Advances in the mechanisms of vascular calcification in chronic kidney disease.

Vascular calcification (VC) is common in patients with advanced chronic kidney disease (CKD).A series of factors, such as calcium and phosphorus metabolism disorders, uremic toxin accumulation, inflammation and oxidative stress and cellular senescence, cause osteoblast-like differentiation of vascular smooth muscle cells, secretion of extracellular vesicles, and imbalance of calcium regulatory factors, which together promote the development of VC in CKD. Recent advances in epigenetics have provided better tools for the investigation of VC etiology and new approaches for finding more accurate biomarkers. These advances have not only deepened our understanding of the pathophysiological mechanisms of VC in CKD, but also provided valuable clues for the optimization of clinical predictors and the exploration of potential therapeutic targets. The aim of this article is to provide a comprehensive overview of the pathogenesis of CKD VC, especially the new advances made in recent years, including the various key factors mentioned above. Through the comprehensive analysis, we expect to provide a solid theoretical foundation and research direction for future studies targeting the specific mechanisms of CKD VC, the establishment of clinical predictive indicators and the development of potential therapeutic strategies.

Spatial multiomics atlas reveals smooth muscle phenotypic transformation and metabolic reprogramming in diabetic macroangiopathy.

BACKGROUND: Diabetic macroangiopathy has been the main cause of death and disability in diabetic patients. The mechanisms underlying smooth muscle cell transformation and metabolic reprogramming other than abnormal glucose and lipid metabolism remain to be further explored. METHOD: Single-cell transcriptome, spatial transcriptome and spatial metabolome sequencing were performed on anterior tibial artery from 11 diabetic patients with amputation. Multi-omics integration, cell communication analysis, time series analysis, network analysis, enrichment analysis, and gene expression analysis were performed to elucidate the potential molecular features. RESULT: We constructed a spatial multiomics map of diabetic blood vessels based on multiomics integration, indicating single-cell and spatial landscape of transcriptome and spatial landscape of metabolome. At the same time, the characteristics of cell composition and biological function of calcified regions were obtained by integrating spatial omics and single cell omics. On this basis, our study provides favorable evidence for the cellular fate of smooth muscle cells, which can be transformed into pro-inflammatory chemotactic smooth muscle cells, macrophage-like smooth muscle cells/foam-like smooth muscle cells, and fibroblast/chondroblast smooth muscle cells in the anterior tibial artery of diabetic patients. The smooth muscle cell phenotypic transformation is driven by transcription factors net including KDM5B, DDIT3, etc. In addition, in order to focus on metabolic reprogramming apart from abnormal glucose and lipid metabolism, we constructed a metabolic network of diabetic vascular activation, and found that HNMT and CYP27A1 participate in diabetic vascular metabolic reprogramming by combining public data. CONCLUSION: This study constructs the spatial gene-metabolism map of the whole anterior tibial artery for the first time and reveals the characteristics of vascular calcification, the phenotypic transformation trend of SMCs, and the transcriptional driving network of SMCs phenotypic transformation of diabetic macrovascular disease. In the perspective of combining the transcriptome and metabolome, the study demonstrates the activated metabolic pathways in diabetic blood vessels and the key genes involved in diabetic metabolic reprogramming.

Acetylated Histone Modifications: Intersection of Diabetes and Atherosclerosis.

ABSTRACT: Worldwide, type 2 diabetes is predominant form of diabetes, and it is mainly affected by the environment. Furthermore, the offspring of patients with type 2 diabetes and metabolic disorder syndrome may have a higher risk of diabetes and cardiovascular disease, which indicates that the environmental impact on diabetes prevalence can be transmitted across generations. In the process of diabetes onset and intergenerational transmission, the genetic structure of the individual is not directly changed but is regulated by epigenetics. In this process, genes or histones are modified, resulting in selective expression of proteins. This modification will affect not only the onset of diabetes but also the related onset of atherosclerosis. Acetylation and deacetylation may be important regulatory factors for the above lesions. Therefore, in this review, based on the whole process of atherosclerosis evolution, we explored the possible existence of acetylation/deacetylation caused by diabetes. However, because of the lack of atherosclerosis-related acetylation studies directly based on diabetic models, we also used a small number of experiments involving nondiabetic models of related molecular mechanisms.

