bims-evecad 2026-07-26 papers

bims-evecad

Biomed News

on Extracellular vesicles and cardiovascular disease

Issue of 2026–07–26
eight papers selected by
Cliff Dominy

Brown Adipose Tissue Activation Alleviates Cerebral Ischemia-Reperfusion Injury by Increasing 14-3-3ζ Secretion from Circulating Extracellular Vesicles to Suppress P53 Activity.
Platelet membrane-fusing MSC-derived apoptotic extracellular vesicles enhanced cardiac repair after ischemia/reperfusion injury.
Extracellular vesicles with unique proteomic signatures from self-organized cardiac spheroids under hydrodynamic stimulation.
The Role of Exosomes in Atherosclerosis.
Small Extracellular Vesicles From Cardiomyocytes Activate Microglia Aggravating HFpEF.
A Unified Model of Cardiovascular Injury: How PANoptosis Connects Atherosclerotic Inflammation to Myocardial Death.
Pericardial Extracellular Vesicles As Drug Carriers: Beyond Native Vesicle Therapy in Heart Failure.
Long non-coding RNAs as molecular hubs integrating inflammatory and osteogenic pathways in calcific aortic valve disease.

Mol Neurobiol. 2026 Jul 22. pii: 782. [Epub ahead of print]63(1):

Brown Adipose Tissue Activation Alleviates Cerebral Ischemia-Reperfusion Injury by Increasing 14-3-3ζ Secretion from Circulating Extracellular Vesicles to Suppress P53 Activity.

Hui Yue, Xiaohua Wang, Yue Liu, Yinglian Zhou, Yifei Wang, Xuemei Zhang, Shan Huang, Changsi Ai, Jin Fu, Rui Wang.

  Brown adipose tissue (BAT) possesses thermogenic and endocrine functions, leading to it being considered a therapeutic target, but its role in cerebrovascular pathologies is largely unknown. Here, we elucidated BAT activation effects on cerebral ischemic stroke, using in vivo, in vitro, and acute ischemic stroke (AIS) patient analyses. In vivo, recipient mice received BAT transplants, then subjected to ischemic stroke by middle cerebral artery occlusion (MCAO) for 90 min, followed by 24 h reperfusion. Another MCAO mouse group was injected with extracellular vesicles (EVs) from non- and BAT-transplanted mouse plasma. In vitro, HT-22 cells were subjected to oxygen-glucose deprivation, 24 h re-oxygenation (OGD/R), and incubation with PKH67-labelled EVs (BAT-EVs + OGD/R). Genomic, proteomic, and apoptotic analyses were conducted, particularly in relation to 14-3-3ζ expression and the p53 apoptotic pathway. BAT transplantation and activation in MCAO mice significantly alleviated cerebral ischemic injury, manifesting as reduced infarct sizes and neurological severity scores. This was likely via BAT producing 14-3-3ζ protein-enriched EVs, which were taken up by ischemic penumbra neuronal cells, where they exerted anti-apoptotic and neuroprotective effects. Similar findings were observed in BAT-EVs + OGD/R cells, along with discovering that 14-3-3ζ knock-down increased, while 14-3-3ζ overexpression reduced p53 phosphorylation and cell apoptosis. Moreover, AIS patients with higher peripheral blood 14-3-3ζ had greater percentages of NIH Stroke Scale/Score decreases ≥ 2, indicating greater short-term neurological recovery. Therefore, increased 14-3-3ζ from circulating EVs, obtained from BAT-transplanted donors, resulted in lowered apoptosis and increased neuroprotection in ischemic penumbra cells taking up those EVs, likely via 14-3-3ζ suppressing the pro-apoptotic p53 pathway.

Keywords:  14–3-3ζ; Apoptosis; Brown adipose tissue; Cerebral ischemic injury; Extracellular vesicles; P53

DOI:  https://doi.org/10.1007/s12035-026-06079-1
Drug Deliv Transl Res. 2026 Jul 21.

Platelet membrane-fusing MSC-derived apoptotic extracellular vesicles enhanced cardiac repair after ischemia/reperfusion injury.

Zhifeng Song, Fangshun Tan, Yu Jiang, Shuo Wang, ZhiYao Wei, Miao Yu, Hongrui Yu, YanXia Tu, Liaoming He, Weixian Yang, Haiyan Qian.

