Vascular pharmacology最新文献

Despite the innovations introduced in the 2022 European Society of Cardiology/European Respiratory Society Guidelines on Pulmonary Hypertension, risk discrimination and management of pulmonary arterial hypertension (PAH) patients at intermediate risk still represents a grey zone. Additionally, clinical evidence derived from currently available studies is limited. This expert panel survey intends to aid physicians in choosing the best therapeutic strategy for patients at intermediate risk despite ongoing oral therapy. An expert panel of 24 physicians, specialized in cardiology and/or pulmonology with expertise in handling all drugs available for the treatment of PAH participated in the survey. All potential therapeutic options for patients at intermediate risk were explored and analyzed to produce graded consensus statements regarding: the switch from endothelin receptor antagonist (ERA) or phosphodiesterase 5 inhibitor (PDE5i) to another oral drug of the same class; the addition of a drug targeting the prostacyclin pathway administered by different routes; the switch from PDE5i to riociguat.

Serum Response Factor (SRF) is a key regulatory transcription factor present in various cell types throughout the body, playing essential roles in cellular functions under physiological conditions. Mutations and abnormal expression of SRF have been linked to the development of various diseases and disorders. Recent evidence highlights that post-translational modifications (PTMs) are critical for regulating SRF function in different cell types and contribute to disease pathogenesis. Targeting SRF-related PTMs is emerging as a promising therapeutic approach for treating SRF-associated diseases. In this review, we summarize recent advances in understanding SRF PTMs and their underlying regulatory mechanisms. We also explore the implications of SRF-PTM in related cardiovascular and neurological diseases and their potential for therapeutic intervention. This information underscores the significance of SRF PTMs in both physiological and pathological contexts, enhancing our understanding of disease mechanisms and paving the way for the development of novel therapeutic strategies.

Aortic dissection, characterized by a high immediate mortality, is primarily caused by excessive bleeding within the walls of the aorta or a severe tear within the intimal layer of the aorta. Inflammation, as well as oxidative stress and the degradation of extracellular matrix (ECM), are significant factors in the development and occurrence of aortic dissection. Matrix metalloproteinases (MMPs) are pivotal enzymes responsible for degrading the ECM. Inflammatory factors and oxidants can interact with MMPs, indicating the potential significance of MMPs in aortic dissection. A substantial body of evidence indicates that numerous MMPs are significantly upregulated in aortic dissection, playing a critical role in ECM degradation and the pathogenesis of aortic dissection. Furthermore, targeting these enzymes has demonstrated potential in facilitating ECM restoration and reducing the incidence of aortic dissection. This review initially provides a brief overview of MMP biology before delving into their expression patterns, regulatory mechanisms, and therapeutic applications in aortic dissection. A profound comprehension of the catabolic pathways associated with aortic dissection is imperative for the future development of potential preventive or therapeutic bio-interventions for aortic dissection.

Macrophages are a dynamic cell type of the immune system implicated in the pathophysiology of vascular diseases and are a major contributor to pathological inflammation. Excessive macrophage accumulation, activation, and polarization is observed in aortic aneurysm (AA), atherosclerosis, and pulmonary arterial hypertension. In general, macrophages become activated and polarized to a pro-inflammatory phenotype, which dramatically changes cell behavior to become pro-inflammatory and infiltrative. These cell types become cumbersome and fail to be cleared by normal mechanisms such as autophagy. The result is a hyper-inflammatory environment causing the recruitment of adjacent cells and circulating immune cells to further augment the inflammatory response. In AA, this leads to excessive ECM degradation and chemokine secretion, ultimately causing macrophages to dominate the immune cell landscape in the aortic wall. In atherosclerosis, monocytes are recruited to the vascular wall, where they polarize to the pro-inflammatory phenotype and induce inflammatory pathway activation. This leads to the development of foam cells, which significantly contribute to neointima and necrotic core formation in atherosclerotic plaques. Pro-inflammatory macrophages, which affect other vascular diseases, present with fragmented mitochondria and corresponding metabolic dysfunction. Targeting macrophage mitochondrial dynamics has proved to be an exciting potential therapeutic approach to combat vascular disease. This review will summarize mitochondrial and metabolic mechanisms of macrophage activation, polarization, and accumulation in vascular diseases.

Myocardial infarction (MI) and the ensuing heart failure (HF) remain the main cause of morbidity and mortality worldwide. One of the strategies to combat MI and HF lies in the ability to accurately predict the onset of these disorders. Alterations in mitochondrial homeostasis have been reported to be involved in the pathogenesis of various cardiovascular diseases (CVDs). In this regard, perturbations to mitochondrial dynamics leading to impaired clearance of dysfunctional mitochondria have been previously established to be a crucial trigger for MI/HF.

