The understanding of endothelin's role in carotid plaque instability is limited. We have studied the big endothelin-1 (ET-1) axis and its role in carotid plaque stability in patients undergoing carotid endarterectomy (CEA). The interactions of endothelins with known CVD risk factors were also evaluated.

We studied 77 patients, who were divided into subgroups based on the optimal cut-off for grey-scale median (GSM), a marker of plaque instability. GSM values < 46.87 were designated as unstable carotid plaque, while GSM ≥ 46.87 were assigned to stable plaque. Twelve people without carotid atherosclerosis served as controls. Big ET-1, ET-1 and ET-1 (1-31) were measured and the endothelin-converting enzyme-1 (ECE-1) and chymase activity were calculated. Clinical and laboratory parameters were also evaluated.

ET-1 levels and ECE-1 activity were increased in all patient groups compared to controls (all P < 0.001) - and were higher in patients with unstable plaque than in those with stable plaque (P < 0.01). ET-1 (1-31) did not differ between the groups. ET-1 levels and ECE-1 activity inversely correlated with total cholesterol, LDL-cholesterol, and GSM values, whereas GSM was positively associated with total cholesterol and LDL fractions. Detailed analysis of patients according to the pharmacotherapy used revealed that statins favored ET-1 formation independently of cholesterol-lowering properties, whereas aspirin reduced this effect.

ET-1 formation is the main pathway of big ET-1 metabolism in patients with carotid atherosclerosis, especially in those with plaque instability. Statins and aspirin appear to have opposing effects on ET-1 formation, suggesting the greater benefit related to plaque stability in patients taking both drugs concomitantly.

Cardiomyopathy is an anatomical and pathologic condition that is related to the cardiac muscle or left ventricular failure. A diverse range of illnesses known as cardiomyopathies often result in progressive heart failure with high morbidity and death rates. Primary cardiomyopathies are hereditary, mixed, or adopted. Secondary cardiomyopathies are infiltrative, harmful, or pathogenic. The activation of many paracrine, autocrine, and neuroendocrine factors is closely linked to pathological left ventricular (LV) deformation. After the myocardial injury, in the context of higher LV wall pressure and haemodynamic disturbance, these variables are raised. New therapy techniques have been focused on these novel targets after recent studies revealed that endothelin, nitric oxide or cytokines may be implicated in the remodelling process. Vasoconstrictive peptide endothelin-1 (ET-1) is mostly generated in the endothelium and works by binding to the ETA- and ETB-endothelin receptors (ET-Rs). The expression of both ET-Rs is widespread in cardiac tissues. Heart failure, pulmonary arterial hypertension, hypertension, cardiomyopathy, and coronary artery disease are just a few of the cardiovascular disorders for which the endothelin system has been shown to play a crucial role over the years. The occurrence, pathogenesis, and natural history of endothelin antagonists in cardiomyopathies are currently not well understood, and specific aspects of their treatment responses have not received comprehensive attention. Therefore, in this study, we address the variable degrees of success that have been achieved in treating cardiomyopathy using endothelin-targeting treatments, such as endothelin receptor antagonists.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide. Endothelin-1 (ET-1) is a potent vasoconstrictor secreted by vascular endothelial cells, actively involved in the pathophysiology of numerous cardiovascular diseases. Based on the differential downstream effects of ET-1 binding to its two distinct types of receptors (ETA/ETB) within the kidney, selective ETA receptor blockade has been long proposed as a promising treatment modality for DKD.

This review aims to examine the available evidence base for the use of ERAs in the treatment of DKD, by critically reappraising available landmark trials and discussing their possible position in the context of current treatment of this disease.

Despite early enthusiasm and widespread expectations, endothelin receptor antagonists (ERAs) faded into obscurity following the release of the first randomized controlled trials (RCTs). More recent RCTs using different compounds have re-introduced ERAs as a promising treatment in the growing pharmaceutical armamentarium of DKD. While the future of DKD management will be based on a more personalized approach, new, robust evidence from appropriately designed RCTs is eagerly anticipated to clearly define the role of ERAs in DKD.

Mitophagy is a selective way to eliminate dysfunctional mitochondria and recycle their constituents, which plays an important role in regulating and maintaining intracellular homeostasis. Real-time monitoring mitophagy process is of great importance for cellular physiological and pathological processes related to mitochondria. Howbeit, most of the current methods only focus on single-parameter detection of mitochondrial microenvironmental changes such as pH, viscosity and polarity. The mitochondrial molecular responses under mitophagy are not clear. Therefore, developing a new and simple method for molecular profiling is of great importance for accurately and comprehensively visualizing mitophagy.

In this work, Au NPs-based mitochondria-targeting nanoprobe was developed and the nanoprobe-based label-free surface enhanced Raman spectroscopy (SERS) method was proposed to track starvation induced mitophagy process at molecular level. The nanoprobe displayed good SERS performance and low cytotoxicity. Based on the developed strategy, the molecular response within mitochondria under mitophagy was validated. Meanwhile, the protein denaturation, conformational change, lipid degradation and DNA fragmentation within mitochondria under mitophagy were revealed for the first time, which provides molecular evidence for mitophagy. The changes in reactive oxygen species level and mitochondrial membrane potential further confirmed the damage of mitochondria. Moreover, the developed label-free SERS strategy was used to detect mitophagy in drug (cisplatin)-induced liver injury (DILI) cell model, and obvious mitophagy in DILI cells was observed.

The molecular biochemical signature dynamic changes within mitochondria during mitophagy process were revealed by SERS for the first time. Moreover, compared with the current research, our study can provide new insights into mitophagy and mitophagy-involved diseases at molecular level. This study will provide new insights into the molecular mechanism of mitophagy and offer a simple and effective method for mitochondrial molecular event monitoring in mitophagy-involved cellular processes.

