Damage to myocardial tissues, leading to myocardial fibrosis, is a significant pathological hallmark across various heart diseases. SMAD3, a central transcriptional regulator within the transforming growth factor-beta (TGF-β) signaling pathway, plays a pivotal role in the pathological progression of myocardial fibrosis and cardiac remodeling. It intricately regulates physiological and pathological processes encompassing cell proliferation, differentiation, tissue repair, and fibrosis. Notably, SMAD3 exerts crucial influences in myocardial fibrosis subsequent to myocardial infarction, pressure overload-induced myocardial fibrosis, diabetic cardiomyopathy (DCM), aging-associated cardiac fibrosis and myocarditis-related myocardial fibrosis. The targeted modulation of genes or the utilization of compounds, including traditional Chinese medicine (paeoniflorin, baicalin, and genistein et al.) and other pharmaceutical agents that modulate SMAD3, may offer avenues for restraining the pathological cascade of myocardial fibrosis. Consequently, targeted regulation of SMAD3 associated with myocardial fibrosis may herald novel therapeutic paradigms for ameliorating myocardial diseases.

With rising incidence, mortality and limited therapeutic options, heart failure with preserved ejection fraction (HFpEF) remains one of the most important topics in cardiovascular medicine today. Characterised by left ventricular diastolic dysfunction partially due to impaired Ca2+ homeostasis, one ion channel in particular, SarcoEndoplasmic Reticulum Ca2+-ATPase (SERCA2a), may play a significant role in its pathophysiology. A better understanding of the complex mechanisms interplaying to contribute to SERCA2a dysfunction will help develop treatments targeting it and thus address the growing clinical challenge HFpEF poses. This review examines the conflicting evidence present for changes in SERCA2a expression and activity in HFpEF, explores potential underlying mechanisms, and finally evaluates the drug and gene therapy trials targeting SERCA2a in heart failure. Recent positive results from trials involving widely used anti-diabetic agents such as sodium-glucose co-transporter protein 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) agonists offer advancement in HFpEF management. The potential interplay between these agents and SERCA2a regulation presents a novel angle that could open new avenues for modulating diastolic function; however, the mechanistic research in this emerging field is limited. Overall, the direct role of SERCA2a dysfunction in HFpEF remains undetermined, highlighting the need for well-designed pre-clinical studies and robust clinical trials.

Circular RNAs (circRNAs) are involved in the pathogenesis of several cardiovascular diseases, including heart failure. In this study, we report that circular PVT1 (circPVT1) was upregulated in the left ventricle of 31 ischemic heart failure patients compared to 11 non-ischemic controls. RNA sequencing analysis following circPVT1 knockdown in immortalized human cardiomyocytes identified differentially expressed genes, mainly involved in fibrosis. Notably, in human cardiac fibroblasts, circPVT1 expression significantly increased after TGF-β1 treatment and circPVT1 silencing attenuated the levels of pro-fibrotic markers induced by TGF-β1. RNA pull-down assays validated the interaction between circPVT1 and two fibrosis-related miRNAs, miR-30a-5p and miR-125b-5p. The levels of these miRNAs were not altered upon circPVT1 knockdown. However, the expression of their mRNA targets was deregulated upon circPVT1 silencing, suggesting that circPVT1 modulates miRNA cellular bioavailability. Accordingly, inhibition of either miR-30a-5p or miR-125b-5p restored the expression of TGF-β1-induced pro-fibrotic markers following circPVT1 silencing, indicating that both miR-30a-5p and miR-125b-5p act as downstream effectors of circPVT1 in cardiac fibroblast activation. In conclusion, these findings highlight a pro-fibrotic role for circPVT1, which can regulate cardiac fibroblast activation interacting with the anti-fibrotic miR-30a-5p and miR-125b-5p. The modulation of circPVT1 expression may represent a potential strategy to reduce cardiac fibrosis and remodeling.

The phenomenon of endothelial-mesenchymal transition (EndMT), a distinct subtype of epithelial-mesenchymal transition (EMT), has garnered significant attention from scholars. EndMT refers to the process whereby endothelial cells (ECs) transform into mesenchymal cells in response to various stimuli, resulting in the loss of their original characteristics. This process has diverse implications in both physiological and pathological states. Under physiological conditions, EndMT plays a crucial role in the development of the cardiovascular system. Conversely, under pathological conditions, EndMT has been identified as a pivotal factor in the development of cardiovascular diseases. Nonetheless, a comprehensive overview of EndMT in cerebrovascular disease is currently lacking. Here, we discuss the heterogeneity of EndMT occurrence and the regulatory factors involved in its development and analyze the feasibility of EndMT as a therapeutic target, aiming to provide a solid theoretical foundation and evidence to address diseases caused by pathological EndMT.

Sepsis-associated pulmonary fibrosis (SAPF) is a critical pathological stage in the progression of sepsis-induced acute respiratory distress syndrome. While the aggregation and activation of lung fibroblasts are central to the initiation of pulmonary fibrosis, the macrophage-myofibroblast transition (MMT) has recently been identified as a novel source of fibroblasts in this context. However, the mechanisms driving MMT remain inadequately understood. Given the emerging role of migrasomes (novel extracellular vesicles mediating intercellular communication), we investigated their involvement in pulmonary fibrosis. Here we utilized a lipopolysaccharide-induced SAPF mouse model and an in vitro co-culture system of fibroblasts and macrophages to observe the MMT process during SAPF. We found that lipopolysaccharide exposure suppresses PGC-1α expression in lung fibroblasts, resulting in mitochondrial dysfunction and the accumulation of cytosolic mitochondrial DNA (mtDNA). This dysfunction promotes the secretion of mtDNA-containing migrasomes, which, in turn, initiate the MMT process and contribute to fibrosis progression. Notably, the activation of PGC-1α mitigates mitochondrial dysfunction, reduces mtDNA-migrasome release, inhibits MMT and alleviates SAPF. In conclusion, our study identifies the suppression of PGC-1α in lung fibroblasts and the subsequent release of mtDNA migrasomes as a novel mechanism driving MMT in SAPF. These findings suggest that targeting the crosstalk between fibroblasts and immune cells mediated by migrasomes could represent a promising therapeutic strategy for SAPF.

