Vascular Pharmacology[JOURNAL]
Sun
200 papers
Exploring bradykinin: A common mediator in the pathophysiology of sepsis and atherosclerotic cardiovascular disease.
Siti-Zubaidah MZ, Harafinova HS, Liba AN … +3 more , Nordin ML, Hambali KA, Siti HN
Vascul Pharmacol · 2024 Sep · PMID 39089528 · Publisher ↗
Sepsis and atherosclerotic cardiovascular disease (ASCVD) are major health challenges involving complex processes like inflammation, renin-angiotensin system (RAS) dysregulation, and thrombosis. Despite distinct clinical...
Sepsis and atherosclerotic cardiovascular disease (ASCVD) are major health challenges involving complex processes like inflammation, renin-angiotensin system (RAS) dysregulation, and thrombosis. Despite distinct clinical symptoms, both conditions share mechanisms mediated by bradykinin. This review explores bradykinin's role in inflammation, RAS modulation, and thrombosis in sepsis and ASCVD. In sepsis, variable kininogen-bradykinin levels may correlate with disease severity and progression, though the effect of bradykinin receptor modulation on inflammation remains uncertain. RAS activation is present in both diseases, with sepsis showing variable or low levels of Ang II, ACE, and ACE2, while ASCVD consistently exhibits elevated levels. Bradykinin may act as a mediator for ACE2 and AT2 receptor effects in RAS regulation. It may influence clotting and fibrinolysis in sepsis-associated coagulopathy, but evidence for an antithrombotic effect in ASCVD is insufficient. Understanding bradykinin's role in these shared pathologies could guide therapeutic and monitoring strategies and inform future research.
Novel therapeutic targets for reperfusion injury in ischemic stroke: Understanding the role of mitochondria, excitotoxicity and ferroptosis.
Awasthi VA, Dhankar V, Singh S
Vascul Pharmacol · 2024 Sep · PMID 39059676 · Publisher ↗
Ischemic reperfusion injury (IRI) remains a significant challenge in various clinical settings, including stroke. Despite advances in reperfusion strategies, the restoration of blood flow to ischemic tissues often exacer...
Ischemic reperfusion injury (IRI) remains a significant challenge in various clinical settings, including stroke. Despite advances in reperfusion strategies, the restoration of blood flow to ischemic tissues often exacerbates tissue damage through a complex cascade of cellular and molecular events. In recent years, there has been growing interest in identifying novel therapeutic targets to ameliorate the detrimental effects of IRI and improve patient outcomes. This review critically evaluates emerging therapeutic targets and strategies for IRI management, such as R-spondin 3, neurolysin, glial cell gene therapy and inter alpha inhibitors. Diverse pathophysiology involved in IRI stroke such as oxidative stress, inflammation, mitochondrial dysfunction, and ferroptosis are also closely discussed. Additionally, we explored the intricate interplay between inflammation and IRI, focusing on cell-mediated gene therapy approaches and anti-inflammatory agents that hold promise for attenuating tissue damage. Moreover, we delve into novel strategies aimed at preserving endothelial function, promoting tissue repair, and enhancing cellular resilience to ischemic insults. Finally, we discuss challenges, future directions, and translational opportunities for the development of effective therapies targeting ischemic reperfusion injury.
Cardiac biogenic amine profile and its relationship with parameters of cardiovascular disease in obesity.
Belin MAF, Vieira TA, Grandini NA … +12 more , Siqueira JS, Palacio TLN, Cruzeiro J, Sormani LE, Tanganini MD, Barbosa GS, Gregolin CS, de Campos DHS, Bazan SGZ, Minatel IO, Lima GPP, Correa CR
Vascul Pharmacol · 2024 Sep · PMID 39033868 · Publisher ↗
AIMS: To identify the cardiac biogenic amine profile of obese rats and associate these compounds with parameters of cardiovascular disease. MAIN METHODS: Wistar rats (n = 20) were randomly distributed into two groups: co...
