Pub Date : 2024-08-15DOI: 10.1161/ATVBAHA.124.321165
Selin Bilgic, Karol M Pencina, Michael J Pencina, Justine Cole, Line Dufresne, George Thanassoulis, Allan D Sniderman
Background: Recent observational and Mendelian randomization analyses have reported significant effects of very-low-density lipoprotein cholesterol (VLDL-C) on risk that is independent of ApoB.
Objectives: To determine the independent association of VLDL-C and ApoB with the risk of new-onset cardiovascular events in the UK Biobank and the Framingham Heart Study Cohort.
Methods: We included 294 289 UK Biobank participants with a median age of 56 years, 42% men, and 2865 Framingham Heart Study participants (median age, 52 years; 47% men). The residual resulting from regressing VLDL-C on ApoB expresses the portion of VLDL-C not explained by ApoB, while the residual from regressing ApoB on VLDL-C expresses the portion of ApoB not explained by VLDL-C. Cox proportional hazards models for atherosclerotic cardiovascular disease incidence were created for residual VLDL-C and residual ApoB. Models were analyzed with and without high-density lipoprotein cholesterol (HDL-C). Furthermore, we investigated the independent effects of VLDL-C after accounting for ApoB and HDL-C and of HDL-C after accounting for ApoB and VLDL-C.
Results: In the UK Biobank, ApoB was highly correlated with VLDL-C (r=0.70; P<0.001) but weakly negatively correlated with HDL-C (r=-0.11; P<0.001). The ApoB residual and the VLDL-C residual were significantly associated with new-onset atherosclerotic cardiovascular disease (hazard ratio [HR], 1.08 and 1.06, respectively; P<0.001). After adjusting for HDL-C, the ApoB residual remained similar in magnitude (HR, 1.10; P<0.001), whereas the effect size of the VLDL-C residual was reduced (HR, 1.02; P=0.029). The independent effect of HDL-C (after accounting for ApoB and VLDL-C) remained robust (HR, 0.86; P<0.0001), while the independent effect of VLDL-C (after accounting for ApoB and HDL-C) was modest (HR, 1.02; P=0.029). All results were consistent in the Framingham cohort.
Conclusions: When adjusted for HDL-C, the association of VLDL-C with cardiovascular risk was no longer clinically meaningful. Our residual discordance analysis suggests that adjustment for HDL-C cannot be ignored.
背景:最近的观察性分析和孟德尔随机分析报告了极低密度脂蛋白胆固醇(VLDL-C)对风险的显著影响,而这种影响与载脂蛋白B无关:在英国生物库和弗雷明汉心脏研究队列中确定 VLDL-C 和载脂蛋白与新发心血管事件风险的独立关联:我们纳入了 294 289 名英国生物库参与者(中位年龄 56 岁,42% 为男性)和 2865 名弗雷明汉心脏研究参与者(中位年龄 52 岁,47% 为男性)。将 VLDL-C 对载脂蛋白 B 进行回归得到的残差表示 VLDL-C 中载脂蛋白 B 无法解释的部分,而将载脂蛋白 B 对 VLDL-C 进行回归得到的残差表示载脂蛋白 B 中 VLDL-C 无法解释的部分。针对残余 VLDL-C 和残余载脂蛋白建立了动脉粥样硬化性心血管疾病发病率的 Cox 比例危险模型。分析了有高密度脂蛋白胆固醇(HDL-C)和无高密度脂蛋白胆固醇(HDL-C)的模型。此外,我们还研究了VLDL-C对载脂蛋白B和高密度脂蛋白胆固醇的独立影响,以及HDL-C对载脂蛋白B和VLDL-C的独立影响:在英国生物库中,载脂蛋白B与 VLDL-C 高度相关(r=0.70;PPPPP=0.029)。HDL-C的独立效应(考虑载脂蛋白B和VLDL-C后)仍然很强(HR,0.86;PPP=0.029)。所有结果在弗雷明汉队列中都是一致的:经高密度脂蛋白胆固醇调整后,VLDL-C 与心血管风险的关系不再具有临床意义。我们的残差分析表明,不能忽视对高密度脂蛋白胆固醇的调整。
