Hypertrophic cardiomyopathy (HCM) is a common inherited cardiomyopathy, and the mechanisms by which oxidative stress contributes to HCM remain unclear. This study aimed to identify HCM-associated oxidative stress genes and evaluate their significance in HCM pathogenesis through bioinformatic analysis of public datasets. GSE36961 and GSE141910 were downloaded from the Gene expression Omnibus (GEO) database, and genes associated with oxidative stress were searched in the Gene Ontology (GO) database. After differential analysis, marker genes were obtained using LASSO and SVM-RFE algorithms. DAVID was used, along with the GSVA and GSEA packages to perform gene ontology, pathway function enrichment, and gene set enrichment analyses. CIBERSORT was used to analyze immune cell infiltration. Subsequently, validation of these genes was performed using the GSE141910 dataset. Finally, we validated gene expression and levels of oxidative stress in cellular models. In total, 33 OS-DEGs related to HCM were identified. These were closely related to apoptosis and immune response. Subsequently, seven marker genes from OS-DEGs were identified: JAK2, EDNRA, KCNA5, DNAJC15, CA3, PRKCD and KLF2. The functional enrichment analysis suggested that these markers may play corresponding roles in HCM by regulating oxidative stress, immune responses, cytokine interactions, and multiple other processes. In addition, according to CIBERSORT analysis, PRKCD and EDNRA may have an effect on the immune microenvironment of HCM patients. In vitro studies using neonatal rat cardiomyocytes showed increased ROS production and caspase activation, suggesting elevated oxidative stress and apoptosis in HCM. This study identified 7 oxidative stress-related genes in HCM, and deeply analyzed the function and regulation of the marker genes. At the same time, we also proposed that oxidative stress participate in HCM through apoptosis.

Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. It is essential to develop novel interventions to prevent/delay CVDs by targeting their fundamental cellular and molecular processes. Melatonin is a small indole molecule acting both as a hormone of the pineal gland and as a local regulator molecule in various tissues. It has multiple features that may contribute to its cardiovascular protection. Moreover, melatonin enters all cells and subcellular compartments and crosses morphophysiological barriers. Additionally, this indoleamine also serves as a safe exogenous therapeutic agent. Increasing evidence has demonstrated the beneficial effects of melatonin in preventing and improving cardiovascular risk factors. Exogenous administration of melatonin, as a result of its antioxidant and anti-inflammatory properties, has been reported to decrease blood pressure, protect against atherosclerosis, attenuate molecular and cellular damage resulting from cardiac ischemia/reperfusion, and improve the prognosis of myocardial infarction and heart failure. This review aims to summarize the beneficial effects of melatonin against these conditions, the possible protective mechanisms of melatonin, and its potential clinical applicability in CVDs.

新医科背景下虚拟教研室的建设是落实国家"双一流"专业建设目标、提升高校教学水平和人才培养质量的重要举措.苏州大学医学机能学团队积极响应国家需要与时代呼唤,与贵州医科大学和右江民族医学院联合申报跨校医学机能学虚拟教研室建设点,成为首批江苏省虚拟教研室建设培育点.教研室结合新医科人才培养要求,对教学理念、课程体系、教学内容和教学方法进行重构,为新医科背景下医学基层教学组织的构建与运行提供了有益参考.

血管外周脂肪(perivascular adipose tissue,PVAT)是贴近血管外膜的脂肪组织,是活跃的旁自分泌器官,能够分泌多种活性物质,由外而内地影响着血管的稳态.PVAT是一种起源于独特前体细胞的脂肪组织,它兼具白色和棕色脂肪组织样特征.生理状态下,PVAT具有产热能力,并发挥机械保护和血管扩张的作用.病理状态下,比如肥胖、糖尿病、高脂血症、高血压和衰老等,PVAT表型改变和功能失调,表现为脂肪组织扩张、棕色脂肪"白色化"、脂肪细胞中脂质的异常积累和脂肪因子的异常分泌等.近年研究显示,PVAT表型的改变参与了血管重塑、动脉粥样硬化、腹主动脉瘤和高血压等多种病理过程或疾病的发生发展.