The present study provides a detailed review of cardiovascular biomarkers critical for the diagnosis, prognosis, and pathophysiology of cardiovascular diseases, the leading cause of global morbidity and mortality. These biomarkers aid in detecting disease onset, progression, and therapeutic responses, providing insights into molecular mechanisms. Enzyme markers like AST, CK-MB, LDH, CA-III, and HBDH are pivotal for detecting myocardial injury during acute events. Protein markers such as CRP, H-FABP, and MPO shed light on inflammation and oxidative stress. Cardiac Troponins, the gold standard for myocardial infarction diagnosis, exhibit high specificity and sensitivity, while IMA and GPBB indicate ischemia and early myocardial damage. Peptide markers, including BNP and NT-proBNP, are crucial for heart failure diagnosis and management, reflecting ventricular stress and remodeling. Novel peptides like MR-proANP and MR-proADM aid in assessing disease severity. Lipid markers such as lipoprotein-associated phospholipase A2 and oxylipins provide insights into lipid metabolism and atherosclerosis. Inflammatory and stress-related biomarkers, including TNFα, IL-6, GDF-15, and Pentraxin 3, illuminate chronic inflammation in CVDs. Hormonal markers like copeptin and endothelin-1 highlight neurohormonal activation, while emerging markers such as ST2, galectin-3, PAPP-A, and TMAO elucidate fibrosis, remodeling, and metabolic dysregulation. The inclusion of microRNAs and long non-coding RNAs represents a breakthrough in biomarker research, offering sensitive tools for early detection, risk stratification, and therapeutic targeting. This review emphasizes the diagnostic and prognostic utility of these biomarkers, advancing cardiovascular care through personalized medicine.

Endothelin-1 (ET-1) levels are altered in atherosclerosis, while the roles of the endothelin receptors ETAR and ETBR during the pathogenesis of atherosclerosis remain unclear. Therefore, the focus of this study was to clarify how endothelin receptors are expressed in advanced human atherosclerotic plaques and how this is related to atherosclerotic risk factors. Ex vivo expression analysis was performed by quantitative real-time PCR (qRT-PCR) of 98 atherosclerotic plaques and controls that were obtained from adult patients undergoing vascular surgery. Correlation analyses of atherosclerosis-promoting factors were accomplished using a linear regression model. We found an overall reduced expression of ET receptors and smooth muscle actin (SMA), a marker of healthy vascular smooth muscle cells, in atherosclerotic plaques, whereas the levels of ET-1 and matrix metalloproteinase 2 (MMP-2), a marker of atherosclerosis progression, remained unchanged. Reduced expression was predominantly correlated with hypertension, which affects both receptors as well as SMA. Age, body mass index (BMI) and gender also correlated with either ETAR, ETBR or SMA expression in advanced plaques. In contrast, no effect of diabetes mellitus or smoking was found, indicating an ancillary effect of those risk factors. The results of our study indicate that endothelin receptor expression during the pathogenesis of atherosclerosis is predominantly correlated with hypertension.

Gut dysbiosis serves as an underlying risk factor for the development of hypertension. The resolution of this dysbiosis has emerged as a promising strategy in improving hypertension. Food-derived bioactive protein peptides have become increasingly more attractive in ameliorating hypertension, primarily due to their anti-inflammatory and anti-oxidant activities. However, the regulatory mechanisms linking rice peptides (RP), gut dysbiosis, and hypertension remain to be fully elucidated. In our study, male spontaneously hypertensive rats (SHR) were fed with chow diet and concomitantly treated with ddH2O (Ctrl) or varying doses of rice peptides (20, 100, or 500 mg (kg bw day)-1 designated as low-dose RP, LRP; medium-dose RP, MRP; high-dose RP, HAP) or captopril (Cap) by intragastric administration. Wistar-Kyoto (WKY) rats served as the normotensive control group and were orally administered with ddH2O. We observed beneficial effects of RP in lowering blood pressure and ameliorating cardiovascular risk profiles, as evidenced by improvements in glucolipid metabolic disorders, hepatic and renal damage, left ventricular hypertrophy and endothelial dysfunction in hypertensive rats. More importantly, we found that RP attenuated intestinal pathological damage, improved impaired intestinal barrier, and reduced intestinal inflammation by inhibiting the HMGB1-TLR4-NF-κB pathway. Notably, multi-omics integrative analyses have revealed that RP altered the composition and function of the gut microbiota. This is exemplified by the observed enrichment of beneficial bacterial constituents, such as g_Lactobacillus, g_Lactococcus, s_Lactobacillus_intestinalis, and Lactococcus lactis, and elevated production of microbiota-derived short-chain fatty acid metabolites. Collectively, these studies suggest that the hypotensive effects of RP may be associated with modulation of the gut microbiota and its short-chain fatty acids metabolites. This implicates the microbiota-gut-HMGB1-TLR4-NF-κB axis as a novel venue for the amelioration of hypertension and its complications.

The binding of endothelin-1 (ET-1) to endothelin type A receptor (ETAR) performs a critical action in pulmonary arterial smooth muscle cell (PASMC) proliferation leading to pulmonary vascular structural remodeling. More evidence showed that cystathionine γ-lyase (CSE)-catalyzed endogenous hydrogen sulfide (H2S) was involved in the pathogenesis of cardiovascular diseases. In this study, we aimed to explore the effect of endogenous H2S/CSE pathway on the ET-1/ETAR binding and its underlying mechanisms in the cellular and animal models of PASMC proliferation.

Both live cell imaging and ligand-receptor assays revealed that H2S donor, NaHS, inhibited the binding of ET-1/ETAR in human PASMCs (HPASMCs) and HEK-293A cells, along with an inhibition of ET-1-activated HPASMC proliferation. While, an upregulated Ki-67 expression by the pulmonary arteries, a marked pulmonary artery structural remodeling, and an increased pulmonary artery pressure were observed in CSE knockout (CSE-KO) mice with a deficient H2S/CSE pathway compared with those in the wild type (WT) mice. Meanwhile, NaHS rescued the enhanced binding of ET-1 with ETAR and cell proliferation in the CSE-knockdowned HPASMCs. Moreover, the ETAR antagonist BQ123 blocked the enhanced proliferation of CSE-knockdowned HPASMCs. Mechanistically, ETAR persulfidation was reduced in the lung tissues of CSE-KO mice compared to that in WT mice, which could be reversed by NaHS treatment. Similarly, NaHS persulfidated ETAR in HPASMCs and HEK-293A cells. Whereas a thiol reductant dithiothreitol (DTT) reversed the H2S-induced ETAR persulfidation and further blocked the H2S-inhibited binding of ET-1/ETAR and HPASMC proliferation. Furthermore, the mutation of ETAR at cysteine (Cys) 69 abolished the persulfidation of ETAR by H2S, and subsequently blocked the H2S-suppressed ET-1/ETAR binding and HPASMC proliferation.

Endogenous H2S persulfidated ETAR at Cys69 to inhibit the binding of ET-1 to ETAR, subsequently suppressed PASMC proliferation, and antagonized pulmonary vascular structural remodeling.

To investigate the roles of oxidative stress-related differentially expressed genes (OSRDEGs) in keloid formation and explore their potential value in diagnosis and treatment.