{"title":"Discordance Analysis of VLDL-C and ApoB in UK Biobank and Framingham Study: A Prospective Observational Study.","authors":"Selin Bilgic, Karol M Pencina, Michael J Pencina, Justine Cole, Line Dufresne, George Thanassoulis, Allan D Sniderman","doi":"10.1161/ATVBAHA.124.321165","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321165","url":null,"abstract":"<p><strong>Background: </strong>Recent observational and Mendelian randomization analyses have reported significant effects of very-low-density lipoprotein cholesterol (VLDL-C) on risk that is independent of ApoB.</p><p><strong>Objectives: </strong>To determine the independent association of VLDL-C and ApoB with the risk of new-onset cardiovascular events in the UK Biobank and the Framingham Heart Study Cohort.</p><p><strong>Methods: </strong>We included 294 289 UK Biobank participants with a median age of 56 years, 42% men, and 2865 Framingham Heart Study participants (median age, 52 years; 47% men). The residual resulting from regressing VLDL-C on ApoB expresses the portion of VLDL-C not explained by ApoB, while the residual from regressing ApoB on VLDL-C expresses the portion of ApoB not explained by VLDL-C. Cox proportional hazards models for atherosclerotic cardiovascular disease incidence were created for residual VLDL-C and residual ApoB. Models were analyzed with and without high-density lipoprotein cholesterol (HDL-C). Furthermore, we investigated the independent effects of VLDL-C after accounting for ApoB and HDL-C and of HDL-C after accounting for ApoB and VLDL-C.</p><p><strong>Results: </strong>In the UK Biobank, ApoB was highly correlated with VLDL-C (r=0.70; <i>P</i><0.001) but weakly negatively correlated with HDL-C (r=-0.11; <i>P</i><0.001). The ApoB residual and the VLDL-C residual were significantly associated with new-onset atherosclerotic cardiovascular disease (hazard ratio [HR], 1.08 and 1.06, respectively; <i>P</i><0.001). After adjusting for HDL-C, the ApoB residual remained similar in magnitude (HR, 1.10; <i>P</i><0.001), whereas the effect size of the VLDL-C residual was reduced (HR, 1.02; <i>P</i>=0.029). The independent effect of HDL-C (after accounting for ApoB and VLDL-C) remained robust (HR, 0.86; <i>P</i><0.0001), while the independent effect of VLDL-C (after accounting for ApoB and HDL-C) was modest (HR, 1.02; <i>P</i>=0.029). All results were consistent in the Framingham cohort.</p><p><strong>Conclusions: </strong>When adjusted for HDL-C, the association of VLDL-C with cardiovascular risk was no longer clinically meaningful. Our residual discordance analysis suggests that adjustment for HDL-C cannot be ignored.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1161/ATVBAHA.124.319864
Richard J Travers, Alec Stepanian, Iris Jaffe
Kinase inhibitors (KIs) targeting oncogenic molecular pathways have revolutionized cancer therapy. By directly targeting specific tumor-driving kinases, targeted therapies have fewer side effects compared with chemotherapy. Despite the enhanced specificity, cardiovascular side effects have emerged with many targeted cancer therapies that limit long-term outcomes in patients with cancer. Endothelial cells lining all blood vessels are critical to cardiovascular health and are also exposed to circulating levels of systemic anticancer therapies. Both on- and off-target perturbation of signaling pathways from KIs can cause endothelial dysfunction, resulting in cardiovascular toxicity. As such, the endothelium is a potential source, and also a therapeutic target for prevention, of cardiovascular toxicity. In this review, we examine the evidence for KI-induced endothelial cell dysfunction as a mechanism for the cardiovascular toxicities of vascular endothelial growth factor inhibitors, BCR-Abl KIs, Bruton tyrosine inhibitors, and emerging information regarding endothelial toxicity of newer classes of KIs.