Epithelial mesenchymal transition (EMT) is a contributing factor in remodeling events of chronic obstructive pulmonary disease (COPD). Hydrogen sulfide (H2S) has been implicated in the pathogenesis of COPD, but the effect of H2S in regulating EMT and the underlying mechanisms is not clear. In this study, we assessed endoplasmic reticulum (ER) stress markers, EMT markers and associated signal molecules in rat lungs, bronchial epithelial cells, and human peripheral lung tissues to investigate the effect of H2S in regulating EMT and the underlying mechanisms. We found that EMT and ER stress occurred in lung epithelial cells, especially in the bronchial epithelial cells of smokers and COPD patients. In cigarette smoke (CS)-exposed rats, intraperitoneal injection of NaHS significantly alleviated CS-induced lung tissue damage, small airway fibrosis, ER stress, and EMT, while intraperitoneal injection of propargylglycine (cystathionine-gamma-lyase inhibitor) aggravated these effects induced by CS. In the nicotine-exposed 16HBE cells, an appropriate concentration of H2S donor not only inhibited nicotine-induced ER stress, but also inhibited nicotine-induced enhancement of cell migration ability and EMT. ER stress nonspecific inhibitors taurine and 4-phenyl butyric acid also inhibited nicotine-induced enhancement of cell migration ability and EMT. Both H2S and inositol-requiring enzyme 1 (IRE1) activation inhibitor 4μ8C inhibited nicotine-induced activation of IRE1, Smad2/3 and EMT. These results suggest that H2S inhibits CS- or nicotine-induced ER stress and EMT in bronchial epithelial cells and alleviates CS-induced lung tissue damage and small airway fibrosis. The IRE1 signal pathway and Smad2/3 may be responsible for the inhibitory effect of H2S.

"打造金课,淘汰水课"是教育部提出的明确要求,也是目前高校每门课程的建设目标.神经生物学是苏州大学临床医学本科生的专业基础课.在当下打造金课的导向下,苏州大学生理学与神经生物学系结合神经生物学的教学实际情况及存在的问题,研究和探索神经生物学课程改革的合理路径,既符合打造金课的新要求,又有利于提高医学人才的培养质量.文章结合金课建设标准,着重从学科教材、教学内容、教学方法、师资等方面,对神经生物学课程改革进行探索,以提升课程教学质量.

Vascular aging is a specific type of organic aging that plays a central role in the morbidity and mortality of cardiovascular and cerebrovascular diseases among the elderly. It is essential to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes. Endogenous vasoactive peptides are compounds formed by a group of amino acids connected by peptide chains that exert regulatory roles in intercellular interactions involved in a variety of biological and pathological processes. Emerging evidence suggests that a variety of vasoactive peptides play important roles in the occurrence and development of vascular aging and related diseases such as atherosclerosis, hypertension, vascular calcification, abdominal aortic aneurysms, and stroke. This review will summarize the cumulative roles and mechanisms of several important endogenous vasoactive peptides in vascular aging and vascular aging-related diseases. In addition, we also aim to explore the promising diagnostic function as biomarkers and the potential therapeutic application of endogenous vasoactive peptides in vascular aging-related diseases.

Intermedin (IMD), a paracrine/autocrine peptide, protects against cardiac fibrosis. However, the underlying mechanism remains poorly understood. Previous study reports that activation of Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributed to cardiac fibrosis. In this study, we aimed to investigate whether IMD mitigates cardiac fibrosis by inhibiting NLRP3. Cardiac fibrosis was induced by angiotensin II (Ang II) infusion for 2 weeks in rats. Western blot, real-time PCR, histological staining, immunofluorescence assay, RNA sequencing, echocardiography and hemodynamics were used to detect the role and the mechanism of IMD in cardiac fibrosis. Ang II infusion resulted in rat cardiac fibrosis, shown as over-deposition of myocardial interstitial collagen and cardiac dysfunction. Importantly, NLRP3 activation and endoplasmic reticulum stress (ERS) was found in Ang II treated rat myocardium. Ang II infusion decreased the expression of IMD and increased the expression of the receptor system of IMD in the fibrotic rat myocardium. IMD treatment attenuated the cardiac fibrosis and improved cardiac function. In addition, IMD inhibited the upregulation of NLRP3 markers and ERS markers induced by Ang II. In vitro, IMD knockdown by small interfering RNA significantly promoted the Ang II-induced cardiac fibroblast and NLRP3 activation. Moreover, silencing of inositol requiring enzyme 1 α (IRE1α) blocked the effects of IMD inhibiting fibroblast and NLRP3 activation. Pre-incubation with PKA pathway inhibitor H89 blocked the effects of IMD on the anti-ERS, anti-NLRP3 and anti-fibrotic response. In conclusion, IMD alleviates cardiac fibrosis by inhibiting NLRP3 inflammasome activation via suppressing IRE1α and cAMP/PKA pathway.

