Proprotein convertase subtilisin/kexin type‐9 (PCSK9), a member of the proprotein convertase family, is an important drug target because of its crucial role in lipid metabolism. Emerging evidence ...suggests a direct role of localized PCSK9 in the pathogenesis of vascular diseases. With this in our consideration, we reviewed PCSK9 physiology with respect to recent development and major studies (clinical and experimental) on PCSK9 functionality in vascular disease. PCSK9 upregulates low‐density lipoprotein (LDL)‐cholesterol levels by binding to the LDL‐receptor (LDLR) and facilitating its lysosomal degradation. PCSK9 gain‐of‐function mutations have been confirmed as a novel genetic mechanism for familial hypercholesterolemia. Elevated serum PCSK9 levels in patients with vascular diseases may contribute to coronary artery disease, atherosclerosis, cerebrovascular diseases, vasculitis, aortic diseases, and arterial aging pathogenesis. Experimental models of atherosclerosis, arterial aneurysm, and coronary or carotid artery ligation also support PCSK9 contribution to inflammatory response and disease progression, through LDLR‐dependent or ‐independent mechanisms. More recently, several clinical trials have confirmed that anti‐PCSK9 monoclonal antibodies can reduce systemic LDL levels, total nonfatal cardiovascular events, and all‐cause mortality. Interaction of PCSK9 with other receptor proteins (LDLR‐related proteins, cluster of differentiation family members, epithelial Na+ channels, and sortilin) may underlie its roles in vascular disease. Improved understanding of PCSK9 roles and molecular mechanisms in various vascular diseases will facilitate advances in lipid‐lowering therapy and disease prevention.
Proprotein convertase subtilisin/kexin type‐9 (PCSK9) gain‐of‐function mutations have been confirmed as a novel genetic mechanism for familial hypercholesterolemia. Elevated serum PCSK9 levels in patients with vascular diseases may contribute to coronary artery disease, atherosclerosis, cerebrovascular diseases, vasculitis, aortic diseases, and arterial aging pathogenesis. Experimental models of atherosclerosis, arterial aneurysm, and coronary or carotid artery ligation support PCSK9 contribution to inflammatory response and disease progression, through low‐density lipoprotein receptor (LDLR)‐dependent or ‐independent mechanisms.
Bromodomain‐containing protein 4 (BRD4), a chromatin‐binding protein, is involved in the development of various tumors. Recent evidence suggests that BRD4 also plays a significant role in ...cardiovascular diseases, such as ischemic heart disease, hypertension, and cardiac hypertrophy. This review summarizes the roles of BRD4 as a potential regulator of various pathophysiological processes in cardiovascular diseases, implicating that BRD4 may be a new therapeutic target for cardiovascular diseases in the future.
This review summarizes the roles of BRD4 as a potential regulator of various pathophysiological processes in cardiovascular diseases, implicating that BRD4 may be a new therapeutic target for cardiovascular diseases in the future.
Diversity and plasticity are the hallmarks of cells from the monocyte-macrophage lineage. Macrophages undergo classical M1 or alternative M2 activation in response to the microenvironment signals. ...Several transcription factors, such as peroxisome proliferator-activated receptors, signal transducers and activators of transcription, CCAAT-enhancer-binding proteins, interferon regulatory factors, Kruppel-like factors, GATA binding protein 3, nuclear transcription factor-κB, and c-MYC, were found to promote the expression of specific genes, which dictate the functional polarization of macrophages. Importantly, these transcription factors can be regulated by microRNAs (miRNAs), a group of small non-coding RNAs, which regulate gene expression through translation repression or mRNA degradation. Recent studies have also revealed that miRNAs control macrophage polarization by regulating transcription factors in response to the microenvironment signals. This review will summarize recent progress of miRNAs in the transcriptional regulation of macrophage polarization and provide the insights into the development of macrophage-centered diagnostic and therapeutic strategies.
Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the secretory serine protease family. It binds to low‐density lipoprotein receptor (LDLR) for endocytosis and lysosome ...degradation in the liver, resulting in an increasing in circulating LDL‐cholesterol (LDL‐c) level. Since a PCSK9 induced increase in plasma LDL‐c contributes to atherosclerosis, PCSK9 inhibition has become a new strategy in preventing and treating atherosclerosis. However, in addition to the effect of PCSK9 on elevating blood LDL‐c levels, accumulating evidence shows that PCSK9 plays an important role in inflammation, likely representing another major mechanism for PCSK9 to promote atherosclerosis. In this review, we discuss the association of PCSK9 and inflammation, and highlight the specific effects of PCSK9 on different vascular cellular components involved in the atherosclerotic inflammation. We also discuss the clinical evidence for the association between PCSK9 and inflammation in atherosclerotic cardiovascular disease. A better understanding of the direct association of PCSK9 with atherosclerotic inflammation might help establish a new role for PCSK9 in vascular biology and identify a novel molecular mechanism for PCSK9 therapy.