以致癌分子通路为靶点的激酶抑制剂(KIs)给癌症治疗带来了革命性的变化。通过直接靶向特定的肿瘤驱动激酶,靶向疗法与化疗相比副作用更小。尽管特异性增强了,但许多癌症靶向疗法还是出现了心血管副作用,限制了癌症患者的长期治疗效果。内衬所有血管的内皮细胞对心血管健康至关重要,它们也暴露在循环水平的全身性抗癌疗法中。KIs 信号通路的靶上和靶下扰动都会导致内皮细胞功能障碍,造成心血管毒性。因此,内皮是心血管毒性的潜在来源,也是预防心血管毒性的治疗靶点。在这篇综述中,我们研究了 KI 诱导的内皮细胞功能障碍是血管内皮生长因子抑制剂、BCR-Abl KIs、Bruton 酪氨酸抑制剂的心血管毒性机制的证据,以及有关新型 KIs 内皮毒性的新信息。
{"title":"Endothelium as a Source of Cardiovascular Toxicity From Antitumor Kinase Inhibitors.","authors":"Richard J Travers, Alec Stepanian, Iris Jaffe","doi":"10.1161/ATVBAHA.124.319864","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.319864","url":null,"abstract":"<p><p>Kinase inhibitors (KIs) targeting oncogenic molecular pathways have revolutionized cancer therapy. By directly targeting specific tumor-driving kinases, targeted therapies have fewer side effects compared with chemotherapy. Despite the enhanced specificity, cardiovascular side effects have emerged with many targeted cancer therapies that limit long-term outcomes in patients with cancer. Endothelial cells lining all blood vessels are critical to cardiovascular health and are also exposed to circulating levels of systemic anticancer therapies. Both on- and off-target perturbation of signaling pathways from KIs can cause endothelial dysfunction, resulting in cardiovascular toxicity. As such, the endothelium is a potential source, and also a therapeutic target for prevention, of cardiovascular toxicity. In this review, we examine the evidence for KI-induced endothelial cell dysfunction as a mechanism for the cardiovascular toxicities of vascular endothelial growth factor inhibitors, BCR-Abl KIs, Bruton tyrosine inhibitors, and emerging information regarding endothelial toxicity of newer classes of KIs.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1161/ATVBAHA.124.319843
Justine Deroissart, Christoph J Binder, Florentina Porsch
Atherosclerosis is a lipid-driven chronic inflammatory disease that is modulated by innate and adaptive immunity including humoral immunity. Importantly, antibody alterations achieved by genetic means or active and passive immunization strategies in preclinical studies can improve or aggravate atherosclerosis. Additionally, a wide range of epidemiological data demonstrate not only an association between the total levels of different antibody isotypes but also antibody levels targeting specific antigens with atherosclerotic cardiovascular disease. Here, we discuss the potential role of atherogenic dyslipidemia on the antibody repertoire and review potential antibody-mediated effector mechanisms involved in atherosclerosis development highlighting the major atherosclerosis-associated antigens that trigger antibody responses.
{"title":"Role of Antibodies and Their Specificities in Atherosclerotic Cardiovascular Disease.","authors":"Justine Deroissart, Christoph J Binder, Florentina Porsch","doi":"10.1161/ATVBAHA.124.319843","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.319843","url":null,"abstract":"<p><p>Atherosclerosis is a lipid-driven chronic inflammatory disease that is modulated by innate and adaptive immunity including humoral immunity. Importantly, antibody alterations achieved by genetic means or active and passive immunization strategies in preclinical studies can improve or aggravate atherosclerosis. Additionally, a wide range of epidemiological data demonstrate not only an association between the total levels of different antibody isotypes but also antibody levels targeting specific antigens with atherosclerotic cardiovascular disease. Here, we discuss the potential role of atherogenic dyslipidemia on the antibody repertoire and review potential antibody-mediated effector mechanisms involved in atherosclerosis development highlighting the major atherosclerosis-associated antigens that trigger antibody responses.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1161/ATVBAHA.124.321334
Christopher P Mack
{"title":"Targeting Vascular Stiffness.","authors":"Christopher P Mack","doi":"10.1161/ATVBAHA.124.321334","DOIUrl":"10.1161/ATVBAHA.124.321334","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1161/ATVBAHA.124.321415
Natalia Eberhardt, Chiara Giannarelli
{"title":"Innate Immune Dysregulations and Cross Talk in COVID-19: Novel Players in Atherogenesis.","authors":"Natalia Eberhardt, Chiara Giannarelli","doi":"10.1161/ATVBAHA.124.321415","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321415","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-07-03DOI: 10.1161/ATVBAHA.124.321141
Damian Martus, Sarah K Williams, Kira Pichi, Stefanie Mannebach-Götz, Nicolas Kaiser, Barbara Wardas, Claudia Fecher-Trost, Markus R Meyer, Frank Schmitz, Andreas Beck, Richard Fairless, Ricarda Diem, Veit Flockerzi, Anouar Belkacemi
Background: Tight control of cytoplasmic Ca2+ concentration in endothelial cells is essential for the regulation of endothelial barrier function. Here, we investigated the role of Cavβ3, a subunit of voltage-gated Ca2+ (Cav) channels, in modulating Ca2+ signaling in brain microvascular endothelial cells (BMECs) and how this contributes to the integrity of the blood-brain barrier.