AIMS: To identify the cardiac biogenic amine profile of obese rats and associate these compounds with parameters of cardiovascular disease. MAIN METHODS: Wistar rats (n = 20) were randomly distributed into two groups: control and obese. Obesity was induced by a high-sugar fat diet. Biochemical parameters were evaluated. Doppler Echocardiography and systolic blood pressure; interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), protein carbonylation, ferric reducing antioxidant power (FRAP), and catalase activity were measured in cardiac tissue. HPLC evaluated the cardiac biogenic profile. Data were compared using the Student's T or Mann-Whitney tests and Spearman's correlation at 5% significance. The principal component analysis (PCA) was performed. KEY FINDINGS: Obesity generated hypertension, cardiac remodeling and dysfunction, and imbalanced all biochemical, inflammatory, and oxidative markers (p < 0.001). Eight biogenic amines were found in cardiac tissue. Obesity increased serotonin and decreased agmatine, putrescine, cadaverine, and spermidine. Serotonin (r = 0.534 to 0.808) was strong and positively correlated with obesity, biochemical parameters, cardiac inflammation, oxidative stress, hypertension, cardiac remodeling, and dysfunction (p < 0.001). Spermidine (r = -0.560 to -0.680), putrescine (r = -0.532 to -0.805), cadaverine (r = -0.534 to -0.860), and agmatine (r = -0.579 to -0.884) were inversely correlated with the same parameters (p < 0.001). PCA allowed for distinguishing the control and obese groups. SIGNIFICANCE: There are strong correlations between cardiac biogenic amine levels, cardiac remodeling, and dysfunction resulting from obesity. CONCLUSION: There is an association between cardiac biogenic amines and cardiovascular disease in obesity. In addition, agmatine, putrescine, cadaverine, and, mainly, serotonin may be new biomarkers for cardiovascular health in obesity and help to improve the diagnosis and treatment of CVD resulting or not from obesity. However, more research is needed to support this conclusion.
Antithrombotic properties of Tafamidis: An additional protective effect for transthyretin amyloid cardiomyopathy patients.
Ministrini S, Niederberger R, Akhmedov A … +13 more , Beer G, Puspitasari YM, Franzini M, Vergaro G, Cannie DE, Elliott P, Kahr PC, Hock C, Kobza R, Toggweiler S, Lüscher TF, Camici GG, Stämpfli SF
Vascul Pharmacol · 2024 Sep · PMID 39029855 · Publisher ↗
INTRODUCTION: Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortali...
INTRODUCTION: Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect. METHODS: Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction. RESULTS: Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF. CONCLUSIONS: Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis.
Sodium nitroprusside infusion in patients with advanced heart failure.
Ghio S, Traversi E, Maestri R … +8 more , Camporotondo R, Caporotondi A, Caprino A, Fasolino A, Guazzotti G, Scelsi L, Turco A, La Rovere MT
Vascul Pharmacol · 2024 Sep · PMID 38964495 · Publisher ↗
AIMS: Advanced heart failure (AdvHF) poses significant treatment challenges, particularly when mechanical circulatory support or transplant options are unavailable, highlighting a gap in evidence-based medical management...
AIMS: Advanced heart failure (AdvHF) poses significant treatment challenges, particularly when mechanical circulatory support or transplant options are unavailable, highlighting a gap in evidence-based medical management. The aim of this study was to evaluate the safety and effectiveness of sodium nitroprusside infusion (SNP) for enhancing systemic and renal perfusion in patients with AdvHF, with or without concomitant inotropic support. METHODS AND RESULTS: We retrospectively analyzed the medical records of 406 patients with AdvHF admitted between October 2014 and September 2018 who received nocturnal SNP infusions for at least one week. In 55 patients with symptomatic hypotension or signs of peripheral hypoperfusion (differential systemic BP < 15 mmHg), continuous dobutamine infusion was added. In a subset of 155 patients who required multiple hospitalizations (median 3), data from the last hospitalization were used. No symptomatic hypotension leading to discontinuation of SNP (mean dose: 0.5 ± 0.1 μg/kg/min) was reported. Patients showed a significant increase in differential systemic blood pressure after infusion (29.2 ± 8.1 to 36.8 ± 11.6 mmHg, p < 0.001) independent of dobutamine use. Administration of SNP and dobutamine resulted in greater weight loss compared to SNP alone (-5.33 ± 7.02 vs -3.32 ± 4.0 kg, p < 0.003), but it was also associated with a significant increase in creatinine levels compared to SNP alone (+0.24 ± 0.87 vs +0.02 ± 0.43, p = 0.005). CONCLUSIONS: The results show that SNP is a safe therapeutic choice in AdvHF patients with or without concomitant inotropic support and highlight the potential efficacy of nitroprusside in improving systemic and renal perfusion in these advanced patients.
Zinc alpha 2-glycoprotein associates with features of plaque stability in patients with carotid atherosclerosis.
Tirandi A, Carbone F, Bonaventura A … +6 more , Bertolotto M, Minetti S, Kraler S, Camici GG, Montecucco F, Liberale L
Vascul Pharmacol · 2024 Sep · PMID 38901808 · Publisher ↗
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Fluorinated perhexiline derivative attenuates vascular proliferation in pulmonary arterial hypertension smooth muscle cells.
Griffiths K, Grand RJ, Horan I … +9 more , Certo M, Keeler RC, Mauro C, Tseng CC, Greig I, Morrell NW, Zanda M, Frenneaux MP, Madhani M
Vascul Pharmacol · 2024 Sep · PMID 38901807 · Publisher ↗
Increased proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs) is recognised as a universal hallmark of pulmonary arterial hypertension (PAH), in part related to the association with reduc...