Protective Effect of CD137 Deficiency Against Postinfarction Cardiac Fibrosis and Adverse Cardiac Remodeling by ERK1/2 Signaling Pathways.

ABSTRACT: Myocardial fibrosis, a common complication of myocardial infarction (MI), is characterized by excessive collagen deposition and can result in impaired cardiac function. The specific role of CD137 in the development of post-MI myocardial fibrosis remains unclear. Thus, this study aimed to elucidate the effects of CD137 signaling using CD137 knockout mice and in vitro experiments. CD137 expression levels progressively increased in the heart after MI, particularly in myofibroblast, which play a key role in fibrosis. Remarkably, CD137 knockout mice exhibited improved cardiac function and reduced fibrosis compared with wild-type mice at day 28 post-MI. The use of Masson's trichrome and picrosirius red staining demonstrated a reduction in the infarct area and collagen volume fraction in CD137 knockout mice. Furthermore, the expression of alpha-smooth muscle actin and collagen I, key markers of fibrosis, was decreased in heart tissues lacking CD137. In vitro experiments supported these findings because CD137 depletion attenuated cardiac fibroblast differentiation, and migration, and collagen I synthesis. In addition, the administration of CD137L recombinant protein further promoted alpha-smooth muscle actin expression and collagen I synthesis, suggesting a profibrotic effect. Notably, the application of an inhibitor targeting the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway attenuated the profibrotic effects of CD137L. To conclude, this study provides evidence that CD137 plays a significant role in promoting myocardial fibrosis after MI. Inhibition of CD137 signaling pathways may hold therapeutic potential for mitigating pathological cardiac remodeling and improving post-MI cardiac function.

Coronary artery calcification burden, atherogenic index of plasma, and risk of adverse cardiovascular events in the general population: evidence from a mediation analysis.

BACKGROUND: Dyslipidemia and abnormal cholesterol metabolism are closely related to coronary artery calcification (CAC) and are also critical factors in cardiovascular disease death. In recent years, the atherogenic index of plasma (AIP) has been widely used to evaluate vascular sclerosis. This study aimed to investigate the potential association of AIP between CAC and major adverse cardiovascular events (MACEs). METHODS: This study included 1,121 participants whose CACs were measured by multislice spiral CT. Participants' CAC Agatston score, CAC mass, CAC volume, and number of vessels with CACs were assessed. AIP is defined as the base 10 logarithm of the ratio of triglyceride (TG) concentration to high-density lipoprotein-cholesterol (HDL-C) concentration. We investigated the multivariate-adjusted associations between AIP, CAC, and MACEs. The mediating role of the AIP in CAC and MACEs was subsequently discussed. RESULTS: During a median follow-up of 31 months, 74 MACEs were identified. For each additional unit of log-converted CAC, the MACE risk increased by 48% (HR 1.48 [95% CI 1.32-1.65]). For each additional unit of the AIP (multiplied by 10), the MACEs risk increased by 19%. Causal mediation analysis revealed that the AIP played a partial mediating role between CAC (CAC Agatston score, CAC mass) and MACEs, and the mediating proportions were 8.16% and 16.5%, respectively. However, the mediating effect of CAC volume tended to be nonsignificant (P = 0.137). CONCLUSIONS: An increased AIP can be a risk factor for CAC and MACEs. Biomarkers based on lipid ratios are a readily available and low-cost strategy for identifying MACEs and mediating the association between CAC and MACEs. These findings provide a new perspective on CAC treatment, early diagnosis, and prevention of MACEs.

Sex differences in association of healthy eating pattern with all-cause mortality and cardiovascular mortality.