Methods: We investigated the function of Cavβ3 in BMECs by Ca2+ imaging and Western blot, examined the endothelial barrier function in vitro and the integrity of the blood-brain barrier in vivo, and evaluated disease course after induction of experimental autoimmune encephalomyelitis in mice using Cavβ3-/- (Cavβ3-deficient) mice as controls.
Results: We identified Cavβ3 protein in BMECs, but electrophysiological recordings did not reveal significant Cav channel activity. In vivo, blood-brain barrier integrity was reduced in the absence of Cavβ3. After induction of experimental autoimmune encephalomyelitis, Cavβ3-/- mice showed earlier disease onset with exacerbated clinical disability and increased T-cell infiltration. In vitro, the transendothelial resistance of Cavβ3-/- BMEC monolayers was lower than that of wild-type BMEC monolayers, and the organization of the junctional protein ZO-1 (zona occludens-1) was impaired. Thrombin stimulates inositol 1,4,5-trisphosphate-dependent Ca2+ release, which facilitates cell contraction and enhances endothelial barrier permeability via Ca2+-dependent phosphorylation of MLC (myosin light chain). These effects were more pronounced in Cavβ3-/- than in wild-type BMECs, whereas the differences were abolished in the presence of the MLCK (MLC kinase) inhibitor ML-7. Expression of Cacnb3 cDNA in Cavβ3-/- BMECs restored the wild-type phenotype. Coimmunoprecipitation and mass spectrometry demonstrated the association of Cavβ3 with inositol 1,4,5-trisphosphate receptor proteins.
Conclusions: Independent of its function as a subunit of Cav channels, Cavβ3 interacts with the inositol 1,4,5-trisphosphate receptor and is involved in the tight control of cytoplasmic Ca2+ concentration and Ca2+-dependent MLC phosphorylation in BMECs, and this role of Cavβ3 in BMECs contributes to blood-brain barrier integrity and attenuates the severity of experimental autoimmune encephalomyelitis disease.
{"title":"Cavβ3 Contributes to the Maintenance of the Blood-Brain Barrier and Alleviates Symptoms of Experimental Autoimmune Encephalomyelitis.","authors":"Damian Martus, Sarah K Williams, Kira Pichi, Stefanie Mannebach-Götz, Nicolas Kaiser, Barbara Wardas, Claudia Fecher-Trost, Markus R Meyer, Frank Schmitz, Andreas Beck, Richard Fairless, Ricarda Diem, Veit Flockerzi, Anouar Belkacemi","doi":"10.1161/ATVBAHA.124.321141","DOIUrl":"10.1161/ATVBAHA.124.321141","url":null,"abstract":"<p><strong>Background: </strong>Tight control of cytoplasmic Ca<sup>2+</sup> concentration in endothelial cells is essential for the regulation of endothelial barrier function. Here, we investigated the role of Cavβ3, a subunit of voltage-gated Ca<sup>2+</sup> (Cav) channels, in modulating Ca<sup>2+</sup> signaling in brain microvascular endothelial cells (BMECs) and how this contributes to the integrity of the blood-brain barrier.</p><p><strong>Methods: </strong>We investigated the function of Cavβ3 in BMECs by Ca<sup>2+</sup> imaging and Western blot, examined the endothelial barrier function in vitro and the integrity of the blood-brain barrier in vivo, and evaluated disease course after induction of experimental autoimmune encephalomyelitis in mice using Cavβ3<sup>-/-</sup> (Cavβ3-deficient) mice as controls.</p><p><strong>Results: </strong>We identified Cavβ3 protein in BMECs, but electrophysiological recordings did not reveal significant Cav channel activity. In vivo, blood-brain barrier integrity was reduced in the absence of Cavβ3. After induction of experimental autoimmune encephalomyelitis, Cavβ3<sup>-/-</sup> mice showed earlier disease onset with exacerbated clinical disability and increased T-cell infiltration. In vitro, the transendothelial resistance of Cavβ3<sup>-/-</sup> BMEC monolayers was lower than that of wild-type BMEC monolayers, and the organization of the junctional protein ZO-1 (zona occludens-1) was impaired. Thrombin stimulates inositol 1,4,5-trisphosphate-dependent Ca<sup>2+</sup> release, which facilitates cell contraction and enhances endothelial barrier permeability via Ca<sup>2+</sup>-dependent phosphorylation of MLC (myosin light chain). These effects were more pronounced in Cavβ3<sup>-/-</sup> than in wild-type BMECs, whereas the differences were abolished in the presence of the MLCK (MLC kinase) inhibitor ML-7. Expression of <i>Cacnb3</i> cDNA in Cavβ3<sup>-/-</sup> BMECs restored the wild-type phenotype. Coimmunoprecipitation and mass spectrometry demonstrated the association of Cavβ3 with inositol 1,4,5-trisphosphate receptor proteins.</p><p><strong>Conclusions: </strong>Independent of its function as a subunit of Cav channels, Cavβ3 interacts with the inositol 1,4,5-trisphosphate receptor and is involved in the tight control of cytoplasmic Ca<sup>2+</sup> concentration and Ca<sup>2+</sup>-dependent MLC phosphorylation in BMECs, and this role of Cavβ3 in BMECs contributes to blood-brain barrier integrity and attenuates the severity of experimental autoimmune encephalomyelitis disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Cellular communication among different types of vascular cells is indispensable for maintaining vascular homeostasis and preventing atherosclerosis. However, the biological mechanism involved in cellular communication among these cells and whether this biological mechanism can be used to treat atherosclerosis remain unknown. We hypothesized that endothelial autophagy mediates the cellular communication in vascular tissue through exosome-mediated delivery of atherosclerosis-related genes.