Gene expression data from the GEO database, including GSE145725 and GSE44270 as training sets and GSE7890 as a validation set, were utilized. OSRDEGs were identified, followed by Weighted Gene Co-expression Network Analysis (WGCNA), GO/KEGG enrichment analysis, and Gene Set Enrichment Analysis (GSEA). Key genes were further screened through protein-protein interaction (PPI) network analysis and receiver operating characteristic (ROC) curve analysis. miRNA targets, transcription factors (TF), and potential drug targets of these genes were predicted. Immune cell infiltration analysis was performed to assess the association between OSRDEGs and immune cells, which was validated using GSE7890. Finally, the expression of key genes was experimentally validated using quantitative PCR (qPCR), immunohistochemistry (IHC), and hematoxylin-eosin (HE) staining.

A total of 13 OSRDEGs were identified. WGCNA and functional enrichment analyses revealed that these genes were primarily involved in fibrosis and inflammatory processes in keloids, such as the MAPK signaling pathway, lymphocyte and monocyte proliferation, and inflammatory pathways involving IL-18 and IL-23. PPI network analysis, ROC analysis, and immune infiltration results identified Endothelin-1 (EDN1) and Neurotrophin-3(NTF3) as key genes with high sensitivity and specificity. These genes were positively and negatively correlated with activated mast cells, respectively, suggesting their dual regulatory roles in fibrosis and inflammation. External dataset validation, qPCR, correlation analysis, HE staining, and IHC results demonstrated that EDN1 and NTF3 were highly expressed in keloid tissues and were associated with excessive collagen deposition and immune cell infiltration.

EDN1 and NTF3, as OSRDEGs, play critical roles in the pathogenesis and progression of keloids. They may contribute to fibrosis and inflammation through the regulation of oxidative stress, the MAPK signaling pathway, and mast cell activation. These findings highlight EDN1 and NTF3 as potential diagnostic biomarkers and therapeutic targets, providing novel insights into the pathogenesis and treatment strategies for keloids.

Doxorubicin (DOX) is a widely used chemotherapy drug for cancer while leads to several cardiac disorders including cardiomyopathy and heart failure. Aprocitentan is a novel dual endothelin-1 receptor antagonist and functions as an effective antihypertensive drug for resistant hypertension. However, the exact roles of aprocitentan in DOX-induced cardiotoxicity remains largely unclear.In this work, we explored potential participants of aprocitentan in DOX-induced cardiotoxicity. Mice were treated with DOX to induce cardiotoxicity, and then received either aprocitentan or tetrathiomolybdate interventions respectively. Compared with controls, DOX-treated mice exhibited cardiac impairments and dysfunction. Notably, aprocitentan or tetrathiomolybdate intervention remarkably mitigated DOX-mediated cardiac cardiotoxicity, as evidenced by alleviated myocardial fibrosis and improved cardiac function. Furthermore, aprocitentan or tetrathiomolybdate administration significantly mitigated myocardial cuproptosis, oxidative stress, cardiac aging and inflammation in DOX-treated mice with decreased levels of DLAT accumulation, as well as downregulated expressions of HSP70, P16 and P21, respectively. In cultured primary rat cardiomyocytes, treatment with aprocitentan alleviated DOX-induced augmentation of cuproptosis and oxidative stress with reduced DLAT accumulation. Moreover, aprocitentan administration strikingly reversed DOX-induced and elesclomol-aggravated cellular senescence and mitochondrial injury in cardiomyocytes. More importantly, knock-down of sirtuin 7 (SIRT7) by SIRT7 siRNA blocked the beneficial effects of aprocitentan on DOX-associated cuproptosis, oxidative stress, mitochondrial injury, and senescence in cardiomyocytes. In summary, aprocitentan exerts as a novel therapeutic agent for alleviation of DOX-induced cardiotoxicity through the inhibition of cuproptosis, oxidative stress, cardiac aging and mitochondrial injuries via the activation of SIRT7, offering new possibilities for prevention and treatment of DOX-induced cardiac disorders.

Hypertension is the leading cause of death globally, primarily due to its strong association with cardiovascular disease. The global prevalence of hypertension has surged over the past three decades, driven by rising rates of diabetes mellitus and obesity. Despite current antihypertensive therapies, only a small proportion of patients with hypertension achieve adequate blood pressure control, necessitating novel therapeutic strategies. In this Review we explore the challenges and emerging opportunities in hypertension management. Aprocitentan, a dual endothelin receptor antagonist, is the first agent from a novel class of antihypertensive drug to be licensed since 2007 and exemplifies innovative treatments on the horizon. Here we also address the complex factors contributing to poor hypertension control, including genetic influences, lifestyle factors, therapeutic inertia and poor patient adherence. We discuss the limitations of existing therapies and highlight promising new pharmacological approaches to hypertension management. Integrating these novel treatments alongside current pharmaceuticals combined with improved diagnostic and management strategies could substantially reduce the global burden of hypertension and associated cardiovascular disease.

Chronic kidney disease (CKD) is a serious health issue with rising morbidity and mortality rates. Despite advances in understanding its pathophysiology, effective therapeutic options are limited, necessitating innovative treatment approaches. Also, current frontline treatments that are available against CKD are not uniformly effective and often come with significant side effects. Therefore, identifying new therapeutic targets or improving existing treatments for CKD is crucial. Drug repurposing is a promising strategy in the drug discovery process that involves screening existing approved drugs for new therapeutic applications.

This review discusses the pharmacological mechanisms and clinical evidence that support the efficacy of these repurposed drugs. Various drugs classes such as inodilators, endothelin-1 type A (ET-1A) receptor antagonists, bisphosphonates, mineralocorticoid receptor (MR) antagonists, DNA demethylating agents, nuclear factor erythroid 2-related factor 2 (NRF2) activators, P2X7 inhibitors, autophagy modulators, hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) are discussed that could remarkably contribute against CKD.

The review critically examines the potential for repurposing well-established drugs to slow the progression of CKD and enhance patient outcomes. This review emphasizes the importance of a multidisciplinary approach in advancing the field of drug repurposing, ultimately paving the way for innovative and effective therapies for patients suffering from CKD.