  Myocardial ischemia/reperfusion injury (I/RI) is a common complication following percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI). Mesenchymal stem cell-derived apoptotic vesicles (MSC-apoVs) seem to be a promising cell-free therapy for alleviating cardiac I/RI, but their therapeutic efficiency is hindered by insufficient targeting capability in vivo. The present study aims to explore the platelet membrane-modified apoVs (P-apoVs), utilizing the nature affinity of platelets for apoV delivery to the injured vascular and myocardial sites. P-apoVs exhibited excellent physicochemical properties, and microRNA (miRNA)-sequencing showed that the extrusion process had no detrimental effects on the content and distribution of miRNAs. Compared to non-modified apoVs, the cellular uptake of P-apoVs was greatly enhanced in bone marrow-derived macrophages (BMDMs), human umbilical vein endothelial cells (HUVECs) stressed by oxygen glucose deprivation/reperfusion (OGD/R) and neonatal rat cardiomyocytes (NRCMs) stressed by OGD/R. Functionally, P-apoVs inhibited the apoptosis of OGD/R NRCMs, promoted BMDM polarization toward M2 phenotype, as well as enhanced HUVEC migration and tube formation in vitro. In the myocardial I/RI model, P-apoVs preferentially accumulated in the injured myocardial sites and attenuate cardiac modeling after I/RI without systemic toxicity. In conclusion, this engineering platelet-modified apoVs shows potential as a therapeutic strategy for myocardial I/RI.

Keywords:  Apoptotic vesicles; Myocardial ischemia/reperfusion injury; Platelet-mimetic; Targeted delivery

DOI:  https://doi.org/10.1007/s13346-026-02178-7
Biomaterials. 2026 Jul 16. pii: S0142-9612(26)00487-4. [Epub ahead of print]336 124463

Extracellular vesicles with unique proteomic signatures from self-organized cardiac spheroids under hydrodynamic stimulation.

J E Perez, P Joanne, L Dec, D Loew, O Agbulut, C Wilhelm.

  Cardiac extracellular vesicles (EVs) hold promise as cell-free therapeutics for heart repair. However, robust methods to produce scalable, functional and cardiac-specific EVs at high yield remain a limiting factor in their exploitation. Here, we report an engineered platform that combines 3D cardiac microtissues with hydrodynamic stimulation to address these hurdles. We exploited differential cell mechanics, quantified via surface tension measurements, to establish a unique 3D spheroid architecture showing cardiomyocytes preferentially localizing at the spheroid periphery. A controlled-flow bioreactor then enabled high-yield EV production, at a 10-fold increase compared to non-stimulated spheroids, all while maintaining cell viability comparable to standard 2D production conditions while preserving vesicle structural integrity. Proteomic profiling revealed that EVs generated under these conditions carry a cardiac-specific signature, enriched in sarcomeric, mitochondrial, ribosomal and heat shock proteins, all while retaining core EV markers. Functionally, these EVs enhanced wound closure and reduced fibroblast activation more effectively than EVs derived from standard 2D fibroblast cultures, at 1.3 and 1.5-fold, respectively. Our findings establish a scalable, physiologically relevant strategy for generating cardiac EVs and demonstrate that combining 3D microenvironment engineering with hydrodynamic cues can yield therapeutically potent vesicles suitable for regenerative medicine.

Keywords:  Cardiac spheroids; Extracellular vesicles; Hydrodynamic stress; Proteomics; Scalable bioproduction; iPSC-derived cardiomyocytes

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124463
Angiology. 2026 Jul 20. 33197261469919

The Role of Exosomes in Atherosclerosis.

Wenhui Sun, Shaoying An, Guangrong Meng, Fan Jiang, Zhongcheng Mo.

  Atherosclerosis (AS) is a chronic inflammatory vascular disease in which exosomes play important roles in intercellular communication. Exosomes derived from macrophages, endothelial cells, vascular smooth muscle cells, immune cells, and mesenchymal stem cells participate in several stages of AS progression by transferring bioactive molecules, including microRNAs (miRNAs) and proteins. Macrophage-derived exosomes promote endothelial dysfunction and inflammation, whereas endothelial cell-derived exosomes regulate vascular smooth muscle cell phenotypic switching. Vascular smooth muscle cell-derived exosomes contribute to plaque calcification, while mesenchymal stem cell-derived exosomes appear to exert anti-atherosclerotic effects by suppressing inflammation and promoting M2 macrophage polarization. Exosomal cargos also exhibit potential diagnostic value, with specific expression patterns correlating with disease severity. Furthermore, engineered exosomes have emerged as promising targeted drug delivery systems for AS therapy. This review summarizes the roles of exosomes derived from various cellular sources in the pathogenesis, diagnosis, and treatment of AS, and highlights their potential as biomarkers and therapeutic targets.

Keywords:  atherosclerosis; disease biomarkers; drug delivery vehicles; exosomes; intercellular communication

DOI:  https://doi.org/10.1177/00033197261469919
Circ Res. 2026 Jul 20.