Methods: Rapamycin and adeno-associated virus carrying Atg7 short hairpin RNA under the Tie (TEK receptor tyrosine kinase) promoter were used to activate and inhibit vascular endothelial autophagy in high-fat diet-fed ApoE-/- mice, respectively. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue were used to explore the effects of endothelial autophagy on endothelial function and atherosclerosis and its molecular mechanisms. Quantitative polymerase chain reaction and miRNA sequencing were performed to determine changes in miRNA expression in exosomes. Immunofluorescence and exosome coculture experiments were conducted to examine the role of endothelial autophagy in regulating the communication between endothelial cells and smooth muscle cells (SMCs) via exosomal miRNA.
Results: Endothelial autophagy was inhibited in thoracic aortas of high-fat diet-fed ApoE-/- mice. Furthermore, rapamycin alleviated high-fat diet-induced atherosclerotic burden and endothelial dysfunction, while endothelial-specific Atg7 depletion aggravated the atherosclerotic burden. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue analysis revealed that miR-204-5p was significantly increased in endothelial cells after high-fat diet exposure, which directly targeted Bcl2 to regulate endothelial cell apoptosis. Importantly, endothelial autophagy activation decreased excess miR-204-5p by loading miR-204-5p into multivesicular bodies and secreting it through exosomes. Moreover, exosomal miR-204-5p can effectively transport to SMCs, alleviating SMC calcification by regulating target proteins such as RUNX2 (runt-related transcription factor 2).
Conclusions: Our study revealed the exosomal pathway by which endothelial autophagy protects atherosclerosis: endothelial autophagy activation transfers miR-204-5p from endothelial cells to SMCs via exosomes, both preventing endothelial apoptosis and alleviating SMC calcification.
{"title":"Endothelial Autophagy Promotes Atheroprotective Communication Between Endothelial and Smooth Muscle Cells via Exosome-Mediated Delivery of miR-204-5p.","authors":"Zhen Tian, Hua Ning, Xinyue Wang, Yu Wang, Tianshu Han, Changhao Sun","doi":"10.1161/ATVBAHA.123.319993","DOIUrl":"10.1161/ATVBAHA.123.319993","url":null,"abstract":"<p><strong>Background: </strong>Cellular communication among different types of vascular cells is indispensable for maintaining vascular homeostasis and preventing atherosclerosis. However, the biological mechanism involved in cellular communication among these cells and whether this biological mechanism can be used to treat atherosclerosis remain unknown. We hypothesized that endothelial autophagy mediates the cellular communication in vascular tissue through exosome-mediated delivery of atherosclerosis-related genes.</p><p><strong>Methods: </strong>Rapamycin and adeno-associated virus carrying <i>Atg7</i> short hairpin RNA under the Tie (TEK receptor tyrosine kinase) promoter were used to activate and inhibit vascular endothelial autophagy in high-fat diet-fed <i>ApoE</i><sup><i>-/-</i></sup> mice, respectively. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue were used to explore the effects of endothelial autophagy on endothelial function and atherosclerosis and its molecular mechanisms. Quantitative polymerase chain reaction and miRNA sequencing were performed to determine changes in miRNA expression in exosomes. Immunofluorescence and exosome coculture experiments were conducted to examine the role of endothelial autophagy in regulating the communication between endothelial cells and smooth muscle cells (SMCs) via exosomal miRNA.</p><p><strong>Results: </strong>Endothelial autophagy was inhibited in thoracic aortas of high-fat diet-fed <i>ApoE</i><sup><i>-/</i></sup><sup><i>-</i></sup> mice. Furthermore, rapamycin alleviated high-fat diet-induced atherosclerotic burden and endothelial dysfunction, while endothelial-specific <i>Atg7</i> depletion aggravated the atherosclerotic burden. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue analysis revealed that miR-204-5p was significantly increased in endothelial cells after high-fat diet exposure, which directly targeted <i>Bcl2</i> to regulate endothelial cell apoptosis. Importantly, endothelial autophagy activation decreased excess miR-204-5p by loading miR-204-5p into multivesicular bodies and secreting it through exosomes. Moreover, exosomal miR-204-5p can effectively transport to SMCs, alleviating SMC calcification by regulating target proteins such as RUNX2 (runt-related transcription factor 2).</p><p><strong>Conclusions: </strong>Our study revealed the exosomal pathway by which endothelial autophagy protects atherosclerosis: endothelial autophagy activation transfers miR-204-5p from endothelial cells to SMCs via exosomes, both preventing endothelial apoptosis and alleviating SMC calcification.</p><p><strong>Registration: </strong>URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2200064155.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Pathogenic variants in PLIN1-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1-related FPL.