Lymphatic collecting vessels in the kidney are critical in clearing interstitial fluid, macromolecules, and infiltrating immune cells. Dysfunction of the lymphatic vessels can disrupt this process and exacerbate injury-associated inflammation in many disease conditions. We previously found that sodium accumulates within the kidney interstitium during proteinuric kidney injury and elevated sodium environments stimulate isolevuglandin production in antigen-presenting cells, stimulating T cells, and modulating inflammatory responses. In the present study, we investigated whether proteinuric injury increases production of isolevuglandin-adduct formation in antigen-presenting cells, their effects on lymphatic endothelial cells (LECs), and the role of the ET-3 (endothelin-3)/ETBR (endothelin type B receptor) on lymphatic vessel function.

We used a mouse model of nephrotoxin-induced proteinuric injury to show that proteinuric injury expanded the kidney lymphatic network and to immunophenotype the infiltrating immune cells. To determine mechanisms, we analyzed the interaction of migratory immune cells and LECs using an in vitro transwell migration assay, bulk RNA sequencing, and flow cytometric analysis. To determine the effect of ET-3/ETBR axis on lymphatic vessel contractility, we analyzed microdissected lymphangions utilizing a vessel perfusion chamber.

We found that animals with proteinuric injury have increased kidney lymphangiogenesis, isolevuglandin-producing dendritic cells, and IFN (interferon)-γ-producing CD4+T cells. The sodium avid environment present in kidney injury enhances the interaction between LECs and migratory antigen-presenting cells and LEC production of isolevuglandin-adducts. Elevated sodium environment-induced isolevuglandin-adduct formation facilitates the ET-3/ETBR communication between LECs and dendritic cells. In addition, the ET-3/ETBR axis modulates lymphatic collecting vessel pumping dynamics.

These findings reveal a novel mechanism linking the isolevuglandin-mediated ET-3/ETBR axis with LECs and infiltrating dendritic cells. ET-3/ETBR signaling in lymphatic vessel dynamics is a novel pathogenic component and a possible therapeutic target in kidney disease.

This study explored the effects of long-term cold stress (CS) on aortic vascular function in guinea pigs.

Hartley guinea pigs (n = 32) were divided into the following groups: atherosclerosis (AS), CS, and menthol-stimulated (M), and control (C). On days 1, 15, 30, 45, and 60, guinea pigs in the AS, CS, and M groups were intraperitoneally injected with bovine serum albumin. The C group was provided with maintenance feed and room temperature water. The AS group was provided with a high-fat diet and room temperature water. The CS group was maintained in a refrigerator at 4°C, while providing a high-fat diet and iced water. The M group was administered menthol solution, and provided with a high-fat diet and room temperature water. The modeling period lasted for 120 days. On day 121, abdominal aortic sera and aortic samples were obtained after intraperitoneal injection of sodium pentobarbital. Blood rheology tests were conducted to assess blood adhesion, biochemical tests to assess lipid levels, and enzyme-linked immunosorbent assays to detect serum nuclear factor-κB, tumor necrosis factor-α, and interleukin-1β, and endothelial nitric oxide synthase, nitric oxide, and endothelin-1 (ET-1) in aortic tissue. Hematoxylin and eosin and oil red O staining were used to examine pathologic changes in the aorta, Western blotting to detect transient receptor potential melastatin 8 and protein kinase G protein expression, quantitative polymerase chain reaction was used to measure VCAM-1 mRNA expression level.

Prolonged exposure to CS exacerbated lipid-metabolism disorders in guinea pigs fed a high-fat diet, increased aortic vascular cell adhesion, and exacerbated vascular inflammation, leading to endothelial injury, ultimately worsening pathologic changes associated with aortic atherosclerosis.

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.

Resistant hypertension (RH) is linked to higher risks of cardiovascular events and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline-recommended therapy. Whilst spironolactone is considered the preferred fourth-line therapy, its broad application is limited by its safety profile. Aprocitentan is a novel dual endothelin (ET) A and B receptors antagonist that has been recently approved by the FDA.

This review aims to summarise the available evidence on the discovery, pharmacokinetic, pharmacodynamic, efficacy, and safety of aprocitentan in the pharmacotherapy of RH.

We searched PubMed, Embase, and International Pharmaceutical Abstracts to identify relevant papers on aprocitentan use. Clinical trial registries were also searched.

Aprocitentan targets the ET pathway which remains unopposed by contemporary alternative therapies for RH. It differs from other ET receptor antagonists in its pharmacological profile, as it is eliminated independently of CYP450 or BCRP, making it less likely to cause drug-drug interactions. Current evidence demonstrates that compared to placebo, aprocitentan significantly reduces blood pressure (BP) as measured via unattended automated office BP and 24-hour ambulatory BP. The most frequently reported adverse effects were fluid retention/edema and anaemia.

Aprocitentan is a novel therapy for the management of RH that significantly reduces BP when compared to placebo. It delivers exciting prospects for future therapeutic options in the setting of RH and expands insights into its pathophysiology. However there is lack of data in relation to broader cardiovascular and renal protection, as well as its long-term safety profile.

To explore the relationship between BigET-1 and cardiac remodeling in hypertrophic obstructive cardiomyopathy (HOCM). A retrospective analysis was conducted on the data of 150 HOCM patients in a hospital from September 2021 to August 2023. According to the 2015 American Ultrasound Society's recommended standards for quantifying adult UGG cardiac lumen, left atrial enlargement is defined as having a left atrial diameter greater than 40 mm in males and greater than 38 mm in females. 150 HOCM patients were divided into a left atrial normal group (n = 97) and a left atrial enlargement group (n = 53). Comprehensive patient data were collected, including BigET-1in plasma, N-Terminalpro-B-TypeNatriureticPeptide (NT-pro-BNP), and High-sensitive C-reactive protein (Hs-CRP), as well as cardiac magnetic resonance imaging (CMR) imaging data. The relationship between BigET-1 levels and cardiac remodeling was analyzed. The two groups had no statistical difference in gender, age, heart rate, dyspnea, angina pectoris, etc. (P > 0.05). The χ2-test showed that patients in the left atrial enlargement group had an increased proportion of atrial fibrillation compared to those in the left atrial normal group (P < 0.05). Non parametric tests showed that the Big ET-1 and NT-pro-BNP in the left atrial enlargement group were significantly higher than those in the left atrial normal group (P < 0.05). The t-test results showed that there were statistical differences in Hs-CRP, left atrial anteroposterior diameter, interventricular septum thickness, and LVEDV between the left atrial enlargement group and the left atrial normal group (P < 0.05). Pearson correlation analysis showed that Big ET-1 was positively correlated withNT-pro-BNP, Hs-CRP, left atrial anteroposterior diameter, and interventricular septum thickness (P < 0.05). The multiple linear regression analysis showed that Big ET-1 was positively correlated with NT-pro-BNP and LADap (P < 0.05). In HOCM patients with atrial enlargement, the Big ET-1 is significantly elevated. Cardiac remodeling is more pronounced, indicating that Big ET-1 plays a role in cardiac remodeling in HOCM patients.