Increased proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs) is recognised as a universal hallmark of pulmonary arterial hypertension (PAH), in part related to the association with reduced pyruvate dehydrogenase (PDH) activity, resulting in decreased oxidative phosphorylation of glucose and increased aerobic glycolysis (Warburg effect). Perhexiline is a well-recognised carnitine palmitoyltransferase-1 (CPT1) inhibitor used in cardiac diseases, which reciprocally increases PDH activity, but is associated with variable pharmacokinetics related to polymorphic variation of the cytochrome P450-2D6 (CYP2D6) enzyme, resulting in the risk of neuro and hepatotoxicity in 'slow metabolisers' unless blood levels are monitored and dose adjusted. We have previously reported that a novel perhexiline fluorinated derivative (FPER-1) has the same therapeutic profile as perhexiline but is not metabolised by CYP2D6, resulting in more predictable pharmacokinetics than the parent drug. We sought to investigate the effects of perhexiline and FPER-1 on PDH flux in PASMCs from patients with PAH. We first confirmed that PAH PASMCs exhibited increased cell proliferation, enhanced phosphorylation of AKT, ERK 1/2 and PDH-E1α, indicating a Warburg effect when compared to healthy PASMCs. Pre-treatment with perhexiline or FPER-1 significantly attenuated PAH PASMC proliferation in a concentration-dependent manner and suppressed the activation of the AKT but had no effect on the ERK pathway. Perhexiline and FPER-1 markedly activated PDH (seen as dephosphorylation of PDH-E1α), reduced glycolysis, and upregulated mitochondrial respiration in these PAH PASMCs as detected by Seahorse analysis. However, both perhexiline and FPER-1 did not induce apoptosis as measured by caspase 3/7 activity. We show for the first time that both perhexiline and FPER-1 may represent therapeutic agents for reducing cell proliferation in human PAH PASMCs, by reversing Warburg physiology.
Ex vivo study on the human blood neutrophil circadian features and effects of alpha1-antitrypsin and lipopolysaccharide.
Held J, Sivaraman K, Wrenger S … +4 more , Si W, Welte T, Immenschuh S, Janciauskiene S
Vascul Pharmacol · 2024 Sep · PMID 38897556 · Publisher ↗
AIMS: Neutrophils perform various functions in a circadian-dependent manner; therefore, we investigated here whether the effect of alpha1-antitrypsin (AAT), used as augmentation therapy, is dependent on the neutrophil ci...
AIMS: Neutrophils perform various functions in a circadian-dependent manner; therefore, we investigated here whether the effect of alpha1-antitrypsin (AAT), used as augmentation therapy, is dependent on the neutrophil circadian clock. AAT is a vital regulator of neutrophil functions, and its qualitative and/or quantitative defects have significant implications for the development of respiratory diseases. METHODS: Whole blood from 12 healthy women age years, mean (SD) 29.92 (5.48) was collected twice daily, 8 h apart, and incubated for 30 min at 37 °C alone or with additions of 2 mg/ml AAT (Respreeza) and/or 5 μg/ml lipopolysaccharide (LPS) from Escherichia coli. Neutrophils were then isolated to examine gene expression, migration and phagocytosis. RESULTS: The expression of CD14, CD16, CXCR2 and SELL (encoding CD62L) genes was significantly higher while CDKN1A lower in the afternoon than in the morning neutrophils from untreated blood. Neutrophils isolated in the afternoon had higher migratory and phagocytic activity. Morning neutrophils isolated from AAT-pretreated blood showed higher expression of CXCR2 and SELL than those from untreated morning blood. Pretreatment of blood with AAT enhanced migratory properties of morning but not afternoon neutrophils. Of all genes analysed, only CXCL8 expression was strongly upregulated in morning and afternoon neutrophils isolated from LPS-pretreated blood, whereas CXCR2 expression was downregulated in afternoon neutrophils. The addition of AAT did not reverse the effects of LPS. SIGNIFICANCE: The circadian clock of myeloid cells may affect the effectiveness of various therapies, including AAT therapy used to treat patients with AAT deficiency, and needs further investigation.
Novel NLRP3 inhibitor INF195: Low doses provide effective protection against myocardial ischemia/reperfusion injury.
Gastaldi S, Giordano M, Blua F … +12 more , Rubeo C, Boscaro V, Femminò S, Comità S, Gianquinto E, Landolfi V, Marini E, Gallicchio M, Spyrakis F, Pagliaro P, Bertinaria M, Penna C
Vascul Pharmacol · 2024 Sep · PMID 38897555 · Publisher ↗
BACKGROUND: Several factors contribute to ischemia/reperfusion injury (IRI), including activation of the NLRP3 inflammasome and its byproducts, such as interleukin-1β (IL-1β) and caspase-1. However, NLRP3 may paradoxical...