Diabetic retinopathy (DR) is a common and specific microvascular complication of diabetes and the leading cause of blindness in working-age adults. Endothelial-mesenchymal transition (EndoMT) underlies various chronic vascular diseases, while histone deacetylase 9 (HDAC9) is involved in the pathological process of cardiovascular diseases, cerebrovascular diseases, autoimmune diseases, and breast cancer. Recent evidence has shown that HDAC9 promotes EndoMT, thereby affecting the progression of atherosclerotic disease. In this study, we investigated the critical role of HDAC9 in DR and the underlying mechanism. DR model was established in mice by injecting streptozotocin (STZ, 50 mg/kg) for 5 consecutive days. Blood glucose was monitored regularly and DR experiments were performed 12 weeks after modeling. We showed that the expression levels of HDAC9 were significantly elevated in the vitreous fluid of diabetic patients and the retinal endothelial cells of DR model mice. Knockdown of endothelial HDAC9 reduced EndoMT and alleviated DR pathology in vivo, whereas overexpression of HDAC9 exacerbated EndoMT in DR model mice. To elucidate the downstream target genes of HDAC9 implicated in DR, we conducted integrated ChIP-seq and RNA-seq analysis of the retina in STZ-induced retinopathy and established that HDAC9 was involved in the transcriptional regulation of annexin A2 (ANXA2). We demonstrated that HDAC9 was bound to the promoter region of ANXA2, leading to the downregulation of ANXA2 expression in high glucose-treated human retinal microvascular endothelial cells and STZ-induced DR model mice. Overexpression of ANXA2 significantly reduced the EndoMT process in STZ-induced DR model mice. Collectively, our results demonstrate that HDAC9 promotes EndoMT by regulating ANXA2 transcription, thereby disrupting vascular homeostasis during DR. This study sheds light on the roles of HDAC9 and ANXA2 in DR pathology and provides a theoretical foundation for the potential therapeutic strategies to target DR.

Aging is a very complex process, and it has been linked with Sirtuins. Sirtuin enzymes are a family of deacetylases that are related to caloric restriction and aging by modulating energy metabolism, genomic stability, and stress resistance. Up to now, seven sirtuins have been recognized. This narrative review aimed to analyze the literature produced between January 2005 and March 2025 to evaluate the role of sirtuins in chronic kidney disease and, as heart and kidney diseases are strictly interrelated, to explore their role in heart diseases and cardio-renal cross-talk. A reciprocal relationship between CKD and aging seems to exist since CKD may contribute to premature biological aging of different organ systems. SIRTs are involved in the pathophysiology of renal diseases; their activation can delay the progression of several renal diseases. Notably, an increasing number of studies linked SIRTs with different CVDs. SIRTs affect the production of mitochondrial reactive oxygen species (ROS) by modulating mitochondrial function. The imbalance of SIRT levels may increase the vulnerability to CVDs. SIRTs are involved in the pathophysiological mechanisms of HFpEF (heart failure with preserved ejection fraction) through different signaling pathways. Fibrosis is the linkage mechanism between the heart and kidney in the development of cardio-renal diseases. Current studies on sirtuins, resveratrol, and cardiorenal disease highlight their potential therapeutic benefits in regulating blood pressure, kidney function, lipid profiles, and inflammation, making them a promising area of investigation for improving cardiovascular and renal health outcomes. However, significant gaps remain. The limited availability of highly selective and potent sirtuin modulators hampers their clinical translation, as most existing compounds exhibit poor bioavailability and suboptimal pharmacokinetic properties.

The extracellular matrix (ECM) plays a crucial role in providing structural integrity and regulating cell communication essential for organ development, homeostasis, and regeneration, including hearts. Evidence indicates that disruptions in the spatiotemporal expression or alterations in ECM components lead to cardiac malformations, including a wide range of congenital heart diseases (CHDs). Furthermore, research on injured hearts across various vertebrate species, some of which show effective regeneration while others experience irreversible fibrosis, underscores the significance of ECM molecules in cardiac regeneration. This review presents an overview of heart development and the dynamics of ECM during cardiac morphogenesis, beginning with the formation of the contractile heart tube and advancing to the development of distinct chambers separated by valves to facilitate unidirectional blood flow. Furthermore, we discuss research emphasizing the multifaceted roles of secreted molecules in mediating fibrosis and regeneration following myocardial injury.

As heart transplantation continues to be the gold standard therapy for end-stage heart failure, the imbalance between the supply of hearts, and the demand for them, continues to get worse. In the US alone, with less than 4,000 hearts suitable for transplant and over 100,000 potential recipients, this therapy is only available to a very few. The use of hearts Donated after Circulatory Death (DCD) and Donation after Brain Death (DBD) using ex vivo machine perfusion (EVMP) is a promising approach that has already increased the availability of suitable organs for heart transplantation. EVMP offers the promise of enabling the expansion of the overall number of heart transplants and lower rates of early graft dysfunction. These are realized through (1) safe extension of the time between procurement and transplantation and (2) ex vivo assessment of preserved hearts. Notably, ex vivo perfusion has facilitated the donation of DCD hearts and improved the success of transplantation. Nevertheless, DCD hearts suffer from serious preharvest ischemia/reperfusion injury (IRI). Despite these developments, only 40% of hearts offered for transplantation can be utilized. These devices do offer an opportunity to evaluate donor hearts for transplantation, resuscitate organs previously deemed unsuitable for transplantation, and provide a platform for the development of novel therapeutics to limit cardiac injury. Bone Morphogenetic Protein (BMP) signaling is a new target which holds the potential for ameliorating myocardial IRI. Recent studies have demonstrated that BMP signaling has a significant role in blocking the deleterious effects of injury to the heart. We have designed novel small peptide BMP mimetics that act via activin receptor-like kinase (ALK3), a type I BMP receptor. They are capable of (1) inhibiting inflammation and apoptosis, (2) blocking/reversing the epithelial-mesenchymal transition (EMT) and fibrosis, and (3) promoting tissue regeneration. In this review, we explore the promise that novel therapeutics, including these BMP mimetics, offer for the protection of hearts against myocardial injury during ex vivo transportation for cardiac transplantation. This protection represents a significant advance and a promising ex vivo therapeutic approach to expanding the donor pool by increasing the number of transplantable hearts.