Cardiovascular diseases (CVD) are the leading cause of death worldwide, and advanced age is a main contributor to the prevalence of CVD. Cellular senescence is an irreversible state of cell cycle arrest that occurs in old age or after cells encounter various stresses. Senescent cells not only result in the reduction of cellular function, but also produce senescence-associated secretory phenotype (SASP) to affect surrounding cells and tissue microenvironment. There is increasing evidence that the gradual accumulation of senescent cardiomyocytes is causally involved in the decline of cardiovascular system function. To highlight the role of senescent cardiomyocytes in the pathophysiology of age-related CVD, we first introduced that senescent cardiomyoyctes can be identified by structural changes and several senescence-associated biomarkers. We subsequently provided a comprehensive summary of existing knowledge, outlining the compelling evidence on the relationship between senescent cardiomyocytes and age-related CVD phenotypes. In addition, we discussed that the significant therapeutic potential represented by the prevention of accelerated senescent cardiomyocytes, and the current status of some existing geroprotectors in the prevention and treatment of age-related CVD. Together, the review summarized the role of cardiomyocyte senescence in CVD, and explored the molecular knowledge of senescent cardiomyocytes and their potential clinical significance in developing senescent-based therapies, thereby providing important insights into their biology and potential therapeutic exploration.

Emerging studies suggest that various parental exposures affect offspring cardiovascular health, yet the specific mechanisms, particularly the influence of paternal cardiovascular disease (CVD) risk factors on offspring cardiovascular health, remain elusive. The present study explores how paternal hypercholesterolemia affects offspring atherosclerosis development using the LDL receptor-deficient (LDLR-/-) mouse model. We found that paternal high-cholesterol diet feeding led to significantly increased atherosclerosis in F1 female, but not male, LDLR-/- offspring. Transcriptomic analysis highlighted that paternal hypercholesterolemia stimulated proatherogenic genes, including Ccn1 and Ccn2, in the intima of female offspring. Sperm small noncoding RNAs (sncRNAs), particularly transfer RNA-derived (tRNA-derived) small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), contribute to the intergenerational transmission of paternally acquired metabolic phenotypes. Using a newly developed PANDORA-Seq method, we identified that high-cholesterol feeding elicited changes in sperm tsRNA/rsRNA profiles that were undetectable by traditional RNA-Seq, and these altered sperm sncRNAs were potentially key factors mediating paternal hypercholesterolemia-elicited atherogenesis in offspring. Interestingly, high-cholesterol feeding altered sncRNA biogenesis-related gene expression in the epididymis but not testis of LDLR-/- sires; this may have led to the modified sperm sncRNA landscape. Our results underscore the sex-specific intergenerational effect of paternal hypercholesterolemia on offspring cardiovascular health and contribute to the understanding of chronic disease etiology originating from parental exposures.

Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in coronary artery disease (CAD) and diabetes. This study aimed to determine the prognostic value of ET-1 in the patients with stable CAD under different glucose metabolism states.

In this prospective, large-cohort study, we consecutively enrolled 7,947 participants with angiography-diagnosed stable CAD from April 2011 to April 2017. Patients were categorized by baseline glycemic status into three groups (normoglycemia, prediabetes, and diabetes) and further divided into nine groups by circulating ET-1 levels. Patients were followed for the occurrence of cardiovascular events (CVEs), including nonfatal myocardial infarction, stroke, and cardiovascular mortality.

Of the 7,947 subjects, 3,352, 1,653, and 2,942 had normoglycemia, prediabetes, and diabetes, respectively. Over a median follow-up of 37.5 months, 381 (5.1%) CVEs occurred. The risk for CVEs was significantly higher in patients with elevated ET-1 levels after adjustment for potential confounders. When patients were categorized by both status of glucose metabolism and plasma ET-1 levels, the high ET-1 levels were associated with higher risk of CVEs in prediabetes (adjusted hazard ratio [HR], 2.089; 95% confidence interval [CI], 1.151 to 3.793) and diabetes (adjusted HR, 2.729; 95% CI, 1.623 to 4.588; both P<0.05).

The present study indicated that baseline plasma ET-1 levels were associated with the prognosis in prediabetic and diabetic patients with stable CAD, suggesting that ET-1 may be a valuable predictor in CAD patients with impaired glucose metabolism.

Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.

Endothelins and their receptors, ETA and ETB, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ETA antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ETA in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ETA antagonist, respectively. Notably, a specialized anti-ETA antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ETA and ETB, and the agonist BQ3020-bound ETB, in complex with Gq, unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ETA. Furthermore, our results suggest that ECL2 in ETA can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has a protective effect on acute coronary syndrome (ACS). However, most studies have shown that this protective effect is based on a decrease in low-density lipoprotein cholesterol, while other mechanisms remain limited. This study aimed to determine whether PCSK9i can improve the prognosis of ACS patients by protecting endothelial function.

A total of 113 ACS patients were enrolled and randomly assigned to PCSK9i group (PCSK9i combined with statins) and control group (statins only). Blood lipids and endothelial function indicators were measured and analyzed 6 weeks before and after treatment. The effect of PCSK9i on the expression and secretion of endothelial function indicators in vascular endothelial cells were studied by cell experiments.

After 6 weeks of treatment, endothelial function indicators such as nitric oxide (NO), thrombomodulin, intercellular cell adhesion molecule-1, endothelin-1, and flow-mediated vasodilation were significantly improved in PCSK9i group compared with control group. Only the changes of NO and von Willebrand factor were associated with blood lipid levels, whereas the changes of other endothelial function indicators were not significantly associated with blood lipid levels. PCSK9i reduced the incidence of major adverse cardiovascular events in patients with ACS compared to those in the control group. In cell experiments, PCSK9i treatment significantly ameliorated LPS induced endothelial injury in HUVECs.

PCSK9i can protect vascular endothelial function partly independently of its lipid-lowering effect and ameliorate the prognosis of patients with ACS within 6 weeks. This mechanism may involve heat shock transcription factor 1/heat shock proteins -related signaling pathways. Early use of PCSK9i in patients with ACS should be strongly considered in clinical practice.

Idiopathic restrictive cardiomyopathy (RCM) has a low incidence. This study aimed to determine the prognostic value of big endothelin-1 (ET-1) in idiopathic RCM.