BACKGROUND: Although the Healthy Eating Index (HEI) is widely recommended to reduce the risk of cardiovascular disease and all-cause death, there are significant differences in physiological and nutritional factors between the sexes. The potential impact of sex on adult dietary health is still poorly understood. The study was designed to assess whether the health benefits of diet differed by sex. METHODS: In a prospective study of 39,567 U.S. adults (51.2% female, age 46.8 ± 17.6 years), we examined sex-specific, multivariable-adjusted associations of HEI with all-cause mortality and cardiovascular disease mortality. Restricted cubic splines (RCS), subgroup analysis, propensity score matching (PSM), random forest feature importance, and sensitivity analysis were also used. RESULTS: During 328,403 person-years of follow-up, a total of 4754 all-cause deaths were recorded, including 1481 cardiovascular deaths. Compared to the lowest quartile of HEI, the all-cause mortality rate of females and males in the highest quartile array decreased by 34% (HR 0.66 [95% CI 0.55-0.8]) and 15% (HR 0.85 [95% CI 0.73-0.99]), respectively. The restricted cubic spline showed a linear inverse association between baseline HEI and all-cause mortality and CVD mortality, with similar sex-specific results. Similarly, component scores were sex-specific for mortality risk, with females benefiting more from diet. The benefits of dairy products, vegetables, and sodium scores on the risk of all-cause death were higher in males and females. However, the benefits of vegetable, sodium, and fatty acid scores on the risk of cardiovascular death were different. CONCLUSIONS: In the adult population of the U.S., there are more opportunities for females to reduce the risk of all-cause mortality and cardiovascular mortality from the same dose of healthy dietary intake than males. These findings could reduce the risk of death by motivating the population, especially females, to consume healthy dietary components, especially vegetables and dairy products.

Role of galectin-3 in vascular calcification.

Vascular calcification is an abnormal process in which bone specific hydroxyapatite crystals are actively deposited on the vascular wall mediated by phenotypic differentiated smooth muscle cells and other mesenchymal cells under various pathological conditions. It is one of the important characteristics in the occurrence and development of atherosclerosis, prevalent in patients with type 2 diabetes and advanced chronic kidney disease, especially those requiring maintenance hemodialysis, with severely threatening human health. Previous studies have shown that the early diagnosis and control of vascular calcification is of great significance for cardiovascular risk stratification, prevention of acute cardiovascular events, which can greatly improve the prognosis and quality of life of patients. Galectins are a family of lectin superfamily. It is widely distributed in various animals and plays an important role in many physiological and pathological processes, such as cell adhesion, apoptosis, inflammatory response, tumor metastasis and so on. Many biomarker-and association-related studies and Preclinical-mechanistic studies have suggested that galactose-specific lectin-3 (galectin-3) plays an important role in vascular calcification and vascular intimal calcification (VIC) calcification induced by Wnt/ßcatenin signaling pathway, NF-κB signaling pathway and ERK1/2 signaling pathway. This paper mainly expounds the role and mechanism of galectin-3 in vascular calcification under different pathological conditions including atherosclerosis, diabetes and chronic kidney disease.

Role of Collagen in Vascular Calcification.

ABSTRACT: Vascular calcification is a pathological process characterized by ectopic calcification of the vascular wall. Medial calcifications are most often associated with kidney disease, diabetes, hypertension, and advanced age. Intimal calcifications are associated with atherosclerosis. Collagen can regulate mineralization by binding to apatite minerals and promoting their deposition, binding to collagen receptors to initiate signal transduction, and inducing cell transdifferentiation. In the process of vascular calcification, type I collagen is not only the scaffold for mineral deposition but also a signal entity, guiding the distribution, aggregation, and nucleation of vesicles and promoting the transformation of vascular smooth muscle cells into osteochondral-like cells. In recent years, collagen has been shown to affect vascular calcification through collagen disc-domain receptors, matrix vesicles, and transdifferentiation of vascular smooth muscle cells.

Role of Pericytes in Diabetic Angiogenesis.