Cardiac inflammation and fibrosis contribute significantly to hypertension-related adverse cardiac remodeling. IκB kinase β (IKK-β), a central coordinator of inflammation through activation of NF-κB, has been demonstrated as a key molecular link between inflammation and cardiovascular disease. However, the cell-specific contribution of IKK-β signaling toward adverse cardiac remodeling remains elusive. Cardiac fibroblasts are one of the most populous nonmyocyte cell types in the heart that play a key role in mediating cardiac fibrosis and remodeling. To investigate the function of fibroblast IKK-β, we generated inducible fibroblast-specific IKK-β-deficient mice. Here, we report an important role of IKK-β in the regulation of fibroblast functions and cardiac remodeling. Fibroblast-specific IKK-β-deficient male mice were protected from angiotensin II-induced cardiac hypertrophy, fibrosis, and macrophage infiltration. Ablation of fibroblast IKK-β inhibited angiotensin II-stimulated fibroblast proinflammatory and profibrogenic responses, leading to ameliorated cardiac remodeling and improved cardiac function in IKK-β-deficient mice. Findings from this study establish fibroblast IKK-β as a key factor regulating cardiac fibrosis and function in hypertension-related cardiac remodeling.

Ghrelin, a novel gut hormone, has been shown to exert protective effects on cardiac dysfunction and remodeling. However, the underlying mechanisms of its protective effects remain unclear. Here, we investigated the effects of ghrelin on cardiac hypertrophy and explored the mechanisms involved. Ghrelin (30 μg.kg-1. day-1) was systemically administered to rats with cardiac hypertrophy induced by abdominal aortic constriction (AAC) by a mini-osmotic pump the next day after surgery continuously for 4 weeks. The AAC treated rats without ghrelin infusion showed decreased ghrelin content and expression of its receptors in the hearts. Exogenous ghrelin greatly attenuated cardiac hypertrophy as shown by heart weight to tibial length (HW/TL), hemodynamics, echocardiography, histological analyses, and expression of hypertrophic markers induced by AAC. This corresponded with decreased cardiac fibrosis and inflammation in the hearts of AAC rats treated with ghrelin. Moreover, ghrelin significantly increased the myocardial expression of autophagy markers, which was further confirmed in cultured cardiomyocytes. Concurrently, cardiomyocyte apoptosis in vivo and in vitro was ameliorated by ghrelin, which was reversed by inhibition of autophagy. The enhancement of autophagy and inhibition of apoptosis by ghrelin were eliminated on pretreatment with compound C, an AMP-activated protein kinase (AMPK) inhibitor. Furthermore, inhibition of Ca2+/Calmodulin-dependent protein kinase kinase (CaMKK), an upstream kinase of AMPK, made ghrelin fail to activate AMPK and simultaneously reversed ghrelin's promotion of autophagy. In conclusion, ghrelin could exert its cardioprotective effects on cardiac hypertrophy by promoting autophagy, possibly via CaMKK/AMPK signaling pathway.

Introduction: As the average lifespan of HIV-infected patients receiving anti-retroviral therapy lengthens, morbidity and mortality from cardiovascular disease pose considerable challenges. HIV infection is consistently associated with increased risk of atherosclerosis development, but the underlying mechanisms remain elusive. HIV-1 Tat protein, a transcriptional activator of HIV virus, has been shown to activate NF-κB signaling and promote inflammation in vitro. However, the atherogenic effects of HIV-1 Tat have not been investigated in vivo. Macrophage is one of the major cell types involved in the initiation and progression of atherosclerosis. We and others have previously demonstrated that NF-κB signaling functions in macrophages to regulate atherogenesis. This study aims to investigate the impact of HIV-1 Tat exposure on macrophage functions and atherogenesis. Hypothesis: HIV-1 Tat activates IκB kinase β (IKKβ), a central coordinator in inflammation through activation of NF-κB, to induce macrophage dysfunction and atherosclerosis development. Methods: To investigate the effects of HIV-1 Tat on macrophage IKKβ signaling and atherosclerosis development in vivo, myeloid-specific IKKβ-deficient LDLR-deficient (IKKβ ΔMye LDLR -/- ) mice and their control littermates (IKKβ F/F LDLR -/- ) were exposed to recombinant HIV-1 Tat for 12 weeks. The effects of HIV-1 Tat on macrophage functions including inflammatory responses, adhesion and migration properties were also studied. Results and Conclusions: HIV-1 Tat significantly increased atherosclerotic lesion size in aortic root and brachiocephalic artery of IKKβ F/F LDLR -/- but not IKKβ ΔMye LDLR -/- mice. Deficiency of myeloid IKKβ attenuated macrophage inflammatory responses and decreased atherosclerotic lesional inflammation in IKKβ ΔMye LDLR -/- mice. In addition, HIV-1 Tat stimulated adhesion and migration properties of control macrophages but had no effects on IKKβ-deficient macrophages. In conclusion, our findings reveal the atherogenic effects of HIV-1 Tat in vivo and demonstrate a pivot role of myeloid IKKβ in HIV-1 Tat-driven atherogenesis.