Cardiac immune-related adverse events (irAEs) from PD-1-targeting immune check-point inhibitors (ICIs) are an increasing concern due to their high mortality rate. Collagen plays a crucial role in maintaining cardiac structure, elasticity, and signal transduction; however, the effects and mechanisms of PD-1 inhibitor on cardiac collagen remodeling remain poorly understood.

C57BL/6 mice were injected with anti-mouse PD-1 antibody to create a PD-1 inhibitor-treated model. Cardiac function was measured by echocardiography, and collagen distribution was analyzed with Masson's trichrome staining and Sirius Red staining. Single-nucleus RNA sequencing was performed to examine the effects of PD-1 inhibition on gene expression in cardiac fibroblasts (CFs) and endothelial cells (ECs). EC-CF crosstalk was assessed using co-culture experiments and ELISA. ChIP assay was performed to analyze the regulation of TCF12 on TGF-β1 promoter. Western blot, qRT-PCR, and immunofluorescence staining were used to detect the expression of TCF12, TGF-β1, and endothelial-to-mesenchymal transition (EndMT) markers. Reactive oxygen species (ROS) levels were evaluated by DHE staining, MDA content, and SOD activity assays.

We report a newly discovered cardiotoxic effect of PD-1 inhibitor, which causes aberrant collagen distribution in the heart, marked by a decrease in interstitial collagen and an increase in perivascular collagen deposition. Mechanistically, PD-1 inhibitor does not directly affect CFs but instead impact them through EC-CF crosstalk. PD-1 inhibitor reduces TGF-β1 secretion in ECs by downregulating TCF12, which we identify as a transcriptional promoter of TGF-β1. This subsequently decreases CF activity, leading to reduced interstitial collagen deposition. Additionally, PD-1 inhibitor induces EndMT, increasing perivascular collagen deposition. The endothelial dysfunction induced by PD-1 inhibitor results from ROS accumulation in ECs. Inhibiting ROS with N-acetylcysteine (NAC) preserves normal collagen distribution and cardiac function in PD-1 inhibitor-treated mice by reversing TCF12 downregulation and EndMT in ECs.

Our results suggest that PD-1 inhibitor causes ROS accumulation in cardiac ECs, leading to imbalanced collagen distribution (decrease in interstitial collagen and increase in perivascular collagen) in the heart by modulating TCF12/TGF-β1-mediated EC-CF crosstalk and EndMT. NAC supplementation could be an effective clinical strategy to mitigate PD-1 inhibitor-induced imbalanced collagen distribution and cardiac dysfunction.

Aims: Myocardial fibrosis is an important medium for atrial fibrillation (AF). Exosomes have been demonstrated to affect the development of AF. This study explored the molecular mechanism of exosomes from patients with AF (AF-exo) mediating myocardial fibrosis and thus affecting the development of AF. Results: Prolactin-induced protein (PIP) is highly expressed in AF-exo. AF-exo promoted the proliferation and activation of cardiac fibroblasts (CFs) as well as the migration and endothelial-to-mesenchymal transition (EndMT) of human umbilical vein endothelial cells (HUVECs). However, the effect of AF-exo on CFs and HUVECs was mitigated by PIP-specific short hairpin RNA (shPIP). Adeno-associated virus (AAV)-shPIP reduced the incidence and duration of AF in rats, and improved myocardial fibrosis and collagen deposition. ATPase plasma membrane Ca2+ transporting 2 (ATP2B2) overexpression or inhibition reverses the role of PIP or shPIP in CFs, HUVECs, and AF rats. Activation of the cyclic guanosine monophosphate/protein kinase G (cGMP/PKG) pathway is beneficial to alleviate myocardial fibrosis, but this effect is mitigated by shATP2B2. Innovation: Our investigation substantiates the pivotal role of the PIP/ATP2B2 axis in both HUVEC myocardial fibrosis and EndMT progression. Our findings suggest that AF-exo can suppress the activation of the cGMP/PKG pathway mediated by ATP2B2 through exosomal PIP, thus promoting myocardial fibrosis, indicating potential targets for novel antifibrotic drug development targeting either PIP or ATP2B2. Conclusion: Exosomal PIP can inhibit the activation of cGMP/PKG pathway mediated by ATP2B2, thus promoting the development of AF. Antioxid. Redox Signal. 00, 000-000.

Acute myocardial infarction (AMI) is a leading cause of heart failure, often accompanied by myocardial fibrosis (MF), characterized by excessive extracellular matrix accumulation. Endothelial-to-mesenchymal transition (EndMT) plays a key role in MF progression post-AMI. Neuregulin-1 (NRG-1), a growth factor with cardioprotective properties, has emerged as a potential therapeutic target. Tongxinluo (TXL), a traditional Chinese medicine, mitigates MF by upregulating NRG-1. This study elucidates the mechanisms underlying the protective effects of NRG-1 and TXL against MF following AMI. Left anterior descending artery ligation established a model for mice with AMI. Adeno-associated virus was used to modulate NRG-1 expression in the myocardium. Echocardiography assessed cardiac function, and histological staining was used to evaluate MF. Expression levels of markers for myofibroblasts (α-SMA, FSP-1) and endothelial cells (CD31, VE-cadherin) were analysed to investigate EndMT. The involvement of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway in NRG-1's protective mechanism was validated using biochemical methods. Tongxinluo was administered to mice with AMI via gavage for 4 weeks, and its effects on cardiac function, MF and EndMT were assessed. Overexpression of NRG-1 in mice with AMI ameliorated cardiac dysfunction and reduced interstitial and perivascular fibrosis, whereas NRG-1 deficiency exacerbated these effects. NRG-1 protected against EndMT, as evidenced by changes in myofibroblast and endothelial cell markers. The PI3K/AKT signalling pathway was involved in NRG-1's protective mechanism against MF. The administration of TXL to mice with AMI improved cardiac function and reduced MF by activating NRG-1. Furthermore, TXL inhibited EndMT post-AMI through the NRG-1/PI3K/AKT pathway. NRG-1 and TXL protect against MF post-AMI by mitigating EndMT through the PI3K/AKT pathway. These findings suggest that targeting NRG-1 or using TXL may be promising therapeutic strategies for MF following AMI.