ABSTRACT: In the context of diabetes mellitus, various pathological changes cause tissue ischemia and hypoxia, which can lead to the compensatory formation of neovascularization. However, disorders of the internal environment and dysfunctions of various cells contribute to the dysfunction of neovascularization. Although the problems of tissue ischemia and hypoxia have been partially solved, neovascularization also causes many negative effects. In the process of small blood vessel renewal, pericytes are extremely important for maintaining the normal growth and maturation of neovascularization. Previously, our understanding of pericytes was very limited, and the function of pericytes was not yet clear. Recently, multiple new functions of pericytes have been identified, affecting various processes in angiogenesis and relating to various diseases. Therefore, the importance of pericytes has gradually become apparent. This article presents the latest research progress on the role of pericytes in diabetic angiogenesis, characterizes pericytes, summarizes various potential therapeutic targets, and highlights research directions for the future treatment of various diabetes-related diseases.

[Bioinformatics analysis identifies aging/senescence-induced genes in calcified plaques].

Vascular calcification is an important pathophysiological basis of cardiovascular disease with its underlying mechanism unclear. In recent years, studies have shown that aging is one of the risk factors for vascular calcification. The purpose of this study was to investigate the microenvironmental characteristics of vascular calcification, identify aging/senescence-induced genes (ASIGs) closely related to calcified plaques, and explore the evolution trajectory of vascular calcification cell subsets. Based on the bioinformatics method, the single cell transcriptome sequencing data (Gene Expression Omnibus: GSE159677) of carotid artery samples from 3 patients undergoing carotid endarterectomy were grouped and annotated. Vascular calcification-related aging genes were identified by ASIGs data set. The pseudotime trend of ASIGs in cell subsets was analyzed by Monocle 3, and the evolution of vascular calcification cells was revealed. After quality control, all cells were divided into 8 cell types, including B cells, T cells, smooth muscle cells, macrophages, endothelial cells, fibroblasts, mast cells, and progenitor cells. Ten ASIGs related to vascular calcification were screened from the data set of ASIGs, which include genes encoding complement C1qA (C1QA), superoxide dismutase 3 (SOD3), lysozyme (LYZ), insulin-like growth factor binding protein-7 (IGFBP7), complement C1qB (C1QB), complement C1qC (C1QC), Caveolin 1 (CAV1), von Willebrand factor (vWF), clusterin (CLU), and αB-crystallin (CRYAB). Pseudotime analysis showed that all cell subsets were involved in the progression of vascular calcification, and these ASIGs may play an important role in cell evolution. In summary, AGIS plays an important role in the progression of vascular calcification, and these high expression genes may provide ideas for early diagnosis and treatment of vascular calcification.

Galectin-3 mediates cardiac remodeling caused by impaired glucose and lipid metabolism through inhibiting two pathways of activating Akt.

Pathological cardiac remodeling is a leading cause of mortality in patients with diabetes. Given the glucose and lipid metabolism disorders (GLDs) in patients with diabetes, it is urgent to conduct a comprehensive study of the myocardial damage under GLDs and find key mechanisms. Apolipoprotein E knockout (ApoE-/-) mice, low-density lipoprotein receptor heterozygote (Ldlr+/-) Syrian golden hamsters, or H9C2 cells were used to construct GLDs models. GLDs significantly promoted cardiomyocyte fibrosis, apoptosis, and hypertrophy in vivo and in vitro, but inhibition of galectin-3 (Gal-3) could significantly reverse this process. Then, the signal transmission pathways were determined. It was found that GLDs considerably inhibited the phosphorylation of Akt at Thr308/Ser473, whereas the silencing of Gal-3 could reverse the inhibition of Akt activity through phosphoinositide 3-kinase-AktThr308 (PI3K-AktThr308) and AMP-activated protein kinase-mammalian target of rapamycin complex 2-AktSer473 (AMPK-mTOR2-AktSer473) pathways. Finally, the PI3K, mTOR, AMPK inhibitor, and Akt activator were used to investigate the role of pathways in regulating cardiac remodeling. Phospho-AktThr308 could mediate myocardial fibrosis, whereas myocardial apoptosis and hypertrophy were regulated by both phospho-AktThr308 and phospho-AktSer473. In conclusion, Gal-3 was an important regulatory factor in GLDs-induced cardiac remodeling, and Gal-3 could suppress the phosphorylation of Akt at different sites in mediating cardiomyocyte fibrosis, apoptosis, and hypertrophy.NEW & NOTEWORTHY Studies on the pathogenesis of diabetic cardiac remodeling are highly desired. Glucose and lipid metabolism are both disordered in diabetes. Glucose and lipid metabolism disturbances promote myocardial fibrosis, apoptosis, and hypertrophy through galectin-3. Galectin-3 promotes cardiac remodeling by inhibiting phosphorylation of AktThr308 or AktSer473. The present study finds that glucose and lipid metabolism disorders are important causes for myocardial damage and provides novel ideas for the prevention and treatment of diabetic cardiac remodeling.