In this study, we found that MI patients could be classified into three clusters based on the expression levels of mitophagy-related genes and consensus clustering. We identified a mitophagy-related diagnostic 5-genes signature for MI using support vector machines-Recursive Feature Elimination (SVM-RFE) and random forest, with the area under the ROC curve (AUC) value of the predictive model at 0.813. Additionally, the single-cell transcriptome and pseudo-time analyses showed that the mitoscore was significantly upregulated in macrophages, endothelial cells, pericytes, fibroblasts and monocytes in patients with ischemic cardiomyopathy, while sequestosome 1 (SQSTM1) exhibited remarkable increase in the infarcted (ICM) and non-infarcted (ICMN) myocardium samples dissected from the left ventricle compared with control samples. Lastly, through analysis of peripheral blood from MI patients, we found that the expression of SQSTM1 is positively correlated with troponin-T (P < 0.0001, R = 0.4195, R2 = 0.1759). Therefore, this study provides the rationale for a cell-specific mitophagy-related gene signature as an additional supporting diagnostic for CVDs.

Substituted catechols include both natural and synthetic compounds found in the environment and foods. Some of them are flavonoid metabolites formed by the gut microbiota which are absorbed afterwards. Our previous findings showed that one of these metabolites, 4-methylcatechol, exerts potent vasorelaxant effects in rats. In the current study, we aimed at testing of its 22 structural congeners in order to find the most potent structure and to investigate the mechanism of action. 3-methoxycatechol (3-MOC), 4-ethylcatechol, 3,5-dichlorocatechol, 4-tert-butylcatechol, 4,5-dichlorocatechol, 3-fluorocatechol, 3-isopropylcatechol, 3-methylcatechol and the parent 4-methylcatechol exhibited high vasodilatory activities on isolated rat aortic rings with EC₅₀s ranging from ∼10 to 24 μM. Some significant sex-differences were found. The most potent compound, 3-MOC, relaxed also resistant mesenteric artery but not porcine coronary artery, and decreased arterial blood pressure in both male and female spontaneously hypertensive rats in vivo without affecting heart rate. It potentiated the vasodilation mediated by cAMP and cGMP, but did not impact L-type Ca²⁺-channels. By using two inhibitors, activation of voltage-gated potassium channels (K_V) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the K_V7.4 channel. None of the most active catechols decreased the viability of the A-10 rat embryonic thoracic aorta smooth muscle cell line. Our findings showed that various catechols can relax vascular smooth muscles and hence could provide templates for developing new antihypertensive vasodilator agents without affecting coronary circulation.

Objective

This study explores the association of serum 25-hydroxyvitamin D3 (25(OH)D3) levels with carotid artery intima-media thickness (CIMT), and the presence of carotid atherosclerotic plaques in individuals with a history of smoking.

Methods

A total of 469 patients suspected of having carotid atherosclerosis, aged 52 to 73 years with an average age of 65.26 ± 4.37 years, were recruited from the author's hospital from January 2023 to October 2023. All patients had a smoking history of nearly 5 years. Based on their serum 25(OH)D3 levels, they were divided into two groups: the normal group (serum level 30–50 ng/mL, n = 300) and the deficiency group (<30 ng/mL, n = 169). General details of the two patient groups were collected. Carotid artery ultrasound was employed to assess pulse wave velocity (PWV), carotid artery compliance coefficient (CC), and CIMT. Blood chemistry analysis measured serum lipid metabolism indicators including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HD-LC). The relationship between CIMT and each variable was analyzed through Pearson correlation, and logistic regression was used to identify risk factors influencing carotid artery plaque development.

Results

General patient information between the two groups showed no significant differences (P > 0.05). Patients in the 25(OH)D3 deficiency group exhibited elevated left and right PWV and CC compared to the 25(OH)D3 normal group (P < 0.05). The deficiency group exhibited larger CIMT and plaque area compared to the normal group (P < 0.05). Additionally, the deficiency group demonstrated higher levels of TC, LDL-C, and HD-LC compared to the normal group (P < 0.05). A moderate positive correlation was found between TC, LDL-C, and CIMT (P < 0.05), while a strong positive correlation existed between 25(OH)D3 and CIMT (P < 0.05). In smokers, the formation of carotid artery plaque was associated with factors such as patient age, CIMT, serum LDL-C, and 25(OH)D3 levels (P < 0.05). As age, CIMT, LDL-C levels increased, and 25(OH)D3 levels decreased, the risk of carotid plaques in smokers increased (P < 0.05).

Conclusions

Smokers with lower 25(OH)D3 levels exhibit higher CIMT and more prominent carotid atherosclerotic plaques, indicating increased arterial stiffness and elevated cardiovascular risk. These findings demonstrate crucial implications that insufficient levels of vitamin D may potentially contribute to a higher risk of atherosclerosis among smokers.

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.

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.