BACKGROUND: Several factors contribute to ischemia/reperfusion injury (IRI), including activation of the NLRP3 inflammasome and its byproducts, such as interleukin-1β (IL-1β) and caspase-1. However, NLRP3 may paradoxically exhibit cardioprotective properties. This study aimed to assess the protective effects of the novel NLRP3 inhibitor, INF195, both in vitro and ex vivo. METHODS: To investigate the relationship between NLRP3 and myocardial IRI, we synthetized a series of novel NLRP3 inhibitors, and investigated their putative binding mode via docking studies. Through in vitro studies we identified INF195 as optimal for NLRP3 inhibition. We measured infarct-size in isolated mouse hearts subjected to 30-min global ischemia/one-hour reperfusion in the presence of three different doses of INF195 (5, 10, or 20-μM). We analyzed caspase-1 and IL-1β concentration in cardiac tissue homogenates by ELISA. Statistical significance was determined using one-way ANOVA followed by Tukey's test. RESULTS AND CONCLUSION: INF195 reduces NLRP3-induced pyroptosis in human macrophages. Heart pre-treatment with 5 and 10-μM INF195 significantly reduces both infarct size and IL-1β levels. Data suggest that intracardiac NLRP3 activation contributes to IRI and that low doses of INF195 exert cardioprotective effects by reducing infarct size. However, at 20-μM, INF195 efficacy declines, leading to a lack of cardioprotection. Research is required to determine if high doses of INF195 have off-target effects or dual roles, potentially eliminating both harmful and cardioprotective functions of NLRP3. Our findings highlight the potential of a new chemical scaffold, amenable to further optimization, to provide NLRP3 inhibition and cardioprotection in the ischemia/reperfusion setting.
Plasma proteins associate with carotid plaques and predict incident atherosclerotic cardiovascular events.
Baragetti A, Grigore L, Olmastroni E … +2 more , Mattavelli E, Catapano AL
Vascul Pharmacol · 2024 Sep · PMID 38866119 · Publisher ↗
PURPOSE: Performing non-invasive carotid imaging is challenging, owing inter-operator variability and organizational barriers, but plasma proteomics can offer an alternative. We sought plasma proteins that associate with...
PURPOSE: Performing non-invasive carotid imaging is challenging, owing inter-operator variability and organizational barriers, but plasma proteomics can offer an alternative. We sought plasma proteins that associate with the presence of carotid plaques, their number and predict the incidence of clinically overt atherosclerotic cardiovascular events (ASCVD) above currently recognized risk factors in "apparently healthy" subjects. METHODS: We studied the plasma levels of 368 proteins in 664 subjects from the PLIC study, who underwent an ultrasound imaging screening of the carotids to check for the presence of plaques. We clustered, by artificial intelligence (A.I.), the proteins that associate with the presence, the number of plaques and that predict incident ASCVDs over 22 years (198 events were registered). FINDINGS: 299/664 subjects had at least 1 carotid plaque (1+) (77 with only one plaque, 101 with 2 plaques, 121 with ≥3 plaques (3+)). The remaining 365 subjects with no plaques acted as controls. 106 proteins were associated with 1+ plaques, but 97 proteins significantly predicted 3+ plaques only (AUC = 0.683 (0.601-0.785), p < 0.001), when considered alone. A.I. underscored 87 proteins that improved the performance of the classical risk factors both in detecting 3+ plaques (AUC = 0.918 (0.887-0.943) versus risk factors alone, AUC = 0.760 (0.716-0.801), p < 0.001) and in predicting the incident ASCVD (AUC = 0.739 (0.704-0.773) vs risk factors alone AUC = 0.559 (0.521-0.598), p < 0.001). The chemotaxis/migration of leukocytes and interleukins/cytokines signaling were biological pathways mostly represented by these proteins. DISCUSSION AND CONCLUSIONS: Plasma proteomics marks the number of carotid plaques and improve the prediction of incidence ASCVDs in apparently healthy subjects.
The life cycle of a capillary: Mechanisms of angiogenesis and rarefaction in microvascular physiology and pathologies.
Manning D, Rivera EJ, Santana LF
Vascul Pharmacol · 2024 Sep · PMID 38857638 · Full text
Capillaries are the smallest blood vessels (<10 μm in diameter) in the body and their walls are lined by endothelial cells. These microvessels play a crucial role in nutrient and gas exchange between blood and tissues. C...
