Despite the global impact of macrophage activation in vascular disease, the underlying mechanisms remain obscure. Here we show, with global proteomic analysis of macrophage cell lines treated with either IFNγ or IL-4, that PARP9 and PARP14 regulate macrophage activation. In primary macrophages, PARP9 and PARP14 have opposing roles in macrophage activation. PARP14 silencing induces pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells, whereas it suppresses anti-inflammatory gene expression and STAT6 phosphorylation in M(IL-4) cells. PARP9 silencing suppresses pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells. PARP14 induces ADP-ribosylation of STAT1, which is suppressed by PARP9. Mutations at these ADP-ribosylation sites lead to increased phosphorylation. Network analysis links PARP9–PARP14 with human coronary artery disease. PARP14 deficiency in haematopoietic cells accelerates the development and inflammatory burden of acute and chronic arterial lesions in mice. These findings suggest that PARP9 and PARP14 cross-regulate macrophage activation.
Background-Clinical studies have demonstrated that 50% of individuals with chronic renal disease (CRD) die of cardiovascular causes, including advanced calcific arterial and valvular disease; however, the mechanisms of accelerated calcification in CRD remain obscure, and no therapies can prevent disease progression. We recently demonstrated in vivo that inflammation triggers cardiovascular calcification. In vitro evidence also indicates that elastin degradation products may promote osteogenesis. Here, we used genetically modified mice and molecular imaging to test the hypothesis in vivo that cathepsin S (catS), a potent elastolytic proteinase, accelerates calcification in atherosclerotic mice with CRD induced by 5/6 nephrectomy. Methods and Results-Apolipoprotein-deficient (apoE Ϫ/Ϫ )/catS ϩ/ϩ (nϭ24) and apoE Ϫ/Ϫ /catS Ϫ/Ϫ (nϭ24) mice were assigned to CRD and control groups. CRD mice had significantly higher serum phosphate, creatinine, and cystatin C levels than those without CRD. To visualize catS activity and osteogenesis in vivo, we coadministered catS-activatable and calcification-targeted molecular imaging agents 10 weeks after nephrectomy. Imaging coregistered increased catS and osteogenic activities in the CRD apoE Ϫ/Ϫ /catS ϩ/ϩ cohort, whereas CRD apoE Ϫ/Ϫ /catS Ϫ/Ϫ mice exhibited less calcification. Quantitative histology demonstrated greater catS-associated elastin fragmentation and calcification in CRD apoE Ϫ/Ϫ /catS ϩ/ϩ than CRD apoE Ϫ/Ϫ /catS Ϫ/Ϫ aortas and aortic valves. Notably, catS deletion did not cause compensatory increases in RNA levels of other elastolytic cathepsins or matrix metalloproteinases. Elastin peptide and recombinant catS significantly increased calcification in smooth muscle cells in vitro, a process further amplified in phosphate-enriched culture medium. Key Words: calcification Ⅲ aortic valve Ⅲ atherosclerosis Ⅲ kidney failure, chronic Ⅲ elastin W esternized societies face a growing burden of cardiovascular calcification, a disease of disordered mineral metabolism. [1][2][3][4] The interaction of prevalent epidemiological factors such as age, hypercholesterolemia, and renal insufficiency accelerates arterial and aortic valve calcification. 5 Clinical studies have demonstrated that approximately 50% of individuals with chronic renal disease (CRD) die of a cardiovascular cause. 6 -8 In addition to the classic risk factors such as age and dyslipidemia, patients with CRD have hyperphosphatemia, which is considered an independent risk factor for cardiovascular death. 9,10 CRD accelerates the development of atherosclerosis and excessive calcification in both the intima and media of atheromatous lesions. 11,12 Although they have different causes, intimal and medial calcification both involve the activation of proinflammatory mechanisms and smooth muscle cell (SMC) proliferation, which likely share common calcification pathways. Conclusions-The Clinical Perspective p 1794Recent studies suggest that arterial and valvular calcification occurs through highly regulated molecular proce...
Background-Calcification is a common finding in human coronary arteries; however, the relationship between calcification patterns, plaque morphology, and patterns of remodeling of culprit lesions in a comparison of patients with acute coronary syndromes (ACS) and those with stable conditions has not been documented. Methods and Results-Preinterventional intravascular ultrasound (IVUS) images of 178 patients were studied, 61 with acute myocardial infarction (AMI), 70 with unstable angina pectoris (UAP), and 47 with stable angina pectoris (SAP). The frequency of calcium deposits within an arc of less than 90°for all calcium deposits was significantly different in culprit lesions of patients with AMI, UAP, and SAP (PϽ0.0001). Moreover, the average number of calcium deposits within an arc of Ͻ90°per patient was significantly higher in AMI than in SAP (PϽ0.0005; meanϮSD, AMI 1.4Ϯ1.3, SAP 0.5Ϯ0.8). Conversely, calcium deposits were significantly longer in SAP patients (PϽ0.0001; meanϮSD, AMI 2.2Ϯ1.6, UAP 1.9Ϯ1.8, and SAP 4.3Ϯ3.2 mm). In AMI patients, the typical pattern was spotty calcification, associated with a fibrofatty plaque and positive remodeling. In ACS patients showing negative remodeling, no calcification was the most frequent observation. Conversely, SAP patients had the highest frequency of extensive calcification. Conclusions-Our observations show that IVUS allows the identification of vulnerable plaques in coronary arteries, not only by identifying a fibrofatty plaque and positive remodeling, but also by identifying a spotty pattern of calcification.
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