We prospectively enrolled patients with idiopathic RCM from 2009 to 2017 and followed them up. The primary outcome was a composite of all-cause mortality and cardiac transplantation, and the secondary outcome was a composite of cardiac death and cardiac transplantation.

Ninety-one patients were divided into the high big ET-1 (>0.85 pmol/L, n = 56) and low big ET-1 (≤0.85 pmol/L, n = 35) groups, and 87 of them completed the follow-up. Big ET-1 concentrations (hazard ratio: 1.756, 95 % confidence interval [CI]: 1.117-2.760) and late gadolinium enhancement (LGE) (hazard ratio: 3.851, 95 % CI: 1.238-11.981) were independent risk factors for the primary outcome. Big ET-1 concentrations (C-statistic estimation: 0.764, 95 % CI: 0.657-0.871) and the combination of LGE and big ET-1 concentrations (C-statistic estimation: 0.870, 95 % CI: 0.769-0.970) could accurately predict the 5-year transplant-free survival rate, and 0.85 pmol/L was a suitable cutoff for big ET-1.

Big ET-1 and its combination with LGE may be useful to predict an adverse prognosis in patients with idiopathic RCM.

Resistant hypertension is characterized by the inability of guideline-recommended triple combination therapy to control blood pressure (BP) to target. It is associated with a significantly increased risk of adverse outcomes. Despite abundant preclinical evidence supporting the critical role of the endothelin pathway in resistant hypertension (RH), clinical implementation of endothelin antagonists for the treatment of hypertension was hindered by various factors. Recently, the novel dual endothelin-receptor antagonist aprocitentan was tested in individuals with resistant hypertension in the PRECISION trial and provided compelling evidence supporting both short and longer-term safety and clinically meaningful and sustained BP lowering efficacy. These findings resulted in the recent regulatory approval of aprocitentan by the FDA. Aprocitentan may be a particularly useful antihypertensive option for individuals with advanced age, chronic kidney disease, and albuminuria.

Hypertension represents one of the primary and most common risk factors leading to the development of heart failure (HF) across the entire spectrum of left ventricular ejection fraction. A large body of evidence has demonstrated that adequate blood pressure (BP) control can reduce cardiovascular events, including the development of HF. Although the pathophysiological and epidemiological role of hypertension in the development of HF is well and largely known, some critical issues still deserve to be clarified, including BP targets, particularly in HF patients. Indeed, the management of hypertension in HF relies on the extrapolation of findings from high-risk hypertensive patients in the general population and not from specifically designed studies in HF populations. In patients with hypertension and HF with reduced ejection fraction (HFrEF), it is recommended to combine drugs with documented outcome benefits and BP-lowering effects. In patients with HF with preserved EF (HFpEF), a therapeutic strategy with all major antihypertensive drug classes is recommended. Besides commonly used antihypertensive drugs, different evidence suggests that other drugs recommended in HF for the beneficial effect on cardiovascular outcomes exert advantageous blood pressure-lowering actions. In this regard, type 2 sodium glucose transporter inhibitors (SGLT2i) have been shown to induce BP-lowering actions that favorably affect cardiac afterload, ventricular arterial coupling, cardiac efficiency, and cardiac reverse remodeling. More recently, it has been demonstrated that finerenone, a non-steroidal mineralocorticoid receptor antagonist, reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF. Other proposed agents, such as endothelin receptor antagonists, have provided contrasting results in the management of hypertension and HF. A novel, promising strategy could be represented by small interfering RNA, whose actions are under investigation in ongoing clinical trials.

The endothelin family of peptides has long been recognized as a physiological regulator of diverse biological functions and mechanistically involved in various disease states, encompassing, among others, the cardiovascular system, the kidney, and the nervous system. Pharmacological blockade of the endothelin system, however, has encountered strong obstacles in its entry into the clinical mainstream, having obtained only a few proven indications until recently. This translational gap has been attributable predominantly to the relevant side effects associated with endothelin receptor antagonism (ERA), particularly fluid retention. Of recent, however, an expanding understanding of the pathophysiological processes involving endothelin, in conjunction with the development of new antagonists of endothelin receptors or adjustment of their doses, has driven a flourish of new clinical trials. The favorable results of some of them have extended the proven indications for ET targeting to a variety of clinical conditions, including resistant arterial hypertension and glomerulopathies. In addition, on the ground of strong preclinical evidence, other studies are ongoing to test the potential benefits of ERA in combination with other treatments, such as sodium-glucose co-transporter 2 inhibition in fluid retentive states or anti-cancer therapies in solid tumors. Furthermore, antibodies providing long-term blockade of endothelin receptors are under testing to overcome the short half-life of most small molecule endothelin antagonists. These efforts may yet bring new life to the translation of endothelin targeting strategies in clinical practice.

The retinal microcirculation system constitutes a unique terminal vessel bed of the systemic circulation, and its perfusion status is directly associated with the neural function of the retina. This vascular network, essential for nourishing various layers of the retina, comprises two primary microcirculation systems: the retinal microcirculation and the choroidal microcirculation, with each system supplying blood to distinct retinal layers and maintaining the associated neural function. The blood flow of those capillaries is regulated via different mechanisms. However, a range of internal and external factors can disrupt the normal architecture and blood flow within the retinal microcirculation, leading to several retinal pathologies, including diabetic retinopathy, macular edema, and vascular occlusions. Metabolic disturbances such as hyperglycemia, hypertension, and dyslipidemia are known to modify retinal microcirculation through various pathways. These alterations are observable in chronic metabolic conditions like diabetes, coronary artery disease, and cerebral microvascular disease due to advances in non-invasive or minimally invasive retinal imaging techniques. Thus, examination of the retinal microcirculation can provide insights into the progression of numerous chronic metabolic disorders. This review discusses the anatomy, physiology and pathophysiology of the retinal microvascular system, with a particular emphasis on the connections between retinal microcirculation and systemic circulation in both healthy states and in the context of prevalent chronic metabolic diseases.

To define resistant hypertension (RHT), review its pathophysiology and disease burden, identify barriers to effective hypertension management, and to highlight emerging treatment options.