Glaucomatous trabecular meshwork (GTM) tissue is characterized by excess fibrotic-like extracellular matrices, which negatively impacts aqueous humor outflow. Endothelial-to-mesenchymal transition (EndMT) is the process by which tissues develop fibrosis. In this study, we investigated fibrotic-related gene and protein profiles of non-glaucomatous trabecular meshwork (NTM) and GTM cells.

Primary cells were cultured from NTM (n = 6) and GTM (n = 5) age-matched cadaver eyes. RNA was harvested and mRNA profiling of 750 genes was performed using the human fibrosis panel (NanoString). Quantitative PCR (qPCR), Western blotting, and immunofluorescence microscopy were performed. A matrix metalloproteinase (MMP) fluorogenic assay was used to quantitate enzyme activity.

Classic EndMT biomarkers, α-SMA, SNAI2, TWIST1, TWIST2, and VIM, were upregulated in GTM cells, whereas increased phosphorylated SMAD2-3 indicated increased TGFβ signaling. GTM cells had increased deposition of FN-EDA fibronectin fibrils, but reduced amounts of FN-EDB fibrils, and altered immunostaining of active α5β1 and αvβ3 integrins. NanoString analysis showed that 2 genes were upregulated and 28 genes were downregulated in GTM cells compared with NTM cells. Western immunoblotting confirmed increased protein levels of N-cadherin and decreased MMP2, CHI3L1, COL6A3, and SERPINF1 proteins in GTM cells. Whereas MMP2 gene and protein levels were reduced, there was increased MMP activity.

Increased expression of α-SMA, FN-EDA, N-cadherin, SNAI2, TWISTs, VIM, TGFβ signaling, and MMP activity are consistent with GTM cells acquiring an EndMT phenotype. In combination with tissue studies, cultured GTM cells are a useful in vitro model for studying the fibrotic process in glaucoma.

Sustained β-adrenergic activation induces cardiac fibrosis characterized by excessive deposition of extracellular matrix (ECM). Prostaglandin E2 (PGE2) receptor EP4 is essential for cardiovascular homeostasis. This study aims to investigate the roles of cardiomyocyte (CM) and cardiac fibroblast (CF) EP4 in isoproterenol (ISO)-induced cardiac fibrosis. By crossing the EP4f/f mice with α-MyHC-Cre or S100A4-Cre mice, this work obtains the CM-EP4 knockout (EP4f/f-α-MyHCCre+) or CF-EP4 knockout (EP4f/f-S100A4Cre+) mice. The mice of both genders are subcutaneously injected with ISO (5 mg kg-1 day-1) for 7 days. Compared to the control mice, both EP4f/f-α-MyHCCre+ and EP4f/f-S100A4Cre+ mice show a significant improvement in cardiac diastolic function and fibrosis as assessed by echocardiography and histological staining, respectively. In the CMs, inhibition of EP4 suppresses ISO-induced TGF-β1 expression via blocking the cAMP/PKA pathway. In the CFs, inhibition of EP4 reversed TGF-β1-triggers production of ECM via preventing the formation of the TGF-β1/TGF-β receptor complex and blocks CF proliferation via suppressing the ERK1/2 pathway. Furthermore, double knockout of the CM- and CF-EP4 or administration of EP4 antagonist, grapiprant, markedly improves ISO-induced cardiac diastolic dysfunction and fibrosis. Collectively, this study demonstrates that both CM-EP4 and CF-EP4 contribute to β-adrenergic activation-induced cardiac fibrosis. Targeting EP4 may offer a novel therapeutic approach for cardiac fibrosis.

The first sodium-glucose cotransporter-2 inhibitor (SGLT2I), canagliflozin, was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in 2013. Since then, other members of this drug class (such as dapagliflozin, empagliflozin, and ertugliflozin) have become widely used. Unlike classical antidiabetic agents, these drugs do not interfere with insulin secretion or action, but instead promote renal glucose excretion. Since their approval, many preclinical and clinical studies have been conducted to investigate the diverse effects of SGLT2Is. While originally introduced as antidiabetic agents, the SGLT2Is are now recognized as pillars in the treatment of heart failure and chronic kidney disease, in patients with or without diabetes. The beneficial cardiac effects of this class have been attributed to several mechanisms. Among these, SGLT2Is inhibit fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress. They regulate mitochondrial function and ion transport, and stimulate autophagy through several underlying mechanisms. This review details the potential effects of SGLT2Is on cardiac cells.

In this study, we aimed to uncover genes associated with stressed cardiomyocytes by combining single-cell transcriptomic datasets from failing cardiac tissue from both humans and mice.

Our bioinformatic analysis identified SORBS2 as conserved NPPA correlated gene. Using mouse models and cardiac tissue from human heart failure patients, we demonstrated that SORBS2 expression is consistently increased during pathological remodeling, correlates to disease severity and is regulated by GATA4. By affinity-purification mass-spectrometry, we showed SORBS2 to interact with the integrin-cytoskeleton connections. Cardiomyocyte-specific genetic loss of Sorbs2 in adult mice changed integrin interactions, indicated by the increased expression of several integrins and altered extracellular matrix components connecting to these integrins, leading to an exacerbated fibrotic response during pathological remodeling.