Capillaries are the smallest blood vessels (<10 μm in diameter) in the body and their walls are lined by endothelial cells. These microvessels play a crucial role in nutrient and gas exchange between blood and tissues. Capillary endothelial cells also produce vasoactive molecules and initiate the electrical signals that underlie functional hyperemia and neurovascular coupling. Accordingly, capillary function and density are critical for all cell types to match blood flow to cellular activity. This begins with the process of angiogenesis, when new capillary blood vessels emerge from pre-existing vessels, and ends with rarefaction, the loss of these microvascular structures. This review explores the mechanisms behind these processes, emphasizing their roles in various microvascular diseases and their impact on surrounding cells in health and disease. We discuss recent work on the mechanisms controlling endothelial cell proliferation, migration, and tube formation that underlie angiogenesis under physiological and pathological conditions. The mechanisms underlying functional and anatomical rarefaction and the role of pericytes in this process are also discussed. Based on this work, a model is proposed in which the balance of angiogenic and rarefaction signaling pathways in a particular tissue match microvascular density to the metabolic demands of the surrounding cells. This negative feedback loop becomes disrupted during microvascular rarefaction: angiogenic mechanisms are blunted, reactive oxygen species accumulate, capillary function declines and eventually, capillaries disappear. This, we propose, forms the foundation of the reciprocal relationship between vascular density, blood flow, and metabolic needs and functionality of nearby cells.
Myocardin related transcription factor and galectin-3 drive lipid accumulation in human blood vessels.
Arévalo-Martinez M, Ede J, van der Have O … +6 more , Ritsvall O, Zetterberg FR, Nilsson UJ, Leffler H, Holmberg J, Albinsson S
Vascul Pharmacol · 2024 Sep · PMID 38830455 · Publisher ↗
OBJECTIVE: Diabetes and hypertension are important risk factors for vascular disease, including atherosclerosis. A driving factor in this process is lipid accumulation in smooth muscle cells of the vascular wall. The glu...
OBJECTIVE: Diabetes and hypertension are important risk factors for vascular disease, including atherosclerosis. A driving factor in this process is lipid accumulation in smooth muscle cells of the vascular wall. The glucose- and mechano-sensitive transcriptional coactivator, myocardin-related transcription factor A (MRTF-A/MKL1) can promote lipid accumulation in cultured human smooth muscle cells and contribute to the formation of smooth muscle-derived foam cells. The purpose of this study was to determine if intact human blood vessels ex vivo can be used to evaluate lipid accumulation in the vascular wall, and if this process is dependent on MRTF and/or galectin-3/LGALS3. Galectin-3 is an early marker of smooth muscle transdifferentiation and a potential mediator for foam cell formation and atherosclerosis. APPROACH AND RESULTS: Human mammary arteries and saphenous veins were exposed to altered cholesterol and glucose levels in an organ culture model. Accumulation of lipids, quantified by Oil Red O, was increased by cholesterol loading and elevated glucose concentrations. Pharmacological inhibition of MRTF with CCG-203971 decreased lipid accumulation, whereas adenoviral-mediated overexpression of MRTF-A had the opposite effect. Cholesterol-induced expression of galectin-3 was decreased after inhibition of MRTF. Importantly, pharmacological inhibition of galectin-3 with GB1107 reduced lipid accumulation in the vascular wall after cholesterol loading. CONCLUSION: Ex vivo organ culture of human arteries and veins can be used to evaluate lipid accumulation in the intact vascular wall, as well as adenoviral transduction and pharmacological inhibition. Although MRTF and galectin-3 may have beneficial, anti-inflammatory effects under certain circumstances, our results, which demonstrate a significant decrease in lipid accumulation, support further evaluation of MRTF- and galectin-3-inhibitors for therapeutic intervention against atherosclerotic vascular disease.
Use of lipid-lowering drugs in restricted health access settings: Results from the Trends in Drug Utilization During COVID-19 Pandemic in Turkey (PANDUTI-TR) study.
Vizdiklar C, Aydin V, Tazegul G … +2 more , Kaskal M, Akici A
Vascul Pharmacol · 2024 Sep · PMID 38815702 · Publisher ↗
BACKGROUND: COVID-19 restrictions prompted changes in chronic disease management and lifestyle modifications, potentially altering cardiometabolic indicators and lipid-lowering pharmacotherapy patterns. We aimed to asses...