RHT is defined as uncontrolled blood pressure (BP) ≥ 130/80 mm Hg despite concurrent prescription of ≥ 3 or ≥ 4 antihypertensive drugs in different classes or controlled BP despite prescription of  ≥ to 4 drugs, at maximally tolerated doses, including a diuretic. BP is regulated by a complex interplay between the renin-angiotensin-aldosterone system, the sympathetic nervous system, the endothelin system, natriuretic peptides, the arterial vasculature, and the immune system; disruption of any of these can increase BP. RHT is disproportionately manifest in African Americans, older patients, and those with diabetes and/or chronic kidney disease (CKD). Amongst drug-treated hypertensives, only one-quarter have been treated intensively enough (prescribed > 2 drugs) to be considered for this diagnosis. New treatment strategies aimed at novel therapeutic targets include inhibition of sodium-glucose cotransporter 2, aminopeptidase A, aldosterone synthesis, phosphodiesterase 5, xanthine oxidase, and dopamine beta-hydroxylase, as well as soluble guanylate cyclase stimulation, nonsteroidal mineralocorticoid receptor antagonism, and dual endothelin receptor antagonism. The burden of RHT remains high. Better use of currently approved therapies and integrating emerging therapies are welcome additions to the therapeutic armamentarium for addressing needs in high-risk aTRH patients.

ET (endothelin) is a powerful vasoconstrictor 21-amino acid peptide present in many tissues, which exerts many physiological functions across the body and participates as a mediator in many pathological conditions. ETs exert their effects through ETA and ETB receptors, which can be blocked by selective receptor antagonists. ETs were shown to play important roles among others, in systemic hypertension, particularly when resistant or difficult to control, and in pulmonary hypertension, atherosclerosis, cardiac hypertrophy, subarachnoid hemorrhage, chronic kidney disease, diabetic cardiovascular disease, scleroderma, some cancers, etc. To date, ET antagonists are only approved for the treatment of primary pulmonary hypertension and recently for IgA nephropathy and used in the treatment of digital ulcers in scleroderma. However, they may soon be approved for the treatment of patients with resistant hypertension and different types of nephropathy. Here, the role of ETs is reviewed with a special emphasis on participation in and treatment of hypertension and chronic kidney disease.

Chronic kidney disease (CKD) is one of the major causes of morbidity and mortality, affecting >800 million persons globally. While we still lack efficient, targeted therapies addressing the major underlying pathophysiologic processes in CKD, findings of several recent trials have brought about a shifting landscape of promising therapies. The endothelin system has been implicated in the pathophysiology of CKD and endothelin receptor antagonists are one class of drugs for which we have increasing evidence of efficacy in these patients. In this review we summarize the most recent findings on the safety and efficacy of endothelin receptor antagonists in diabetic and non-diabetic CKD, future directions of research and upcoming treatments.

This study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effects (FE) of SC0062, a highly active endothelin-A (ETA ) receptor antagonist, in healthy subjects. The primary objectives of this first-in-human phase I study, comprised of single-ascending-dose, multiple-ascending-dose, and FE parts, were to characterize the safety and tolerability of SC0062, and FE. The secondary objectives were to determine the PK behavior of SC0062 and its major active metabolite M18, whereas exploratory objectives focused on PD effects, principally effects on endothelin-1 (ET-1) and total bile acids (TBA). Single doses of 10 to 100 mg and multiple daily doses of 20 and 50 mg for 6 days were well tolerated. SC0062 was rapidly absorbed and plasma exposure of SC0062 and M18 increased disproportionately with dose, achieving steady state by day 3, with accumulation ratios of 1.22 and 1.89 on day 6 for SC0062 and M18, respectively. The geometric mean (geometric standard deviation) terminal elimination half-life (t1/2 ) values of SC0062 and M18 were 7.25 (1.70) h and 13.73 (1.32) h, respectively. Plasma ET-1 concentrations were dose-proportional, whereas plasma TBA concentrations behaved erratically. Following a single 50 mg dose of SC0062 after a high-fat meal, Cmax values for SC0062 and M18 increased by 41% and 32%, respectively, and median Tmax values for SC0062 were 3 h longer than fasting values; exposure was unaffected. These favorable safety, PK, and PD results provide a foundation for further studies of SC0062 in pulmonary arterial hypertension, chronic kidney disease, and other relevant indications.

Systemic sclerosis (SSc) is a multifaceted connective tissue disease whose aetiology remains largely unknown. Autoimmunity is thought to play a pivotal role in the development of the disease, but the direct pathogenic role of SSc-specific autoantibodies remains to be established. The recent discovery of functional antibodies targeting G-protein-coupled receptors (GPCRs), whose presence has been demonstrated in different autoimmune conditions, has shed some light on SSc pathogenesis. These antibodies bind to GPCRs expressed on immune and non-immune cells as their endogenous ligands, exerting either a stimulatory or inhibitory effect on corresponding intracellular pathways. Growing evidence suggests that, in SSc, the presence of anti-GPCRs antibodies correlates with specific clinical manifestations. Autoantibodies targeting endothelin receptor type A (ETAR) and angiotensin type 1 receptor (AT1R) are associated with severe vasculopathic SSc-related manifestations, while anti-C-X-C motif chemokine receptors (CXCR) antibodies seem to be predictive of interstitial lung involvement; anti-muscarinic-3 acetylcholine receptor (M3R) antibodies have been found in patients with severe gastrointestinal involvement and anti-protease-activated receptor 1 (PAR1) antibodies have been detected in patients experiencing scleroderma renal crisis. This review aims to clarify the potential pathogenetic significance of GPCR-targeting autoantibodies in SSc, focusing on their associations with the different clinical manifestations of scleroderma. An extensive examination of functional autoimmunity targeting GPCRs might provide valuable insights into the underlying pathogenetic mechanisms of SSc, thus enabling the development of novel therapeutic strategies tailored to target GPCR-mediated pathways.

Endothelin receptor B (ETB) together with ETA mediates cellular effects of endothelin 1 (ET-1), an autocrine and endocrine peptide produced by the endothelium and other cells. It regulates vascular tone and controls kidney function. Metabolic syndrome is due to high caloric intake and is characterized by insulin resistance, dyslipidemia, and white adipose tissue (WAT) accumulation. ETA/ETB antagonism has been demonstrated to favorably influence insulin resistance. Our study explored the role of ETB in metabolic syndrome.

Wild type (etb+/+) and rescued ETB-deficient (etb-/-) mice were fed a high-fat diet, and energy, glucose, and insulin metabolism were analyzed, and hormones and lipids measured in serum and tissues. Cell culture experiments were performed in HepG2 cells.

Compared to etb+/+ mice, etb-/- mice exhibited better glucose tolerance and insulin sensitivity, less WAT accumulation, lower serum triglycerides, and higher energy expenditure. Protection from metabolic syndrome was paralleled by higher hepatic production of fibroblast growth factor 21 (FGF21) and higher serum levels of free thyroxine (fT4), stimulators of energy expenditure.