In this review, we discuss the association of proprotein convertase subtilisin/kexin 9 (PCSK9) and inflammation, and highlight the specific effects of PCSK9 on different vascular cellular components involved in the atherosclerotic inflammation. We also discuss the clinical evidence for the association between PCSK9 and inflammation in atherosclerotic cardiovascular disease. A better understanding of the direct association of PCSK9 with atherosclerotic inflammation might help establish a new role for PCSK9 in vascular biology and identify a novel molecular mechanism for PCSK9 therapy.
Macrophages play a central role in innate immunity as the first line of defense against pathogen infection. Upon exposure to inflammatory stimuli, macrophages rapidly respond and subsequently undergo ...metabolic reprogramming to substantially produce cellular metabolites such as itaconate. As a derivate of the tricarboxylic acid cycle, itaconate is derived from the decarboxylation of cis‐aconitate mediated by immunoresponsive gene 1 in the mitochondrial matrix. It is well known that itaconate has a direct antimicrobial effect by inhibiting isocitrate lyase. Strikingly, two recent studies published in Nature showed that itaconate markedly decreases the production of proinflammatory mediators in lipopolysaccharide‐treated macrophages and ameliorates sepsis and psoriasis in animal models, revealing a novel biological action of itaconate beyond its regular roles in antimicrobial defense. The mechanism for this anti‐inflammatory effect has been proposed to involve the inhibition of succinate dehydrogenase, blockade of IκBζ translation and activation of Nrf2. These intriguing discoveries provide a new explanation for how macrophages are switched from a pro‐ to an anti‐inflammatory state to limit the damage and facilitate tissue repair under proinflammatory conditions. Thus, the emerging effect of itaconate as a crucial determinant of macrophage inflammation has important implications in further understanding cellular immunometabolism and developing future therapeutics for the treatment of inflammatory diseases. In this review, we focus on the roles of itaconate in controlling the inflammatory response during macrophage activation, providing a rationale for future investigation and therapeutic intervention.
Itaconate protects against macrophage inflammation by inhibiting succinate dehydrogenase (SDH), activating Nrf2 and blocking IκBζ translation. Targeting itaconate could be an important new strategy for the treatment of inflammatory diseases.
Abstract The vascular grafts prepared by electrospinning often have relatively small pores, which limit cell infiltration into the grafts and hinder the regeneration and remodeling of the grafts into ...neoarteries. To overcome this problem, macroporous electrospun polycaprolactone (PCL) scaffolds with thicker fibers (5–6 μm) and larger pores (∼30 μm) were fabricated in the present study. In vitro cell culture indicated that macrophages cultured on thicker-fiber scaffolds tended to polarize into the immunomodulatory and tissue remodeling (M2) phenotype, while those cultured on thinner-fiber scaffolds expressed proinflammatory (M1) phenotype. In vivo implantation by replacing rat abdominal aorta was performed and followed up for 7, 14, 28 and 100 d. The results demonstrated that the macroporous grafts markedly enhanced cell infiltration and extracellular matrix (ECM) secretion. All grafts showed satisfactory patency for up to 100 days. At day 100, the endothelium coverage was complete, and the regenerated smooth muscle layer was correctly organized with abundant ECM similar to those in the native arteries. More importantly, the regenerated arteries demonstrated contractile response to adrenaline and acetylcholine-induced relaxation. Analysis of the cellularization process revealed that the thicker-fiber scaffolds induced a large number of M2 macrophages to infiltrate into the graft wall. These macrophages further promoted cellular infiltration and vascularization. In conclusion, the present study confirmed that the scaffold structure can regulate macrophage phenotype. Our thicker-fiber electrospun PCL vascular grafts could enhance the vascular regeneration and remodeling process by mediating macrophage polarization into M2 phenotype, suggesting that our constructs may be a promising cell-free vascular graft candidate and are worthy for further in vivo evaluation.