BACKGROUND: COVID-19 restrictions prompted changes in chronic disease management and lifestyle modifications, potentially altering cardiometabolic indicators and lipid-lowering pharmacotherapy patterns. We aimed to assess lipid-lowering drug (LLD) utilization trends during COVID-19 restrictions. METHODS: We obtained nationwide outpatient drug sales and prescribing data for 01.03.2018-31.12.2022 from IQVIA™ Turkey. We evaluated average monthly LLD consumption, their costs, and quarterly prescribing levels in three periods: "before restrictions" (BfR, 01.03.2018-31.03.2020), "during restrictions" (DuR, 01.04.2020-31.03.2022), and "after restrictions" (AfR, 01.04.2022-31.12.2022). Drug utilization was measured via "defined daily dose/1000 inhabitants/day" (DID) metric. RESULTS: LLD utilization increased from 25.4 ± 3.1 DID in BfR to 36.2 ± 6.8 DID in DuR (p < 0.001), and to 42.6 ± 5.3 DID in AfR (p < 0.001 vs. BfR). Statin consumption significantly rose from 22.0 ± 3.0 DID in BfR to 31.6 ± 6.3 DID in DuR (p < 0.001), and further to 37.6 ± 4.7 DID in AfR (p < 0.01 vs. DuR). High-intensity statin consumption elevated by 115.9% in AfR compared to baseline (p < 0.001). Prescribing of LLDs decreased from 12.5 ± 0.6 DID in BfR to 7.2 ± 1.2 DID in DuR (p < 0.001), later reached 13.6 ± 3.8 DID in AfR (p < 0.001 vs. DuR), with prescribing for ongoing users following similar trend. Expenditure on LLDs increased from €8.4 m ± 0.9 m in BfR to €11.4 m ± 2.0 m in DuR (p < 0.001) and to €12.8 m ± 1.9 m in AfR (p < 0.001 vs. BfR). CONCLUSIONS: This study revealed a surge in consumption of LLDs in Turkey following the onset of the COVID-19 pandemic. This rise might be related to practices facilitating drug access, in addition to potentially greater adherence, or the necessity for more intense pharmacotherapy due to elevated cardiovascular risk.
Advancements in non-invasive hyperspectral imaging: Mapping blood oxygen levels and vascular health for clinical and research applications.
El-Sharkawy YH
Vascul Pharmacol · 2024 Jun · PMID 38806138 · Publisher ↗
Oxygen content is crucial for the functioning of human body organs, as it plays a vital role in cellular respiration, which generates energy necessary for life-sustaining functions. The absence of adequate oxygen leads t...
Oxygen content is crucial for the functioning of human body organs, as it plays a vital role in cellular respiration, which generates energy necessary for life-sustaining functions. The absence of adequate oxygen leads to cellular dysfunction and eventual organismal death due to energy deprivation. In this study, we designed a rapid, non-invasive, and non-contact custom hyperspectral imaging system to assess blood perfusion in arteries, capillaries, and veins across various human organs, including the arm, eye, and leg. The system recorded cube images consisting of multispectral image ranges, capturing spectral information in both the visible and infrared spectra. Segmentation of the visible spectrum (400 to 700 nm) and the infrared spectrum (700 to 1000 nm) facilitated the mapping of blood oxygen levels in the investigated samples. The estimated oxygen levels were calculated using the custom hyperspectral imaging system and associated algorithm, with validation and calibration performed against the gold standard pulse oximeter. Our results demonstrate that the custom hyperspectral imaging system accurately mapped blood perfusion and oxygen levels in organs, showing strong agreement with pulse oximeter measurements. This study underscores the utility of custom hyperspectral imaging in non-invasively assessing blood oxygenation and perfusion in human organs, offering a promising avenue for clinical diagnostics and monitoring of vascular health.
SEMA3G regulates BMP9 inhibition of VEGF-mediated migration and network formation in pulmonary endothelial cells.
Mirza SL, Upton PD, Hodgson J … +3 more , Gräf S, Morrell NW, Dunmore BJ
Vascul Pharmacol · 2024 Jun · PMID 38795838 · Publisher ↗
AIMS: Bone morphogenetic protein-9 (BMP9) is critical for bone morphogenetic protein receptor type-2 (BMPR2) signalling in pulmonary vascular endothelial cells. Furthermore, human genetics studies support the central rol...
AIMS: Bone morphogenetic protein-9 (BMP9) is critical for bone morphogenetic protein receptor type-2 (BMPR2) signalling in pulmonary vascular endothelial cells. Furthermore, human genetics studies support the central role of disrupted BMPR2 mediated BMP9 signalling in vascular endothelial cells in the initiation of pulmonary arterial hypertension (PAH). In addition, loss-of-function mutations in BMP9 have been identified in PAH patients. BMP9 is considered to play an important role in vascular homeostasis and quiescence. METHODS AND RESULTS: We identified a novel BMP9 target as the class-3 semaphorin, SEMA3G. Although originally identified as playing a role in neuronal development, class-3 semaphorins may have important roles in endothelial function. Here we show that BMP9 transcriptional regulation of SEMA3G occurs via ALK1 and the canonical Smad pathway, requiring both Smad1 and Smad5. Knockdown studies demonstrated redundancy between type-2 receptors in that BMPR2 and ACTR2A were compensatory. Increased SEMA3G expression by BMP9 was found to be regulated by the transcription factor, SOX17. Moreover, we observed that SEMA3G regulates VEGF signalling by inhibiting VEGFR2 phosphorylation and that VEGF, in contrast to BMP9, negatively regulated SEMA3G transcription. Functional endothelial cell assays of VEGF-mediated migration and network formation revealed that BMP9 inhibition of VEGF was abrogated by SEMA3G knockdown. Conversely, treatment with recombinant SEMA3G partially mimicked the inhibitory action of BMP9 in these assays. CONCLUSIONS: This study provides further evidence for the anti-angiogenic role of BMP9 in microvascular endothelial cells and these functions are mediated at least in part via SOX17 and SEMA3G induction.