ETB deficiency confers protection from metabolic syndrome by counteracting glucose intolerance, dyslipidemia, and WAT accumulation due to enhanced energy expenditure, effects at least in part dependent on enhanced production of thyroid hormone/FGF21. ETB antagonism may therefore be a novel therapeutic approach in metabolic syndrome.

Myocardial infarction (MI) is one of the leading causes of death in the developed world, and the loss of cardiomyocytes plays a critical role in the pathogenesis of heart failure. Implicated in this process is a decrease in gap junction intercellular communication due to remodeling of Connexin43 (Cx43). We previously identified that intraperitoneal injection of the Pyk2 inhibitor PF4618433 reduced infarct size, maintained Cx43 at the intercalated disc in left ventricle hypertrophic myocytes, and improved cardiac function in an MI animal model of heart failure. With the emergence of injectable hydrogels as a therapeutic toward the regeneration of cardiac tissue after MI, here, we provide proof of concept that the release of tyrosine kinase inhibitors from hydrogels could have beneficial effects on cardiomyocytes. We developed an injectable hydrogel consisting of thiolated hyaluronic acid and P123-maleimide micelles that can incorporate PF4618433 as well as the Src inhibitor Saracatinib and achieved sustained release (of note, Src activates Pyk2). Using neonatal rat ventricular myocytes in the presence of a phorbol ester, endothelin-1, or phenylephrine to stimulate cardiac hypertrophy, the release of PF4618433 from the hydrogel had the same ability to decrease Cx43 tyrosine phosphorylation and maintain Cx43 localization at the plasma membrane as when directly added to the growth media. Additional beneficial effects included decreases in apoptosis, the hypertrophic marker atrial natriuretic peptide (ANP), and serine kinases upregulated in hypertrophy. Finally, the presence of both PF4618433 and Saracatinib further decreased the level of ANP and apoptosis than each inhibitor alone, suggesting that a combinatorial approach may be most beneficial. These findings provide the groundwork to test if tyrosine kinase inhibitor release from hydrogels will have a beneficial effect in an animal model of MI-induced heart failure.

Myocardial remodeling, which occurs in the final stage of cardiovascular diseases such as hypertension, can ultimately result in heart failure. However, the pathogenesis of myocardial remodeling remains incompletely understood, and there is currently a lack of safe and effective treatment options. Salidroside, which is extracted from the plant Rhodiola rosea, shows remarkable antioxidant and anti-inflammatory characteristics. The purpose of this investigation was to examine the cardioprotective effect of salidroside on myocardial remodeling, and clarify the associated mechanism. Salidroside effectively attenuated cardiac dysfunction, myocardial hypertrophy, myocardial fibrosis, and cardiac inflammation, as well as renal injury and renal fibrosis in an animal model of deoxycortone acetate (DOCA)-salt-induced myocardial remodeling. The cardioprotective effect of salidroside was mediated by inhibiting the endothelin 1 and PI3K/AKT/NFκB signaling pathways. Salidroside was shown to inhibit the expression of endothelin1 in the hearts of mice treated with DOCA-salt. Additionally, it could prevent cardiomyocyte hypertrophy induced by endothelin-1 stimulation. Furthermore, Salidroside could effectively inhibit the excessive activation of the PI3K/AKT/NFκB pathway, which was caused by DOCA-salt treatment in mouse hearts and endothelin 1 stimulation in cardiomyocytes. Our study suggests that salidroside can be used as a therapeutic agent for the treatment of myocardial remodeling.

Current cardiac biomarkers, troponins and brain natriuretic peptide, are primarily used to assist in the diagnosis or exclusion of myocardial damage and congestive heart failure, respectively. The use of these biomarkers in chemotherapy-induced cardiotoxicity has been evaluated by various studies. However, neither biomarker provides early predictive value, leaving many cancer survivors with irreversible cardiac injury. Assessing endothelial dysfunction could be an effective measure of chemotherapy-induced cardiotoxicity at the vascular level. Risk profiling and detection of vascular toxicities may offer predictive biomarkers to prevent chronic manifestation of irreversible cardiotoxicities. Emerging interest has developed in finding biomarkers that could ideally provide earlier prognostic value. Thus, the aim of this review is to give an overview of current blood-based cardiac biomarkers and discuss the potential of endothelin-1 (ET-1) and more stable peptide fragments of ET-1 synthesis as biomarkers of endothelial dysfunction. For instance, endothelin-like domain peptide (ELDP) and C-terminal pro-endothelin-1 (CT-proET-1) demonstrated high-sensitivity and longer clearance rate than ET-1. Thus, investigating their biomarker role in chemotherapy-induced cardiotoxicity is important and could provide additional insights for identifying patients at risk. Also, additional research is required to fully understand ELDP-mediated vasoconstriction. This review will discuss the future development of ET-1, ELDP and CT-proET-1 as prospective predictive biomarkers.

Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases. From the research history and milestone events related to hypoxia in cardiovascular development and diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal and spatial perspectives, encompassing the occurrence and progression of hypoxia (gradual decline in oxygen concentration), the acute and chronic manifestations of hypoxia, and the geographical characteristics of hypoxia (natural selection at high altitudes). Furthermore, hypoxia signaling pathways are associated with natural rhythms, such as diurnal and hibernation processes. In addition to innate factors and natural selection, it has been found that epigenetics, as a postnatal factor, profoundly influences the hypoxic response and progression within the cardiovascular system. Within this intricate process, interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established. Thus, it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research, including FDA-approved drugs and ongoing clinical trials, to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.

The first endothelin (ET)-1 receptor antagonist was approved for clinical use over 20 years ago, but to date this class of compounds has been limited to treating pulmonary arterial hypertension, a rare disease. Translational research over the last 5 years has reignited interest in the ET system as a therapeutic target across the spectrum of cardiovascular diseases including resistant hypertension, microvascular angina and post-coronavirus disease 2019 conditions. Notable developments include approval of a new ETA receptor antagonist and, intriguingly, combining the actions of ETA and an angiotensin II type 1 receptor antagonist within the same novel small molecule. Combinations of ET receptor blockers with other drugs, including phosphodiesterase-5 inhibitors and sodium-glucose co-transporter-2 antagonists, may drive synergistic benefits with the prospect of alleviating side effects. These new therapeutic strategies have the potential to dramatically widen the scope of indications targeting the ET-1 pathway.