Recent Advances in Epigenetics of Macrovascular Complications in Diabetes Mellitus.

Diabetes mellitus is a metabolic and endocrine disorder characterised by hyperglycaemia. Type 2 diabetes mellitus accounts for >90% of people with diabetes. Disorders of blood glucose metabolism and a series of adverse reactions triggered by hyperglycaemia-such as oxidative stress and inflammation-are conducive to the occurrence of diabetic macrovascular complications, which pose severe challenges to the quality of life and life expectancy of people with diabetes. In recent years, epigenetics has attracted more and more researchers' attention as they explore the causes and treatment of diabetes. Epigenetics refers to the regulation of gene expression without changes in gene content. Research focusses on DNA methylation, histone post-translational modification and non-coding RNA. A series of studies have shown that epigenetic regulation accelerates the development of atherosclerosis by interfering with the physiological activities of macrophages, endothelial cells and smooth muscle cells, such as inflammation, lipid deposition and apoptosis. Therefore, it is particularly important to explore new epigenetic discoveries to reduce the severity and harmfulness of diabetes. This study reviewed recent advances in epigenetics in the pathogenesis of diabetes mellitus and its macrovascular complications.

Macrophage galectin-3 enhances intimal translocation of vascular calcification in diabetes mellitus.

The clinical risks and prognosis of diabetic vascular intimal calcification (VIC) and medial calcification (VMC) are different. This study aims to investigate the mechanism of VIC/VMC translocation. Anterior tibial arteries were collected from patients with diabetic foot amputation. The patients were then divided into VIC and VMC groups. There were plaques in all anterior tibial arteries, while the enrichment of galectin-3 in arterial plaques in the VIC group was significantly higher than that in the VMC group. Furthermore, a macrophage/vascular smooth muscle cell (VSMC) coculture system was constructed. VSMC-derived extracellular vesicles (EVs) was labeled with fluorescent probe. After macrophages were pretreated with recombinant galectin-3 protein, the migration of VSMC-derived EVs and VSMC-derived calcification was more pronounced. And anti-galectin-3 antibody can inhibit this process of EVs and calcification translocation. Then, lentivirus (LV)-treated bone marrow cells (BMCs) were transplanted into apolipoprotein E-deficient (ApoE-/-) mice, and a diabetic atherosclerosis mouse model was constructed. After 15 wk of high-fat diet, ApoE-/- mice transplanted with LV-shgalectin-3 BMCs exhibited medial calcification and a concentrated distribution of EVs in the media. In conclusion, upregulation of galectin-3 in macrophages promotes the migration of VSMC-derived EVs to the intima and induces diabetic vascular intimal calcification.NEW & NOTEWORTHY The clinical risk and prognosis of vascular intimal and medial calcification are different. Macrophage galectin-3 regulates the migration of vascular smooth muscle cell-derived extracellular vesicles and mediates diabetic vascular intimal/medial calcification translocation. This study may provide insights into the early intervention in diabetic vascular calcification.

Role of NFATc1 in the Bone-Vascular Axis Calcification Paradox.