The diverging roles of insulin-like growth factor binding proteins in pulmonary arterial hypertension.
Schlueter BC, Quanz K, Baldauf J … +11 more , Petrovic A, Ruppert C, Guenther A, Gall H, Tello K, Grimminger F, Ghofrani HA, Weissmann N, Seeger W, Schermuly RT, Weiss A
Vascul Pharmacol · 2024 Jun · PMID 38762131 · Publisher ↗
Pulmonary hypertension (PH) is a progressive, severe and to date not curable disease of the pulmonary vasculature. Alterations of the insulin-like growth factor 1 (IGF-1) system are known to play a role in vascular patho...
Pulmonary hypertension (PH) is a progressive, severe and to date not curable disease of the pulmonary vasculature. Alterations of the insulin-like growth factor 1 (IGF-1) system are known to play a role in vascular pathologies and IGF-binding proteins (IGFBPs) are important regulators of the bioavailability and function of IGFs. In this study, we show that circulating plasma levels of IGFBP-1, IGFBP-2 and IGFBP-3 are increased in idiopathic pulmonary arterial hypertension (IPAH) patients compared to healthy individuals. These binding proteins inhibit the IGF-1 induced IGF-1 receptor (IGF1R) phosphorylation and exhibit diverging effects on the IGF-1 induced signaling pathways in human pulmonary arterial cells (i.e. healthy as well as IPAH-hPASMCs, and healthy hPAECs). Furthermore, IGFBPs are differentially expressed in an experimental mouse model of PH. In hypoxic mouse lungs, IGFBP-1 mRNA expression is decreased whereas the mRNA for IGFBP-2 is increased. In contrast to IGFBP-1, IGFBP-2 shows vaso-constrictive properties in the murine pulmonary vasculature. Our analyses show that IGFBP-1 and IGFBP-2 exhibit diverging effects on IGF-1 signaling and display a unique IGF1R-independent kinase activation pattern in human pulmonary arterial smooth muscle cells (hPASMCs), which represent a major contributor of PAH pathobiology. Furthermore, we could show that IGFBP-2, in contrast to IGFBP-1, induces epidermal growth factor receptor (EGFR) signaling, Stat-3 activation and expression of Stat-3 target genes. Based on our results, we conclude that the IGFBP family, especially IGFBP-1, IGFBP-2 and IGFBP-3, are deregulated in PAH, that they affect IGF signaling and thereby regulate the cellular phenotype in PH.
Molecular mechanisms of flavonoids in myocardial ischemia reperfusion injury: Evidence from in-vitro and in-vivo studies.
Sharma J, Bhargava P, Mishra P … +2 more , Bhatia J, Arya DS
Vascul Pharmacol · 2024 Jun · PMID 38729253 · Publisher ↗
OBJECTIVES: Flavonoids are polyphenolic compounds found in a wide range of foods, including fruits, vegetables, tea plants, and other natural products. They have been mainly classified as flavanols, flavonols, flavones,...
OBJECTIVES: Flavonoids are polyphenolic compounds found in a wide range of foods, including fruits, vegetables, tea plants, and other natural products. They have been mainly classified as flavanols, flavonols, flavones, isoflavones, flavanones, and flavanonols. In this comprehensive review, we will discuss preclinical pieces of evidence on the potential of flavonoids for the prevention/treatment of myocardial ischemia-reperfusion (IR) injury. KEY FINDINGS: In-vitro and in-vivo studies have shown that flavonoids play an important role in preventing ischemic heart disease (IHD). They possess strong anti-oxidant, anti-inflammatory, anti-bacterial, anti-thrombotic, anti-apoptotic, and anti-carcinogenic activities. In addition, at a molecular level, flavonoids also modulate various pathways like MAPK, NFκB etc. to confer beneficial effects. SUMMARY: The current review of flavonoids in myocardial ischemia-reperfusion injury furnishes updated information that could drive future research. The in-vitro and in-vivo experiments have demonstrated various favourable pharmacological properties of flavonoids. This review provides valuable information to conduct clinical studies, validating the safety aspects of flavonoids in the clinical domain.
Plasma lipidome differences in patients with and without significant carotid plaque.
Malý M, Kučerka O, Bechyňská K … +4 more , Kočí K, Mandys V, Hajšlová J, Kosek V
Vascul Pharmacol · 2024 Jun · PMID 38705432 · Publisher ↗
BACKGROUND: Atherosclerosis is a major cause of ischemic stroke, and early detection of advanced atherosclerosis in the carotid artery is important for reducing morbidity and mortality. What is even more important is not...
