. Dual luciferase assays confirmed direct binding of miR-21a-3p to the Plaur 3'UTR.

The miR-21a-3p/Plaur axis links miRNA regulation to mitochondria associated apoptotic and oxidative damage pathways in ischemia related cellular models and represents a potential target for further mechanistic and translational studies in ischemic stroke.

Immunoglobulin A nephropathy (IgAN), the most common primary glomerular disease and a leading cause of end-stage kidney disease (ESKD), is associated with cardiovascular and metabolic abnormalities. To explore these genetic overlaps, we integrated large-scale GWAS data from IgAN, 21 pan-vascular diseases (PVDs), 13 metabolic traits, 11 immune cell phenotypes, and established IgAN risk factors. Cross-trait analyses (LDSC, GNOVA, SUPERGNOVA) revealed significant genetic correlations between IgAN and multiple PVDs, including coronary artery disease, heart failure, stroke, aortic aneurysm, and varicose veins. Multi-omics prioritization (TWAS, SMR, MAGMA, and fastBAT) identified shared variants and candidate genes associated with immune regulation, lipid transport, and cardiovascular function. Gene expression profiling demonstrated enrichment of these genes in endothelial cells, macrophages, spleen, lung, and blood. Drug repurposing analysis based on gene-drug matching scores (>0.5) identified promising therapeutic candidates, including immunosuppressants (prednisolone, cyclosporine, azathioprine), lipid-lowering agents (pitavastatin, fenofibrate), and the antiplatelet drug aspirin. These findings offer novel opportunities for precision medicine and drug repurposing in IgAN patients with cardiometabolic disorders.

Arterial hypertension is a prevalent condition and a major risk factor for cardiovascular and neurological diseases. Notably, medical treatment fails to control blood pressure in a large proportion of diagnosed subjects, highlighting gaps in our understanding of hypertension's pathophysiology. Using a mathematical model of the human cardiovascular system, we quantify the contributions of various cardiovascular compartments to the hypertensive state. The impact of uncertainty in modelling assumptions is assessed through stochastic modelling. Our results show that reduced venous vascular compliance significantly increases arterial pressure, making it the second most influential factor in determining hypertension, after increased peripheral resistance. KEY POINTS: We used a closed-loop mathematical model of the full human circulation to simulate adaptation to hypertension, including stochastic variation in parameters. The model quantifies the relative importance of different cardiovascular parameters in determining arterial pressure. Venous compliance emerged as the second most influential determinant of arterial pressure, after systemic resistance. Reduced venous compliance alone was sufficient to cause a hypertensive state in the model. These findings highlight the potential of the venous system as a novel therapeutic target for blood pressure regulation.

Cardiovascular diseases (CVDs) are closely associated with mitochondrial dysfunction, including impaired mitochondrial biogenesis, abnormal mitochondrial dynamics, excessive oxidative stress, dysregulated mitophagy, and disorders of energy metabolism. Accumulating evidence indicates that natural products exert significant cardioprotective effects by coordinately regulating multiple mitochondrial pathways, thereby alleviating myocardial injury and slowing disease progression. This review systematically summarises recent advances in natural metabolites and their rational combination strategies for cardiovascular diseases, with a particular focus on mitochondrial regulation. Representative metabolites, including flavonoids, alkaloids, saponins, and polyphenols, regulate key signalling pathways such as SIRT1/PGC-1α, AMPK, Nrf2, PINK1/Parkin, and Drp1/MFN2 to restore mitochondrial homeostasis. Importantly, natural metabolite combinations further demonstrate synergistic and complementary effects through coordinated regulation of distinct mitochondrial pathways. For example, EGCG and Rhein cooperatively alleviate myocardial ischemia/reperfusion injury by simultaneously suppressing oxidative stress and TLR4-mediated inflammatory signalling. Collectively, this review highlights the considerable potential of natural products and their rational combinations as therapeutic strategies for cardiovascular diseases through the modulation of mitochondrial function.