Nuclear factor of activated T cell cytoplasmic 1 (NFATc1), a crucial member of the transcription factor NFAT family, is indispensable in the immune system and the morphogenesis of cardiac valves and septa and is also vital in osteoclasts and atherosclerotic calcification. Currently, osteoporosis and vascular diseases are severely hazardous to health and quality of life, and the 2 conditions always coincide with each other. The bone-vascular axis calcification paradox serves as a bridge between bone and vascular diseases, linking these 2 seemingly separate diseases, and the receptor activator of NF-κB (RANK)/receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) system may be the common mechanism of the bone-vascular axis calcification paradox. NFATc1 provides a new therapeutic target for bone and vascular diseases. However, the specific mechanism by which NFATc1 acts on the bone-vascular axis calcification paradox, whether NFATc1 is related to the RANK/RANKL/OPG system, and how to use NFATc1 as a therapeutic target to avoid its side effects in other systems requires further study.

Advanced Glycation End Products Induce Vascular Smooth Muscle Cell-Derived Foam Cell Formation and Transdifferentiate to a Macrophage-Like State.

BACKGROUND: Advanced glycation end products play an important role in diabetic atherosclerosis. The effects of advanced glycation end products (AGEs) on vascular smooth muscle cell- (VSMC-) derived foam cell formation and phenotypic transformation are unknown. METHODS: Serological and histological samples were obtained from diabetic amputation patients and accident amputation patients from the Affiliated Hospital of Jiangsu University. CD68/Actin Alpha 2 (ACTA2) coimmunofluorescence sections were used to quantify the number of VSMCs with macrophage-like phenotypes. Western blotting was used to detect the expression of the receptor of advanced glycation end products in vascular samples. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the level of serum Nε-carboxymethyl-lysine (CML). In vitro oil red O staining was used to examine lipid accumulation in VSMCs stimulated by CML. The expression of VSMCs and macrophage markers was measured by western blotting and quantitative real-time PCR. Furthermore, changes in VSMC migration and secretion were detected by the Transwell assay and ELISA. RESULTS: In the arterial plaque sections of diabetic patients, VSMCs transformed to a macrophage-like phenotype. The serum CML and RAGE levels in the plaques were significantly higher in the diabetes group than those in the healthy control group and were significantly related to the number of macrophage-like VSMCs. CML stimulation promoted intracellular lipid accumulation. However, CML stimulation decreased the expression of VSMC markers and increased the expression of macrophage phenotype markers. Finally, CML promoted smooth muscle cell migration and the secretion of proinflammatory-related factors. CONCLUSIONS: CML induces VSMC-derived foam cell formation, and VSMCs transdifferentiate to a macrophage-like state, which may be mediated by the activation of RAGE.

Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque.

Vascular calcification is a key character of advanced plaque in diabetic atherosclerosis. Microcalcification induces plaque rupture, whereas macrocalcification contributes to plaque stability. However, there is still no clear explanation for the formation and transition of these two types of calcification. Based on existing work and the latest international progress, this article provides a brief review of four aspects: calcification transition in plaque; matrix vesicle-mediated calcification transition in plaque; regulation mechanism of matrix vesicle-mediated calcification transition in diabetic plaque; and proposal of a new hypothesis, which may offer a new perspective on the study of the mechanism of calcification transition in plaque.

Anti-ß2GPI antibodies enhance atherosclerosis in ApoE-deficient mice.