Methods: We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1-mutated FPL and 3 controls.
Results: Patients with PLIN1-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P<0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P=0.006). Compared with controls, patients with PLIN1-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P=0.005). VLDL-apoB100 production was not different between patients with PLIN1-related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (P=0.031) and IDL-apoB100 (P=0.031). Plasma LPL mass was significantly lower in patients with PLIN1-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P<0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass.
Conclusions: We show that hypertriglyceridemia associated with PLIN1-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.
{"title":"Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in <i>PLIN1</i>-Related Lipodystrophy.","authors":"Bruno Vergès, Marie-Christine Vantyghem, Yves Reznik, Laurence Duvillard, Alexia Rouland, Emilie Capel, Corinne Vigouroux","doi":"10.1161/ATVBAHA.124.320774","DOIUrl":"10.1161/ATVBAHA.124.320774","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in <i>PLIN1</i>-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with <i>PLIN1</i>-related FPL.</p><p><strong>Methods: </strong>We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. <i>LPL</i> mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 <i>PLIN1</i>-mutated FPL and 3 controls.</p><p><strong>Results: </strong>Patients with <i>PLIN1</i>-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; <i>P</i>=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; <i>P</i><0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, <i>P</i>=0.006). Compared with controls, patients with <i>PLIN1</i>-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; <i>P</i>=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; <i>P</i>=0.005). VLDL-apoB100 production was not different between patients with <i>PLIN1</i>-related FPL and controls. Compared with patients with type 2 diabetes, patients with <i>PLIN1</i>-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (<i>P</i>=0.031) and IDL-apoB100 (<i>P</i>=0.031). Plasma LPL mass was significantly lower in patients with <i>PLIN1</i>-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; <i>P</i><0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass.</p><p><strong>Conclusions: </strong>We show that hypertriglyceridemia associated with <i>PLIN1</i>-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-06DOI: 10.1161/ATVBAHA.123.320005
Yuechen Zhou, Tracy Tabib, Mengqi Huang, Ke Yuan, Yunhye Kim, Christina Morse, John Sembrat, Eleanor Valenzi, Robert Lafyatis
Background: Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and a leading cause of mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension). Investigation of transcriptomic alterations in vascular populations is critical to elucidating cellular mechanisms underlying pathobiology of SSc-associated and idiopathic PH.
Methods: We analyzed single-cell RNA sequencing profiles of endothelial and perivascular mesenchymal populations from explanted lung tissue of patients with SSc-associated PH (n=16), idiopathic pulmonary arterial hypertension (n=3), and healthy controls (n=15). Findings were validated by immunofluorescence staining of explanted human lung tissue.