Sorbs2 is a cardiomyocyte-enriched gene that is increased during progression to heart failure in a GATA4-dependent manner and correlates to phenotypical hallmarks of cardiac failure.Our data indicate SORBS2 to function as a crucial regulator of integrin interactions and cardiac fibrosis.

Coronary microvascular dysfunction serves as one of the etiological factors for ischemic heart disease and represents a novel therapeutic direction for coronary artery diseases; however, the research on its pathogenesis remains inconsistent. This study aims to explore the single-cell gene expression profiles in rats with coronary microvascular dysfunction using single-cell RNA sequencing, with a particular focus on the in-depth analysis of endothelial cell gene expression characteristics. By establishing a rat model of coronary microvascular dysfunction, we collected cardiac apical tissue to prepare single-cell suspensions and further analyzed them using bioinformatics methods. From a total of 55,419 cells, we identified 28 distinct cell clusters, with endothelial cells and fibroblasts being the predominant cell types. Compared to the NC group, the proportion of endothelial cells in the CMD group was significantly reduced, while the number of fibroblasts was significantly increased. Through further analysis of the endothelial cells, we classified them into normal phenotype endothelial cells, mesenchymal phenotype endothelial cells, proliferative phenotype endothelial cells, and lymphatic endothelial cells, with mesenchymal and proliferative endothelial cells originating from normal phenotype endothelial cells. Additionally, the CMD group exhibited an increase in immune cells, enhanced inflammatory response, and increased oxidative stress. These findings may provide novel potential therapeutic targets for the treatment of Coronary microvascular dysfunction.

The SOX9 gene locus is not only extensive but also intricate, and it could promote fibrosis in different organs or tissues, including cardiac fibrosis, liver fibrosis, kidney fibrosis, pulmonary fibrosis, as well as other organ fibrosis. Many disorders are associated with the process of fibrosis; moreover, fibrosis is a common symptom of chronic inflammatory diseases, characterized by the accumulation of excessive components in the extracellular matrix through different signaling pathways. The advanced stage of the fibrotic process leads to organ dysfunction and, ultimately, death. In this review, we first give an overview of the original structure and functions of SOX9. Second, we will discuss the role of SOX9 in fibrosis in various organs or tissues. Third, we describe and reveal the possibility of SOX9 as an antifibrotic treatment target. Finally, we will focus on the application of novel technologies for SOX9 and the subsequent investigation of fibrosis.

Endocardial fibroelastosis (EFE) is a major effector in the maldevelopment of the heart in patients with congenital heart disease. Despite successful surgical removal, EFE can redevelop, but the underlying cause of EFE recurrence remains unknown. This study aimed to identify hemodynamic predictors and genetic links to epithelial/endothelial-to-mesenchymal transition (EMT/EndMT) alterations for preoperative risk assessment.

We assessed the impact of preoperative hemodynamic parameters on EFE recurrence in a cohort of 92 patients with congenital heart disease who underwent left ventricular (LV) EFE resection between January 2010 and March 2021. Additionally, whole-exome sequencing in 18 patients was used to identify rare variants (minor allele frequency <10-5) in high-expression heart (HHE) genes related to cardiac EMT/EndMT and congenital heart disease.

EFE recurred in 55.4% of patients, within a median of 2.2 years postsurgery. Multivariable analysis revealed specific hemodynamic parameters (mitral valve inflow and area, LV filling pressure, and aortic valve gradient and diameter) as predictors, forming a predictive model with an area under the receiver operating characteristic curve of 0.782. Furthermore, 89% of the patients exhibited damaging variants in HHE genes, with 38% linked to cardiac EMT/EndMT Gene Ontology processes and 22% associated with known congenital heart disease genes. Notably, HHE genes associated with cardiac EMT/EndMT were significantly associated with faster EFE recurrence in a multivariate analysis (hazard ratio, 3.56; 95% confidence interval, 1.24-10.17; P = .018).

These findings established a predictive scoring system using preoperative hemodynamic parameters for EFE recurrence risk assessment. Alterations in HHE genes, particularly those linked to cardiac EMT/EndMT, exacerbate the risk of recurrence.

Acute myocardial infarction (AMI), primarily caused by coronary atherosclerosis, initiates a series of events that culminate in the obstruction of coronary arteries, resulting in severe myocardial ischemia and hypoxia. The subsequent myocardial ischemia/reperfusion (I/R) injury further aggravates cardiac damage, leading to a decline in heart function and the risk of life-threatening complications. The complex interplay of multiple regulated cell death (RCD) pathways plays a pivotal role in the pathogenesis of AMI. Each RCD pathway is orchestrated by a symphony of molecular regulatory mechanisms, highlighting the dynamic changes and critical roles of key effector molecules. Strategic disruption or inhibition of these molecular targets offers a tantalizing prospect for mitigating or even averting the onset of RCD, thereby limiting the extensive loss of cardiomyocytes and the progression of detrimental myocardial fibrosis. This review systematically summarizes the mechanisms underlying various forms of RCD, provides an in-depth exploration of the pathogenesis of AMI through the lens of RCD, and highlights a range of promising therapeutic targets that hold the potential to revolutionize the management of AMI.

The relationship between the changes in endothelial cell-cell junctions and microvascular abnormalities in the progression of hypertrophic cardiomyopathy (HCM), as well as their potential as early biomarkers, remains unclear. Here, we analysed single-nucleus RNA-sequencing data from the left ventricles of 44 health donors and HCM patients. First, we observed that endothelial cell-cell junctions were significantly altered in HCM vascular endothelial cells (ECs), including tight junctions, gap junctions and adherens junctions, especially in capillary ECs. The proposed pseudo-timing analysis predicted that endothelial cell-cell junctions abnormalities occurred in the early stages of HCM. Second, we verified that endothelial cell-cell junctions disorders occur at early stages of HCM disease progression in two time-series single-nucleus datasets of mice. The expression of eight cell-cell junction genes showed an initial increase in the early stage, followed by a slight decrease in the middle stage, and a sharp increase in the later stage. Subsequently, cell communication and transcription factor analysis were used to explore the underlying mechanisms. Furthermore, an early HCM prediction model was developed and independently validated using three mRNA datasets comprising 204 health individuals and HCM patients for the eight genes panel, the accuracy was 0.81 [0.63-0.98]. Finally, we validated this panel in HCM tissues. This study demonstrated in humans and mice that eight cell-cell junction genes were significantly elevated in the early stages of HCM and may be potential biomarkers for the early diagnosis of HCM.