BACKGROUND: Atherosclerosis is a major cause of ischemic stroke, and early detection of advanced atherosclerosis in the carotid artery is important for reducing morbidity and mortality. What is even more important is not only detection of atherosclerosis but early determination whether the patients are at high risk of an event with adverse effects as the size of the plaque does not necessarily reflect its potential to trigger such events. AIM: We studied whether plasma lipidomics profile can be used as a diagnostic tool for stratification of stable or unstable plaques without the need of removing the carotid plaque. METHODS: This study used liquid chromatography high-resolution tandem mass spectrometry lipidomics to characterize lipid profiles in patients' plasma and found that patients with significant and complicated (vulnerable) atherosclerotic plaque had distinct lipid profiles compared to those with insignificant plaques. RESULTS: The lipid classes that were most predictive of vulnerable plaque were lysophosphoethanolamines, fatty acyl esters of hydroxy fatty acids, free fatty acids, plasmalogens, and triacylglycerols. Most of these compounds were found decreased in plasma of patients with unstable plaques which enabled sufficient performance of a statistical model used for patient stratification. CONCLUSIONS: Plasma lipidomes measured by liquid chromatography-mass spectrometry show differences in patients with stable and unstable carotid plaques, therefore these compounds could potentially be used as biomarkers for unstable plaque in future clinical diagnosis.
Effects of Empagliflozin on Vascular and Skeletal Mineralization in Hyperlipidemic Mice.
Kalanski S, Pradhan S, Hon A … +6 more , Xia Y, Safvati N, Rivera JC, Lu M, Demer LL, Tintut Y
Vascul Pharmacol · 2024 Jun · PMID 38692418 · Full text
Cardiovascular disease and osteoporosis, major causes of morbidity and mortality, are associated with hyperlipidemia. Recent studies show that empagliflozin (EMPA), an inhibitor of sodium-glucose cotransporter-2 (SGLT2),...
Cardiovascular disease and osteoporosis, major causes of morbidity and mortality, are associated with hyperlipidemia. Recent studies show that empagliflozin (EMPA), an inhibitor of sodium-glucose cotransporter-2 (SGLT2), improves cardiovascular health. In preclinical animal studies, EMPA mitigates vascular calcification in the males but its effects in the females are not known. Thus, we used female mice to test the effects of EMPA on calcification in the artery wall, cardiac function, and skeletal bone. By serial in vivo microCT imaging, we followed the progression of aortic calcification and bone mineral density in young and older female Apoe mice fed a high-fat diet with or without EMPA. The two different age groups were used to compare early vs. advanced stages of aortic calcification. Results show that EMPA treatment increased urine glucose levels. Aortic calcium content increased in both the controls and the EMPA-treated mice, and EMPA did not affect progression of aortic calcium content in both young and older mice. However, 3-D segmentation analysis of aortic calcium deposits on microCT images revealed that EMPA-treated mice had significantly less surface area and volume of calcified deposits as well as fewer numbers of deposits than the control mice. To test for direct effects on vascular cell calcification, we treated murine aortic smooth muscle cells with EMPA, and results showed a slight inhibition of alkaline phosphatase activity and inflammatory matrix calcification. As for skeletal bone, EMPA-treated mice had significantly lower BMD than the controls in both the lumbar vertebrae and femoral bones in both young and older mice. The findings suggest that, in hyperlipidemic female mice, unlike males, SGLT2 inhibition with empagliflozin does not mitigate progression of aortic calcification and may even lower skeletal bone density.
Inferior vena cava filters: Concept review and summary of current guidelines.
Visconti L, Celi A, Carrozzi L … +6 more , Tinelli C, Crocetti L, Daviddi F, De Caterina R, Madonna R, Pancani R
Vascul Pharmacol · 2024 Jun · PMID 38663572 · Publisher ↗
Anticoagulation is the first-line approach in the prevention and treatment of pulmonary embolism. In some instances, however, anticoagulation fails, or cannot be administered due to a high risk of bleeding. Inferior vena...
Anticoagulation is the first-line approach in the prevention and treatment of pulmonary embolism. In some instances, however, anticoagulation fails, or cannot be administered due to a high risk of bleeding. Inferior vena cava filters are metal alloy devices that mechanically trap emboli from the deep leg veins halting their transit to the pulmonary circulation, thus providing a mechanical alternative to anticoagulation in such conditions. The Greenfield filter was developed in 1973 and was later perfected to a model that could be inserted percutaneously. Since then, this model has been the reference standard. The current class I indication for this device includes absolute contraindication to anticoagulants in the presence of acute thromboembolism and recurrent thromboembolism despite adequate therapy. Additional indications have been more recently proposed, due to the development of removable filters and of progressively less invasive techniques. Although the use of inferior vena cava filters has solid theoretical advantages, clinical efficacy and adverse event profile are still unclear. This review analyzes the most important studies related to such devices, open issues, and current guideline recommendations.
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