Atrial fibrillation (AF) is the most common type of arrhythmia in cardiovascular diseases. Atrial fibrosis is an important pathophysiological contributor to AF. This study aimed to investigate the ...role of the clustered miR‐23b‐3p and miR‐27b‐3p in atrial fibrosis. Human atrial fibroblasts (HAFs) were isolated from atrial appendage tissue of patients with sinus rhythm. A cell model of atrial fibrosis was achieved in Ang‐II‐induced HAFs. Cell proliferation and migration were detected. We found that miR‐23b‐3p and miR‐27b‐3p were markedly increased in atrial appendage tissues of AF patients and in Ang‐II‐treated HAFs. Overexpression of miR‐23b‐3p and miR‐27b‐3p enhanced the expression of collagen, type I, alpha 1 (COL1A1), COL3A1 and ACTA2 in HAFs without significant effects on their proliferation and migration. Luciferase assay showed that miR‐23b‐3p and miR‐27b‐3p targeted two different sites in 3ʹ‐UTR of transforming growth factor (TGF)‐β1 receptor 3 (TGFBR3) respectively. Consistently, TGFBR3 siRNA could increase fibrosis‐related genes expression, along with the Smad1 inactivation and Smad3 activation in HAFs. Additionally, overexpression of TGFBR3 could alleviate the increase of COL1A1, COL3A1 and ACTA2 in HAFs after transfection with miR‐23b‐3p and miR‐27b‐3p respectively. Moreover, Smad3 was activated in HAFs in response to Ang‐II treatment and inactivation of Smad3 attenuated up‐regulation of miR‐23b‐3p and miR‐27b‐3p in Ang‐II‐treated HAFs. Taken together, these results suggest that the clustered miR‐23b‐3p and miR‐27b‐3p consistently promote atrial fibrosis by targeting TGFBR3 to activate Smad3 signalling in HAFs, suggesting that miR‐23b‐3p and miR‐27b‐3p are potential therapeutic targets for atrial fibrosis.
Abstract To address the growing demand of small-diameter vascular grafts for cardiovascular disease, it is necessary to develop substitutes with bio-functionalities, such as anticoagulation, rapid ...endothelialization, and smooth muscle regeneration. In this study, the small-diameter tubular grafts (2.2 mm) were fabricated by electrospinning of biodegradable polymer polycaprolactone (PCL) followed by functional surface coating with an arginine-glycine-aspartic acid (RGD)-containing molecule. The healing characteristics of the grafts were evaluated by implanting them in rabbit carotid arteries for 2 and 4 weeks. Results showed that at both time points, all 10 of the RGD-modified PCL grafts (PCL-RGD) were patent, whereas 4 of the 10 non-modified PCL grafts were occluded due to thrombus formation. Scanning electron microscopy (SEM) data showed abundant platelets adhering on the surface of the midportion of the PCL grafts. In contrast, only few platelets were observed on the PCL-RGD surface, suggesting that RGD modification significantly improved the hemocompatibility of the PCL grafts. Histological analysis demonstrated enhanced cell infiltration and homogeneous distribution within the PCL-RGD grafts in comparison with the PCL grafts. Furthermore, immunofluorescence staining also showed a 3-fold increase of endothelial coverage of the PCL-RGD grafts than that of PCL grafts at those two time points. After 4-week implantation, 65.3 ± 7.6% of the surface area of the PCL-RGD grafts was covered by smooth muscle cell layer, which is almost 23% more than that on the PCL grafts. The present study indicates that RGD-modified PCL grafts exhibit an improved remodeling and integration capability in revascularization.
Atherosclerosis, the pathological basis of most cardiovascular disease (CVD), is closely associated with cholesterol accumulation in the arterial intima. Excessive cholesterol is removed by the ...reverse cholesterol transport (RCT) pathway, representing a major antiatherogenic mechanism. In addition to the RCT, other pathways are required for maintaining the whole-body cholesterol homeostasis. Thus, we propose a working model of integrated cholesterol transport, termed the cholesterol transport system (CTS), to describe body cholesterol metabolism. The novel model not only involves the classical view of RCT but also contains other steps, such as cholesterol absorption in the small intestine, low-density lipoprotein uptake by the liver, and transintestinal cholesterol excretion. Extensive studies have shown that dysfunctional CTS is one of the major causes for hypercholesterolemia and atherosclerosis. Currently, several drugs are available to improve the CTS efficiently. There are also several therapeutic approaches that have entered into clinical trials and shown considerable promise for decreasing the risk of CVD. In recent years, a variety of novel findings reveal the molecular mechanisms for the CTS and its role in the development of atherosclerosis, thereby providing novel insights into the understanding of whole-body cholesterol transport and metabolism. In this review, we summarize the latest advances in this area with an emphasis on the therapeutic potential of targeting the CTS in CVD patients.
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