Organ fibrosis, a common consequence of chronic tissue injury, presents a significant health challenge. Recent research has revealed the regulatory role of N6-methyladenosine (m6A) RNA modification in fibrosis of various organs, including the lung, liver, kidney, and heart. In this comprehensive review, we summarize the latest findings on the mechanisms and functions of m6A modification in organ fibrosis. By highlighting the potential of m6A modification as a therapeutic target, our goal is to encourage further research in this emerging field and support advancements in the clinical treatment of organ fibrosis.

Endothelial-mesenchymal transition (EndMT) is defined as an important process of cellular differentiation by which endothelial cells (ECs) are prone to lose their characteristics and transform into mesenchymal cells. During EndMT, reduced expression of endothelial adhesion molecules disrupts intercellular adhesion, triggering cytoskeletal reorganization and mesenchymal transition. Numerous studies have proved that EndMT is a multifaceted biological event driven primarily by cytokines such as TGF-β, TNF-α, and IL-1β, alongside signaling pathways like WNT, Smad, MEK-ERK, and Notch. Nevertheless, the exact roles of EndMT in complicated diseases have not been comprehensively reviewed. In this review, we summarize the predominant molecular regulatory mechanisms and signaling pathways that contribute to the development of EndMT, as well as highlight the contributions of a series of imperative non-coding RNAs in curbing the initiation of EndMT. Furthermore, we discuss the significant impact of EndMT on worsening vasculature-related diseases, including cancer, cardiovascular diseases, atherosclerosis, pulmonary vascular diseases, diabetes-associated fibrotic conditions, and cerebral cavernous malformation, providing the implications that targeting EndMT holds promise as a therapeutic strategy to mitigate disease progression.

The modification of endothelial cells (ECs) biological function under pathogenic conditions leads to the expression of mesenchymal stromal cells (MSCs) markers, defined as endothelial-to-mesenchymal transition (EndMT). Invisible in onset and slow in progression, atherosclerosis (AS) is a potential contributor to various atherosclerotic cardiovascular diseases (ASCVD). By triggering AS, EndMT, the "initiator" of AS, induces the progression of ASCVD such as coronary atherosclerotic heart disease (CHD) and ischemic cerebrovascular disease (ICD), with serious clinical complications such as myocardial infarction (MI) and stroke. In-depth research of the pathomechanisms of EndMT and identification of potential targeted therapeutic strategies hold considerable research value for the prevention and treatment of ASCVD-associated with delayed EndMT. Although previous studies have progressively unraveled the complexity of EndMT and its pathogenicity triggered by alterations in vascular microenvironmental factors, systematic descriptions of the most recent pathogenic roles of EndMT in the progression of AS, targeted therapeutic strategies, and their future research directions are scarce.

We aim to provide new researchers with comprehensive knowledge of EndMT in AS. We exhaustively review the latest research advancements in the field and provide a theoretical basis for investigating EndMT, a biological process with sophisticated mechanisms.

This review summarized that altered hemodynamics with microenvironmental crosstalk consisting of inflammatory responses or glycolysis, oxidative stress, lactate or acetyl-CoA (Ac-CoA), fatty acid oxidation (FAO), intracellular iron overload, and transcription factors, including ELK1 and STAT3, modulate the EndMT and affect AS progression. In addition, we provide new paradigms for the development of promising therapeutic agents against these disease-causing processes and indicate promising directions and challenges that need to be addressed to elucidate the EndMT process.

Coronary microvascular dysfunction (CMD) comprises a wide spectrum of structural and/or functional abnormalities of coronary microcirculation that can lead to myocardial ischemia. Emerging evidence has indicated that CMD is a relevant cause of morbidity and mortality and is associated with a high risk of major adverse cardiovascular events (MACEs) and heart failure with preserved ejection fraction as well as poor quality of life. This review aims to elucidate briefly the pathogenesis and diagnostic modalities of CMD and to shed light on contemporary evidence on the prognostic impact of CMD. Finally, we will provide an overview of novel emerging therapeutic strategies for CMD.

As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrix during fibrosis impairs the structure and function of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only for fibrosis but also for the development of antifibrotic therapies.

Various cells such as cardiomyocytes, fibroblasts and endothelial cells constitute integral components of cardiac tissue. The health and stability of cardiac ecosystem are ensured by the action of a certain type of cell and the intricate interactions between multiple cell types. The dysfunctional cells exert a profound impact on the development of cardiovascular diseases by involving in the pathological process. In this paper, we introduce the dynamic activity, cell surface markers as well as biological function of the various cells in the heart. Besides, we discuss the multiple signaling pathways involved in the cardiac injury including Hippo/YAP, TGF-β/Smads, PI3K/Akt, and MAPK signaling. The complexity of different cell types poses a great challenge to the disease treatment. By characterizing the roles of various cell types in cardiovascular diseases, we sought to discuss the potential strategies for preventing and treating cardiovascular diseases.