Results: Three disease-associated endothelial populations emerged. Two angiogenic endothelial cell (EC) subtypes markedly expanded in SSc-associated PH lungs: tip ECs expressing canonical tip markers PGF and APLN and phalanx ECs expressing genes associated with vascular development, endothelial barrier integrity, and Notch signaling. Gene regulatory network analysis suggested enrichment of Smad1 (SMAD family member 1) and PPAR-γ (peroxisome proliferator-activated receptor-γ) regulon activities in these 2 populations, respectively. Mapping of potential ligand-receptor interactions highlighted Notch, apelin-APJ (apelin receptor), and angiopoietin-Tie (tyrosine kinase with immunoglobulin-like and EGF-like domains 1) signaling pathways between angiogenic ECs and perivascular cells. Transitional cells, expressing both endothelial and pericyte/smooth muscle cell markers, provided evidence for the presence of endothelial-to-mesenchymal transition. Transcriptional programs associated with arterial endothelial dysfunction implicated VEGF-A (vascular endothelial growth factor-A), TGF-β1 (transforming growth factor beta-1), angiotensin, and TNFSF12 (tumor necrosis factor ligand superfamily member 12)/TWEAK (TNF-related weak inducer of apoptosis) in the injury/remodeling phenotype of PH arterial ECs.
Conclusions: These data provide high-resolution insights into the complexity and plasticity of the pulmonary endothelium in SSc-associated PH and idiopathic pulmonary arterial hypertension and provide direct molecular insights into soluble mediators and transcription factors driving PH vasculopathy.
{"title":"Molecular Changes Implicate Angiogenesis and Arterial Remodeling in Systemic Sclerosis-Associated and Idiopathic Pulmonary Hypertension.","authors":"Yuechen Zhou, Tracy Tabib, Mengqi Huang, Ke Yuan, Yunhye Kim, Christina Morse, John Sembrat, Eleanor Valenzi, Robert Lafyatis","doi":"10.1161/ATVBAHA.123.320005","DOIUrl":"10.1161/ATVBAHA.123.320005","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and a leading cause of mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension). Investigation of transcriptomic alterations in vascular populations is critical to elucidating cellular mechanisms underlying pathobiology of SSc-associated and idiopathic PH.</p><p><strong>Methods: </strong>We analyzed single-cell RNA sequencing profiles of endothelial and perivascular mesenchymal populations from explanted lung tissue of patients with SSc-associated PH (n=16), idiopathic pulmonary arterial hypertension (n=3), and healthy controls (n=15). Findings were validated by immunofluorescence staining of explanted human lung tissue.</p><p><strong>Results: </strong>Three disease-associated endothelial populations emerged. Two angiogenic endothelial cell (EC) subtypes markedly expanded in SSc-associated PH lungs: tip ECs expressing canonical tip markers <i>PGF</i> and <i>APLN</i> and phalanx ECs expressing genes associated with vascular development, endothelial barrier integrity, and Notch signaling. Gene regulatory network analysis suggested enrichment of Smad1 (SMAD family member 1) and PPAR-γ (peroxisome proliferator-activated receptor-γ) regulon activities in these 2 populations, respectively. Mapping of potential ligand-receptor interactions highlighted Notch, apelin-APJ (apelin receptor), and angiopoietin-Tie (tyrosine kinase with immunoglobulin-like and EGF-like domains 1) signaling pathways between angiogenic ECs and perivascular cells. Transitional cells, expressing both endothelial and pericyte/smooth muscle cell markers, provided evidence for the presence of endothelial-to-mesenchymal transition. Transcriptional programs associated with arterial endothelial dysfunction implicated VEGF-A (vascular endothelial growth factor-A), TGF-β1 (transforming growth factor beta-1), angiotensin, and TNFSF12 (tumor necrosis factor ligand superfamily member 12)/TWEAK (TNF-related weak inducer of apoptosis) in the injury/remodeling phenotype of PH arterial ECs.</p><p><strong>Conclusions: </strong>These data provide high-resolution insights into the complexity and plasticity of the pulmonary endothelium in SSc-associated PH and idiopathic pulmonary arterial hypertension and provide direct molecular insights into soluble mediators and transcription factors driving PH vasculopathy.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-20DOI: 10.1161/ATVBAHA.123.319677
Huiping Shi, Jianhua Song, Liang Gao, Xindi Shan, Sumith R Panicker, Longbiao Yao, Michael McDaniel, Meixiang Zhou, Samuel McGee, Hui Zhong, Courtney T Griffin, Lijun Xia, Bojing Shao
Background: Integrin-regulated monocyte recruitment and cellular responses of monocyte-derived macrophages are critical for the pathogenesis of atherosclerosis. In the canonical model, talin1 controls ligand binding to integrins, a prerequisite for integrins to mediate leukocyte recruitment and induce immune responses. However, the role of talin1 in the development of atherosclerosis has not been studied. Our study investigated how talin1 in myeloid cells regulates the progression of atherosclerosis.