The Notch1-mediated inflammatory response participates in the development of abdominal aortic aneurysm (AAA). The vascular endogenous bioactive peptide intermedin (IMD) plays an important role in maintaining vascular homeostasis. However, whether IMD inhibits AAA by inhibiting Notch1-mediated inflammation is unclear. In this study, we found Notch intracellular domain (NICD) and hes1 expression were higher in AAA patients' aortas than in healthy controls. In angiotensin II (AngII)-induced AAA mouse model, IMD treatment significantly reduced AAA incidence and maximal aortic diameter. IMD inhibited AngII-enlarged aortas and-degraded elastic lamina, reduced NICD, hes1 and inflammatory factors expression, decreased infiltration of CD68 positive macrophages and the NOD-like receptor family pyrin domain containing 3 protein level. IMD inhibited lipopolysaccharide-induced macrophage migration in vitro and regulated macrophage polarization. Moreover, IMD overexpression significantly reduced CaCl2-induced AAA incidence and down-regulated NICD and hes1 expression. However, IMD deficiency showed opposite results. Mechanically, IMD treatment significantly decreased cleavage enzyme-a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) level. Pre-incubation with IMD17-47 (IMD receptors blocking peptide) and the phosphatidylinositol 3-kinase/protein kinase b (PI3K/Akt) inhibitor LY294002 reversed ADAM10 level. In conclusion, exogenous and endogenous IMD could inhibit the development of AAA by inhibiting Notch1 signaling-mediated inflammation via reducing ADAM10 through IMD receptor and PI3K/Akt pathway.

神经生物学是生命科学和医学领域的基础学科,其知识体系快速发展和更新,具有国际前沿性.医学教育国际化已成为一种必然趋势,开展神经生物学全英文教学是培养国际化医学人才的重要途径之一.文章从课程改革前调研、分析课程教学中的问题和确立课程目标;建立全英文教学网络课程、转变教学模式、丰富教学手段和多元化考核等改革措施;课程改革成效评价等几个方面阐述了神经生物学全英文教学的改革与实践,并提出了建议,为推广全英文或者双语教学提供借鉴.

Atherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture of atherosclerotic plaque, and endoplasmic reticulum stress (ERS) has been proved to be a key mechanism of macrophage apoptosis. Intermedin (IMD) is a regulator of ERS. Here, we investigated whether IMD enhances atherosclerotic plaque stability by inhibiting ERS-CHOP-mediated apoptosis and subsequent inflammasome in macrophages. We studied the effects of IMD on features of plaque vulnerability in hyperlipemia apolipoprotein E-deficient (ApoE(-/-)) mice. Six-week IMD1-53 infusion significantly reduced atherosclerotic lesion size. Of note, IMD1-53 lowered lesion macrophage content and necrotic core size and increased fibrous cap thickness and vascular smooth muscle cells (VSMCs) content thus reducing overall plaque vulnerability. Immunohistochemical analysis indicated that IMD1-53 administration prevented ERS activation in aortic lesions of ApoE(-/-) mice, which was further confirmed in oxidized low-density lipoproteins (ox-LDL) induced macrophages. Similar to IMD, taurine (Tau), a non-selective ERS inhibitor significantly reduced atherosclerotic lesion size and plaque vulnerability. Moreover, C/EBP-homologous protein (CHOP), a pro-apoptosis transcription factor involved in ERS, was significantly increased in advanced lesion macrophages, and deficiency of CHOP stabilized atherosclerotic plaques in AopE(-/-) mice. IMD1-53 decreased CHOP level and apoptosis in vivo and in macrophages treated with ox-LDL. In addition, IMD1-53 infusion ameliorated NLRP3 inflammasome and subsequent proinflammatory cytokines in vivo and in vitro. IMD may attenuate the progression of atherosclerotic lesions and plaque vulnerability by inhibiting ERS-CHOP-mediated macrophage apoptosis, and subsequent NLRP3 triggered inflammation. The inhibitory effect of IMD on ERS-induced macrophages apoptosis was probably mediated by blocking CHOP activation.

ghrelin是新发现的一种胃肠多肽,具有强烈的促生长激素释放的作用.ghrelin及其受体在体内广泛表达,除具有增加摄食量及调节能量代谢的作用外,还具有抑制交感神经兴奋、抗凋亡、抗氧化、调节免疫炎症及自噬等多种组织非特异性稳态调节作用.近年研究显示,ghrelin还具有钙稳态调节、内皮保护、降血压、抗心肌缺血/再灌注损伤等心血管系统稳态调节作用.因此,ghrelin及受体后信号通路在心血管稳态维持、疾病的预防和治疗方面具有潜在的临床应用前景.