Small Extracellular Vesicles From Cardiomyocytes Activate Microglia Aggravating HFpEF.

Lintong Men, Qian Wang, Bowen Ren, Yu Cao, Min Du, Shengqi Huo, Moran Wang, Bingyu Huang, Dewei Peng, Xiaoli He, Lujin Wu, Sheng Li, Cuntai Zhang, Jiaogao Lv, Li Lin, Junyi Guo.

   BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is increasingly acknowledged as a major public health concern due to its complex pathophysiology, which involves neuroinflammation and sympathetic activation. The crosstalk between the heart and hypothalamic microglia in HFpEF, particularly the role of small extracellular vesicles (sEVs), remains insufficiently explored.
METHODS AND RESULTS: We constructed an HFpEF model in mice by combining a long-term high-fat diet with the nitric oxide synthase inhibitor l-NAME (N[ω]-nitro-l-arginine methyl ester). These mice exhibited microglial activation and hypothalamic inflammation. Microglial depletion with PLX3397 suppressed sympathetic activity and improved cardiac dysfunction in HFpEF. sEVs derived from the myocardium of HFpEF mice induced a proinflammatory M1 phenotype in microglia, leading to hypothalamic inflammation and sympathetic activation. Intraperitoneal injection of the sEV biogenesis inhibitor GW4869 reversed these changes in HFpEF mice. Similar pathological changes were observed in BV2 microglia treated with sEVs isolated from palmitic acid-treated HL-1 cardiomyocytes. Bioinformatic and RT-qPCR analyses revealed a notable upregulation of miR-200c-3p in sEVs derived from both HFpEF myocardial tissue and palmitic acid-treated HL-1 cardiomyocytes, as well as in microglia. A cardiomyocyte-specific miR-200c-3p sponge inhibited microglial activation, hypothalamic inflammation, and sympathetic activation in HFpEF mice. Conversely, a miR-200c-3p mimic exacerbated proinflammatory responses in BV2 cells, while a miR-200c-3p inhibitor prevented the transition to a proinflammatory phenotype. The antiinflammatory protein DUSP1 (dual-specificity phosphatase 1) was validated as a potential downstream target of miR-200c-3p in microglia.
CONCLUSIONS: Our study reveals that HFpEF prompts cardiomyocytes to release sEVs enriched with miR-200c-3p, leading to hypothalamic inflammation and evoking sympathetic outflow, which in turn exacerbates cardiac dysfunction. Focusing on sEV-mediated communication between cardiomyocytes and microglia may offer a new therapeutic approach for HFpEF.

Keywords:  animals; communication; heart failure; phenotype; stroke volume

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327765
Antioxid Redox Signal. 2026 Jul 23. 15230864261455539

A Unified Model of Cardiovascular Injury: How PANoptosis Connects Atherosclerotic Inflammation to Myocardial Death.

Xin Zhang, Mengdan Liu, Yunyun Yang, Gongliang Guo.

   SIGNIFICANCE: Cardiovascular disease is traditionally viewed through fragmented lenses-atherosclerosis, ischemia-reperfusion injury, and heart failure as distinct entities. Emerging evidence positions PANoptosis, an integrated cell-death program combining pyroptosis, apoptosis, and necroptosis, as a unifying driver of inflammation and tissue destruction along the athero-myocardial axis. This synthesis reframes cardiovascular pathology as a continuum governed by shared immunometabolic triggers and coordinated cell-death machinery.
RECENT ADVANCES: We outline how upstream nucleic acid sensors, notably Z-DNA binding protein 1 (ZBP1) and absent in melanoma 2, orchestrate PANoptosome assembly, engaging receptor-interacting protein kinase (RIPK)1, RIPK3, Caspase-8, gasdermin D (GSDMD), mixed lineage kinase domain-like, and executioner caspases to produce multimodal lytic death. In the vasculature, disturbed flow activates Piezo1-Calpain signaling. This mechanotransduction is proposed to lower the threshold for endothelial PANoptosis, partly through mitochondrial Ca2+ overload, reactive oxygen species (ROS) generation, and mitochondrial DNA (mtDNA) release. Concurrently, macrophage uptake of oxidized lipids triggers a mitochondria-stimulator of interferon genes-GSDMD feed-forward loop. This process expands necrotic cores and destabilizes plaques. In ischemic myocardium, succinate-driven reverse electron transport generates a ROS burst during reperfusion, causing mtDNA release and ZBP1-dependent PANoptosis in cardiomyocytes. This cascade propagates systemic inflammation through defective efferocytosis, bone-marrow trained immunity, and extracellular vesicle (EV) cargo transfer, ultimately driving fibrosis and heart failure.
CRITICAL ISSUES: Several conceptual and translational issues remain critical. Vascular and myocardial injuries may share core PANoptotic machinery, but they are linked systemically through inflammatory, metabolic, and immune feedback loops rather than by a simple linear cascade. Co-activation of pyroptosis, apoptosis, and necroptosis should be distinguished from true molecular shunting within PANoptosomes. Emerging EV-based propagation mechanisms require careful interpretation, and therapeutic windows differ across endothelial injury, plaque progression, reperfusion injury, and remodeling.
FUTURE DIRECTIONS: Future strategies should prioritize nanomedicine-enabled precision delivery, metabolic reprogramming, and time-sensitive intervention across the athero-myocardial axis.
INNOVATION: This review proposes an athero-myocardial axis in which vascular and myocardial injuries share core PANoptotic machinery while being linked systemically through inflammatory, metabolic, and immune feedback loops. It differentiates co-activation from true molecular shunting within PANoptosomes, clarifies emerging EV-based propagation mechanisms, and maps time-sensitive therapeutic windows across endothelial injury, plaque progression, reperfusion injury, and remodeling. Antioxid. Redox Signal. 00, 000-000.