Methods: On an Apoe-/- background, myeloid talin1-deficient mice and the control mice were fed with a high-fat diet for 8 or 12 weeks to induce atherosclerosis. The atherosclerosis development in the aorta and monocyte recruitment into atherosclerotic lesions were analyzed.
Results: Myeloid talin1 deletion facilitated the formation of atherosclerotic lesions and macrophage deposition in lesions. Talin1 deletion abolished integrin β2-mediated adhesion of monocytes but did not impair integrin α4β1-dependent cell adhesion in a flow adhesion assay. Strikingly, talin1 deletion did not prevent Mn2+- or chemokine-induced activation of integrin α4β1 to the high-affinity state for ligands. In an in vivo competitive homing assay, monocyte infiltration into inflamed tissues was prohibited by antibodies to integrin α4β1 but was not affected by talin1 deletion or antibodies to integrin β2. Furthermore, quantitative polymerase chain reaction and ELISA (enzyme-linked immunosorbent assay) analysis showed that macrophages produced cytokines to promote inflammation and the proliferation of smooth muscle cells. Ligand binding to integrin β3 inhibited cytokine generation in macrophages, although talin1 deletion abolished the negative effects of integrin β3.
Conclusions: Integrin α4β1 controls monocyte recruitment during atherosclerosis. Talin1 is dispensable for integrin α4β1 activation to the high-affinity state and integrin α4β1-mediated monocyte recruitment. Yet, talin1 is required for integrin β3 to inhibit the production of inflammatory cytokines in macrophages. Thus, intact monocyte recruitment and elevated inflammatory responses cause enhanced atherosclerosis in talin1-deficient mice. Our study provides novel insights into the roles of myeloid talin1 and integrins in the progression of atherosclerosis.
{"title":"Deletion of Talin1 in Myeloid Cells Facilitates Atherosclerosis in Mice.","authors":"Huiping Shi, Jianhua Song, Liang Gao, Xindi Shan, Sumith R Panicker, Longbiao Yao, Michael McDaniel, Meixiang Zhou, Samuel McGee, Hui Zhong, Courtney T Griffin, Lijun Xia, Bojing Shao","doi":"10.1161/ATVBAHA.123.319677","DOIUrl":"10.1161/ATVBAHA.123.319677","url":null,"abstract":"<p><strong>Background: </strong>Integrin-regulated monocyte recruitment and cellular responses of monocyte-derived macrophages are critical for the pathogenesis of atherosclerosis. In the canonical model, talin1 controls ligand binding to integrins, a prerequisite for integrins to mediate leukocyte recruitment and induce immune responses. However, the role of talin1 in the development of atherosclerosis has not been studied. Our study investigated how talin1 in myeloid cells regulates the progression of atherosclerosis.</p><p><strong>Methods: </strong>On an <i>Apoe</i><sup><i>-/-</i></sup> background, myeloid talin1-deficient mice and the control mice were fed with a high-fat diet for 8 or 12 weeks to induce atherosclerosis. The atherosclerosis development in the aorta and monocyte recruitment into atherosclerotic lesions were analyzed.</p><p><strong>Results: </strong>Myeloid talin1 deletion facilitated the formation of atherosclerotic lesions and macrophage deposition in lesions. Talin1 deletion abolished integrin β2-mediated adhesion of monocytes but did not impair integrin α4β1-dependent cell adhesion in a flow adhesion assay. Strikingly, talin1 deletion did not prevent Mn<sup>2+</sup>- or chemokine-induced activation of integrin α4β1 to the high-affinity state for ligands. In an in vivo competitive homing assay, monocyte infiltration into inflamed tissues was prohibited by antibodies to integrin α4β1 but was not affected by talin1 deletion or antibodies to integrin β2. Furthermore, quantitative polymerase chain reaction and ELISA (enzyme-linked immunosorbent assay) analysis showed that macrophages produced cytokines to promote inflammation and the proliferation of smooth muscle cells. Ligand binding to integrin β3 inhibited cytokine generation in macrophages, although talin1 deletion abolished the negative effects of integrin β3.</p><p><strong>Conclusions: </strong>Integrin α4β1 controls monocyte recruitment during atherosclerosis. Talin1 is dispensable for integrin α4β1 activation to the high-affinity state and integrin α4β1-mediated monocyte recruitment. Yet, talin1 is required for integrin β3 to inhibit the production of inflammatory cytokines in macrophages. Thus, intact monocyte recruitment and elevated inflammatory responses cause enhanced atherosclerosis in talin1-deficient mice. Our study provides novel insights into the roles of myeloid talin1 and integrins in the progression of atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}