Idiopathic pulmonary fibrosis (IPF) remains a challenging disease with no drugs available to change the trajectory. It is a condition associated with excessive and highly progressive scarring of the lungs with remodelling and extracellular matrix deposition. It is a highly "destructive" disease of the lungs. The diagnosis of IPF is challenging due to continuous evolution of the disease, which also makes early interventions very difficult. The role of vascular endothelial cells has not been explored in IPF in great detail. We do not know much about their contribution to arterial or vascular remodelling, extracellular matrix changes and contribution to pulmonary hypertension and lung fibrosis in general. Endothelial to mesenchymal transition appears to be central to such changes in IPF. Similarly, for epithelial changes, the process of epithelial to mesenchymal transition seem to be the key both for airway epithelial cells and type-2 pneumocytes. We focus here on endothelial and epithelial cell changes and its contributions to IPF. In this review we revisit the pathology of IPF, mechanistic signalling pathways, clinical definition, update on diagnosis and new advances made in treatment of this disease. We discuss ongoing clinical trials with mode of action. A multidisciplinary collaborative approach is needed to understand this treacherous disease for new therapeutic targets.

Cardiac fibrosis represents the terminal pathological manifestation of various heart diseases, with the formation of fibroblasts playing a pivotal role in this process. Consequently, targeting the formation and function of fibroblasts holds significant potential for improving outcomes in heart disease. Recent research reveals the considerable potential of fibroblasts in ameliorating cardiac conditions, demonstrating different functional characteristics at various time points and spatial locations. Therefore, precise modulation of fibroblast activity may offer an effective approach for treating cardiac fibrosis and achieving targeted therapeutic outcomes. In this review, we focus on the fate and inhibition of fibroblasts, analyze their dynamic changes in cardiac diseases, and propose a framework for identifying markers of fibroblast activation mechanisms and selecting optimal time windows for therapeutic intervention. By synthesizing research findings in these areas, we aim to provide new strategies and directions for the precise treatment of fibroblasts in cardiac diseases.

Myocardial fibrosis, a condition linked to several cardiovascular diseases, is associated with a poor prognosis. Stem cell therapy has emerged as a potential treatment option and the application of stem cell therapy has been studied extensively. However, a comprehensive bibliometric analysis of these studies has yet to be conducted.

To map thematic trends, analyze research hotspots, and project future directions of stem cell-based myocardial fibrosis therapy.

We conducted a bibliometric and visual analysis of studies in the Web of Science Core Collection using VOSviewer and Microsoft Excel. The dataset included 1510 articles published between 2001 and 2024. Countries, organizations, authors, references, keywords, and co-citation networks were examined to identify evolving research trends.

Our findings revealed a steady increase in the number of publications, with a projected increase to over 200 publications annually by 2030. Initial research focused on stem cell-based therapy, particularly for myocardial infarction and heart failure. More recently, there has been a shift toward cell-free therapy, involving extracellular vesicles, exosomes, and microRNAs. Key research topics include angiogenesis, inflammation, apoptosis, autophagy, and oxidative stress.

This analysis highlights the evolution of stem cell therapies for myocardial fibrosis, with emerging interest in cell-free approaches. These results are expected to guide future scientific exploration and decision-making.

Liver fibrosis is a reversible process that can be delayed or even reversed through appropriate intervention during its development. The protein RECK, encoded by the Reck gene, regulates matrix metalloproteinase (MMP) activity and plays a crucial role in extracellular matrix (ECM) degradation and remodeling. Reduced RECK expression is found in various fibrotic tissues. However, the impact of restoring RECK expression on the development and progression of liver fibrosis has not yet been determined. This study found that the restoration of RECK expression attenuated TGF-β1-induced hepatic stellate cell (HSC) activation and mitigated carbon tetrachloride (CCl4)-induced acute liver injury. In a mouse model of liver fibrosis induced by CCl4, restoration of RECK expression reduced the degree of fibrosis, collagen deposition, and level of oxidative stress. RECK competes with Nrf2 for binding to Keap1, resulting in a decrease in the degradation of Nrf2 by Keap1 and an increase in the accumulation of Nrf2 in the cytoplasm. Under oxidative stress conditions, Nrf2 can be translocated to the nucleus for expression, initiating an antioxidant stress response, furthermore, Nrf2 can also activate MMP-9 and degrade the over-deposited collagen, thereby achieving the effect of alleviating liver fibrosis. Our study reveals a novel mechanism by which restoration of RECK expression ameliorates liver fibrosis, providing a promising target for combating liver fibrosis.

Atrial fibrillation (AF) has high mortality and morbidity rates. However, the intracellular molecular complexity of the atrial tissue of patients with AF has not been adequately assessed.

We investigated the cellular heterogeneity of human atrial tissue and changes in differentially expressed genes between cells using single-cell RNA sequencing, fluorescence in situ hybridization, intercellular communication, and cell trajectory analysis. Using genome-wide association studies (GWAS) and proteomics, we discovered cell types enriched for AF susceptibility genes. We discovered eight different cell types, which were further subdivided into 23 subpopulations. In AF, the communication strength between smooth muscle cells (SMCs) and fibroblast (FB) 3 cells increased and the relevant signaling pathways were quite similar. Subpopulations of endothelial cells (ECs) are mainly involved in fibrosis through TXNDC5 and POSTN. AF susceptibility genes revealed by GWAS were especially enriched in neuronal and epicardial cells, FB3, and lymphoid (Lys) cells, whereas proteomic sequencing differential proteins were concentrated in FB3 cells and SMCs.

This study provides a cellular landscape based on the atrial tissue of patients with AF and highlights intercellular changes and differentially expressed genes that occur during the disease process. A thorough description of the cellular populations involved in AF will facilitate the identification of new cell-based interventional targets with direct functional significance for the treatment of human disease.