Accelerated atherosclerosis often occurs in patients with antiphospholipid syndrome (APS), and auto-antibodies to ß2 glycoprotein I (anti-ß2GPI) are confirmed as pathogenic antibodies to APS. Our previous studies have demonstrated that the conversion of mouse peritoneal macrophages into foam cells could be enhanced by co-existence of ß2GPI and anti-ß2GPI IgG, but this phenomenon has not been explored in vivo. Here, we present a mouse model to observe the effect of anti-ß2GPI IgG in the development of atherosclerosis. Male ApoE-deficient mice were intraperitoneally injected with anti-ß2GPI IgG (100 µg/mouse) and homologous control IgG (100 µg/mouse) every week for 16 weeks. Plasma lipid composition, magnetic resonance imaging (MRI) and histological staining were used to evaluate vascular inflammation, lumen stenosis and plaque stability. The results showed that the levels of total cholesterol, triglycerol and low-density lipoprotein-cholesterol in plasma were not changed in all mice fed with high-fat diet, but the level of high-density lipoprotein-cholesterol was lower and the atherosclerosis index was significantly increased in HD + anti-ß2GPI group than in other high-fat diet groups. In addition, compared with NR IgG-treated mice, anti-ß2GPI IgG-treated mice showed more lipid deposition in the carotid artery, markedly narrowed arteriolar lumen as well as higher MMP-9 expression, more macrophages and fewer collagen fibers in the aortic arch root. Furthermore, the aortic mRNA levels of TNF-α, IL-1ß, and MCP-1 were significantly increased in anti-ß2GPI IgG-treated mice. Together, these data indicate that anti-ß2GPI IgG increases vascular inflammation, aggravates atherosclerosis and promotes the formation of vulnerable plaque in ApoE-deficient mice.

Role of Matrix Vesicles in Bone-Vascular Cross-Talk.

Matrix mineralization can be divided into physiological mineralization and pathological mineralization. There is a consensus among existing studies that matrix vesicles (MVs) are the starting sites of bone mineralization, and each component of MVs serves a certain function in mineralization. In addition, ectopic MVs pathologically promote undesired calcification, the primary focus of which is the promotion of vascular calcification. However, the specific mechanisms of the actions of MVs in bone-vascular axis cross-talk have not been fully elucidated. This review summarizes the latest research in this field and explores the roles of MVs in the bone-vascular axis with the aim of generating new ideas for the prevention and treatment of vascular calcification and bone metabolic disease.

Docosahexaenoic acid inhibits monocrotaline-induced pulmonary hypertension via attenuating endoplasmic reticulum stress and inflammation.

Endoplasmic reticulum (ER) stress and inflammation contribute to pulmonary hypertension (PH) pathogenesis. Previously, we confirmed that docosahexaenoic acid (DHA) could improve hypoxia-induced PH. However, little is known about the link between DHA and monocrotaline (MCT)-induced PH. Our aims were, therefore, to evaluate the effects and molecular mechanisms of DHA on MCT-induced PH in rats. Rat PH was induced by MCT. Rats were treated with DHA daily in the prevention group (following MCT injection) and the reversal group (after MCT injection for 2 wk) by gavage. After 4 wk, mean pulmonary arterial pressure (mPAP), right ventricular (RV) hypertrophy index, and morphological and immunohistochemical analyses were evaluated. Rat pulmonary artery smooth muscle cells (PASMCs) were used to investigate the effects of DHA on cell proliferation stimulated by platelet-derived growth factor (PDGF)-BB. DHA decreased mPAP and attenuated pulmonary vascular remodeling and RV hypertrophy, which were associated with suppressed ER stress. DHA blocked the mitogenic effect of PDGF-BB on PASMCs and arrested the cell cycle via inhibiting nuclear factor of activated T cells-1 (NFATc1) expression and activation and regulating cell cycle-related proteins. Moreover, DHA ameliorated inflammation in lung and suppressed macrophage and T lymphocyte accumulation in lung and adventitia of resistance pulmonary arteries. These findings suggest that DHA could protect against MCT-induced PH by reducing ER stress, suppressing cell proliferation and inflammation.

The role of autophagy in pulmonary hypertension: a double-edge sword.

Autophagy is a recycling process that degrades damaged or unneeded cellular components for renewal. Accumulating evidence suggests that dysregulation of autophagy is involved in pulmonary hypertension (PH). PH is a progressive disease characterized by persistent proliferation of apoptosis-resistant pulmonary vascular cells. However, reports on the role of autophagy in the development of PH are often conflicting. In this review, we discuss recent development in the field with emphasis on pulmonary arterial endothelial cells, pulmonary smooth muscle cells, right ventricular myocyte, as well as pharmacological strategies targeting the autophagic signaling pathway.