Keywords:  PANoptosis; atherosclerosis; ischemia–reperfusion injury; trained immunity

DOI:  https://doi.org/10.1177/15230864261455539
Cardiovasc Drugs Ther. 2026 Jul 23.

Pericardial Extracellular Vesicles As Drug Carriers: Beyond Native Vesicle Therapy in Heart Failure.

Le Wen, YuXin Sheng.

DOI: https://doi.org/10.1007/s10557-026-07915-1
Front Cardiovasc Med. 2026 ;13 1843916

Long non-coding RNAs as molecular hubs integrating inflammatory and osteogenic pathways in calcific aortic valve disease.

Juan Ignacio Muñoz-Manco, Annisa Mardianing Utami, Zhexi Li, Georg Nickenig, Mohammed Rabiul Hosen.

   Significance: Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Among valvular pathologies, CAVD is the most prevalent and poses a growing burden on the aging population. Once considered a passive degenerative process, aortic stenosis (AS) is now understood to be an actively regulated disease characterized by progressive leaflet fibrosis, calcification, and inflammation, ultimately leading to left ventricular outflow obstruction and heart failure. Current treatment options are limited to surgical or transcatheter valve replacement, as no pharmacological therapies exist to halt or reverse disease progression. This review frames the discussion around the potential of long non-coding RNAs (lncRNAs) as therapeutic targets, rather than implying established therapies.
Recent advances: Through the advancement of genetic manipulation techniques and their application in cardiovascular biology, non-coding RNAs have emerged as dynamic regulators of disease pathogenesis. While initial focus centered on microRNAs, recent evidence highlights lncRNAs as critical modulators of gene expression governing valvular interstitial cell (VIC) biology. LncRNAs influence key pathological processes in AS, including osteogenic differentiation, extracellular matrix remodeling, and inflammatory signaling. Furthermore, circulating lncRNAs, either freely circulating or encapsulated within extracellular vesicles, are emerging as novel mediators of intercellular communication within the valve microenvironment and represent promising candidates for diagnostic and prognostic applications, offering the potential for a liquid biopsy approach in AS management. Despite significant advancements in our understanding of non-coding RNA biology, the functional roles of specific lncRNAs in the pathogenesis of aortic stenosis remain largely unexplored. However, emerging evidence from related inflammatory pathways (e.g., NF-κB, MAPK, and JAK/STAT) and other cardiovascular diseases provides a rational basis for investigating the therapeutic potential of lncRNAs in AS, without overstating current knowledge. Elucidating the precise mechanisms by which lncRNAs regulate VIC fate and valvular calcification is crucial for the development of effective targeted interventions aimed at slowing or preventing disease progression and reducing the clinical burden of AS.
Future directions: Key unanswered questions remain: What is the specific lncRNA signature of CAVD? How do individual lncRNAs functionally contribute to disease progression? And how can the delivery and targeting challenges associated with lncRNA-based therapeutics be overcome? This review provides a comprehensive landscape of the current developmental progression of RNA therapeutics, with a specific focus on lncRNA-based strategies as a holistic approach for treating CAVD in preclinical models. Addressing these research priorities will be essential for translating lncRNA-based strategies into clinical applications for this increasingly prevalent disease.

Keywords:  RNA therapeutics; aortic stenosis (AS); biomarker; calcific aortic valve disease (CAVD); long non-coding RNAs (lncRNAs)

DOI:  https://doi.org/10.3389/fcvm.2026.1843916