Cancer stem cells (CSCs) may be dedifferentiated somatic cells following oncogenic processes, representing a subpopulation of cells able to promote tumor growth with their capacities for proliferation and self-renewal, inducing lineage heterogeneity, which may be a main cause of resistance to therapies. It has been shown that the "less differentiated process" may have an impact on tumor plasticity, particularly when non-CSCs may dedifferentiate and become CSC-like. Bidirectional interconversion between CSCs and non-CSCs has been reported in other solid tumors, where the inflammatory stroma promotes cell reprogramming by enhancing Wnt signaling through nuclear factor kappa B activation in association with intracellular signaling, which may induce cells' pluripotency, the oncogenic transformation can be considered another important aspect in the acquisition of "new" development programs with oncogenic features. During cell reprogramming, mutations represent an initial step toward dedifferentiation, in which tumor cells switch from a partially or terminally differentiated stage to a less differentiated stage that is mainly manifested by re-entry into the cell cycle, acquisition of a stem cell-like phenotype, and expression of stem cell markers. This phenomenon typically shows up as a change in the form, function, and pattern of gene and protein expression, and more specifically, in CSCs. This review would highlight the main epigenetic alterations, major signaling pathways and driver mutations in which CSCs, in tumors and specifically, in lung cancer, could be involved, acting as key elements in the differentiation/dedifferentiation process. This would highlight the main molecular mechanisms which need to be considered for more tailored therapies.

Endothelial-to-mesenchymal transition (EndoMT) is associated with neointimal hyperplasia and vein graft failure, and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) has emerged as a major modulator of EMT. We aimed to investigate the functional consequence of EndoMT in neointimal hyperplasia and the precise role of hnRNPA1 in the regulation of EndoMT and neointimal hyperplasia. We investigated the spatial and temporal distribution characteristics of EndoMT cells in a mouse model of vein graft transplantation. In vitro, we studied the interaction between EndoMT cells and VSMCs, and the underlying mechanism was investigated by cytokine antibody assays. In cultured HUVECs, we studied the effect of hnRNPA1 on EndoMT and the cellular interactions by using siRNA-mediated knockdown and adenovirus-mediated overexpression. We further investigated the role of hnRNPA1 in EndoMT and neointimal hyperplasia in vivo with an AAV-mediated EC-specific hnRNPA1 overexpression murine model. We demonstrated the presence of EndoMT cells during the initial stage of neointimal formation, and that EndoMT cells promoted the proliferation and migration of VSMCs in vitro. Mechanistic studies revealed that EndoMT cells express and secrete a higher level of PDGF-B. Furthermore, we found a regulatory role for hnRNPA1 in EndoMT in vitro and in vivo. Similarly, we found that hnRNPA1 overexpression in ECs reduced the expression and secretion of PDGF-B during EndoMT, effectively inhibiting EndoMT cell-mediated activation of VSMCs in vitro and neointimal formation in vivo. Taken together, these findings indicate that EndoMT cells can activate VSMCs through a paracrine mechanism mediated by hnRNPA1 and lead to neointimal hyperplasia.

Structural and functional changes in the intramyocardial microcirculation increase the risk of myocardial infarction (MI). This study investigated intramyocardial perivascular fibrosis and pro-fibrotic cellular transitions in deceased acute and subacute MI patients to explore their involvement in the pathogenesis of MI.

Left ventricular tissue (LV) was obtained from the infarction area of autopsied patients with acute-phase MI (3-6 h; n = 24), subacute-phase MI (5-14 days; n = 12), and noninfarcted controls (n = 14). Perivascular fibrosis and fibroblast activation protein (FAP) expression were quantified using (immuno)histochemistry. Fibroblast-like transitioning of vascular smooth muscle cells (VSMC) and endothelial cells (EC) was quantified using immunofluorescent microscopy.

Perivascular fibrosis was elevated in acute-phase (77.69 %) and subacute-phase (72.19 %: border zone 95.18 %: infarct core) MI patients (p < 0.0001) compared to controls (61.03 %). FAP expression was higher in both acute-phase (1.46 %) and subacute-phase (18.01 %: border zone 5.67 %: infarct core) compared to controls (0.46 %) (p < 0.05). VSMC fibroblast-like cellular transition (SMA + S100A4+ vessels fraction) was higher in acute-phase (31.96 %) and subacute-phase (21.90 %: border zone; 37.25 %: infarct core) MI compared to controls (8.95 %) (p < 0.05). Similarly, EC fibroblast-like cellular transition (CD31 + S100A4+ area fraction) was increased in acute-phase MI (10.14 %) and subacute-phase MI (8.31 %: border zone 10.15 %: infarct core) compared to controls (2.67 %) (p < 0.05).

Increased perivascular fibrosis, fibroblast activation and vascular cellular transition in intramyocardial blood vessels of MI patients may contribute to MI development. Further increases of FAP expression and perivascular fibrosis, particularly in subacute-phase infarct cores, suggest MI itself exacerbates fibroblast activation and perivascular fibrosis, theoretically increasing reinfarction risk.

The accumulation of lactate is a rising risk factor for patients after flap transplantation. Endothelial-to-mesenchymal transition (EndoMT) plays a critical role in skin fibrosis. Nevertheless, whether lactate overproduction directly contributes to flap necrosis and its mechanism remain unknown. The current study reveals that skin flap mice exhibit enhanced PKM2 and fibrotic response. Endothelial-specific deletion of PKM2 attenuates flap necrosis and ameliorates flap fibrosis in mice. Administration of lactate or overexpressing PKM2 promotes dysfunction of endothelial cells and stimulates mesenchymal-like phenotype following hypoxia. Mechanistically, glycolytic-lactate induces a correlation between Twist1 and p300/CBP, leading to lactylation of Twist1 lysine 150 (K150la). The increase in K150la promotes Twist1 phosphorylation and nuclear translocation and further regulates the transcription of TGFB1, hence inducing fibrosis phenotype. Genetically deletion of endothelial-specific PKM2 in mice diminishes lactate accumulation and Twist1 lactylation, then attenuates EndoMT-associated fibrosis following flap ischemia. The serum lactate levels of flap transplantation patients are elevated and exhibit predictive value for prognosis. This findings suggested a novel role of PKM2-derived lactate in mediating Twist1 lactylation and exacerbates flap fibrosis and ischemia. Inhibition of glycolytic-lactate and Twist1 lactylation reduces flap necrosis and fibrotic response might become a potential therapeutic strategy for flap ischemia.