The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXRΔMyeLDLR−/−) to elucidate the role of macrophage PXR signaling in atherogenesis. The myeloid PXR deficiency did not affect metabolic phenotypes and plasma lipid profiles, but PXRΔMyeLDLR−/− mice had significantly decreased atherosclerosis at both aortic root and brachiocephalic arteries compared with control littermates. Interestingly, the PXR deletion did not affect macrophage adhesion and migration properties, but reduced lipid accumulation and foam cell formation in the macrophages. PXR deficiency also led to decreased expression of the scavenger receptor CD36 and impaired lipid uptake in macrophages of the PXRΔMyeLDLR−/− mice. Further, RNA-Seq analysis indicated that treatment with a prototypical PXR ligand affects the expression of many atherosclerosis-related genes in macrophages in vitro. These findings reveal a pivotal role of myeloid PXR signaling in atherosclerosis development and suggest that PXR may be a potential therapeutic target in atherosclerosis management.

Endoplasmic reticulum stress (ERS) is involved in the development of abdominal aortic aneurysm (AAA). Since bioactive peptide intermedin (IMD)1-53 protects against AAA formation, here we investigated whether IMD1–53 attenuates AAA by inhibiting ERS. AAA model was induced by angiotensin II (AngII) in ApoE KO mouse background. AngII-treated mouse aortas showed increased ERS gene transcription of caspase12, eukaryotic translation initiation factor 2a (eIf2a) and activating transcription factor 4(ATF4).The protein level of ERS marker glucose regulated protein 94(GRP94), ATF4 and C/EBP homologous protein 10(CHOP) was also up-regulated by AngII. Increased ERS levels were accompanied by severe VSMC apoptosis in human AAA aorta. In vivo administration of IMD1-53 greatly reduced AngII-induced AAA and abrogated the activation of ERS. To determine whether IMD inhibited AAA by ameliorating ERS, we used 2 non-selective ERS inhibitors phenyl butyrate (4-PBA) and taurine (TAU). Similar to IMD, PBA, and TAU significantly reduced the incidence of AAA and AAA-related pathological disorders. In vitro, AngII infusion up-regulated CHOP, caspase12 expression and led to VSMC apoptosis. IMD siRNA aggravated the CHOP, caspase12-mediated VSMC apoptosis, which was abolished by ATF4 silencing. IMD infusion promoted the phosphorylation of adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) in aortas in ApoE KO mice, and the AMPK inhibitor compound C abolished the protective effect of IMD on VSMC ERS and apoptosis induced by AngII. In conclusion, IMD may protect against AAA formation by inhibiting ERS via activating AMPK phosphorylation.

Background Obesity‐associated chronic inflammation has been known to contribute to atherosclerosis development, but the underlying mechanisms remain elusive. Recent studies have revealed novel functions of IKKβ (inhibitor of NF‐κB [nuclear factor κB] kinase β), a key coordinator of inflammation through activation of NF‐κB, in atherosclerosis and adipose tissue development. However, it is not clear whether IKKβ signaling in adipocytes can also affect atherogenesis. This study aims to investigate the impact of adipocyte IKKβ expression on atherosclerosis development in lean and obese LDLR (low‐density lipoprotein receptor)–deficient (LDLR−/−) mice. Methods and Results To define the role of adipocyte IKKβ in atherogenesis, we generated adipocyte‐specific IKKβ‐deficient LDLR−/− (IKKβΔAdLDLR−/−) mice. Targeted deletion of IKKβ in adipocytes did not affect adiposity and atherosclerosis in lean LDLR−/− mice when fed a low‐fat diet. In response to high‐fat feeding, however, IKKβΔAdLDLR−/− mice had defective adipose remodeling and increased adipose tissue and systemic inflammation. Deficiency of adipocyte IKKβ did not affect atherosclerotic lesion sizes but resulted in enhanced lesional inflammation and increased plaque vulnerability in obese IKKβΔAdLDLR−/− mice. Conclusions These data demonstrate that adipocyte IKKβ signaling affects the evolution of atherosclerosis plaque vulnerability in obese LDLR−/− mice. This study suggests that the functions of IKKβ signaling in atherogenesis are complex, and IKKβ in different cell types or tissues may have different effects on atherosclerosis development.