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  • 11
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    Abstract 281: Local MicroRNA Modulation Using a Novel Anti-mir-21-eluting Stent Effectively Prevents In-stent Restenosis
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Abstract: The major limitation of vascular angioplasty remains the occurrence of in-stent restenosis (ISR). The central role of miRNAs in the pathophysiology of the proliferative response in cardiovascular disease offers attractive concepts for possible therapeutic interventions, with systemic miRNA modulation however potentially causing substantial off-target effects. Aim of the current study was to test the feasibility of local miRNA modulation using drug eluted stent (DES) technology. Utilizing human ISR tissue samples, as well as a humanized rodent model of balloon-injured human internal mammary arteries with subsequent stent implantation in RNU rats, we were able to identify several miRNAs dys-regulated, including the well-characterized miR-21. We inhibited miR-21 (with a FAM-tagged-LNA-anti-miR-21), using either systemic or local delivery via DES. Systemic suppression of miR-21 showed a dose-dependent reduction of luminal obliteration, while not impeding vascular re-endothelialization. However, miR-21 expression in liver, heart, lung, and kidney appeared significantly reduced, with increased levels of serum creatinine, pointing towards the expected off-target effects of systemic miRNA modulation. Local mir-21 suppression, using the anti-miR-21-DES, effectively reduced myointimal hyperplasia and ISR compared to bare metal stents, while not exerting detectable off-target effects on any other organ we investigated. Additional in vitro experiments in cultured human coronary artery smooth muscle and endothelial cells further confirmed the ability of anti_miR-21 to limit SMC proliferation and migration by repressing mRNA and protein levels of its established target PTEN, while not affecting the proliferative response in the ECs. This is the first experimental study to demonstrate the efficacy, feasibility and suitability of an anti-miRNA-eluting stent (anti-miR-21-DES) for the reduction of ISR through dominant inhibition of SMC proliferation.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.281
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 12
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    Mouse Strain–Specific Differences in Vascular Wall Gene Expression and Their Relationship to Vascular Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2005
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 25, No. 2 ( 2005-02), p. 302-308
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 25, No. 2 ( 2005-02), p. 302-308
    Abstract: To gain insights into the molecular pathways that are differentially activated in strains of mice with varied susceptibility to atherosclerosis, we performed comprehensive transcriptional profiling of their vascular wall. Genes identified through these studies expand the repertoire of factors in disease-related signaling pathways and identify novel candidate genes in atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.0000151372.86863.a5
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2005
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  • 13
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    Abstract 297: Segmental Aortic Stiffening is a Mechanism Driving Early Abdominal Aortic Aneurysm Pathogenesis
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. suppl_1 ( 2014-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. suppl_1 ( 2014-05)
    Abstract: Stiffening of the aortic wall is a phenomenon consistently observed in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined. Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening (SAS) precedes aneurysm growth. Finite elements analysis (FEA)-based wall stress calculations reveal that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with reduced segmental stiffness of the AAA-prone aorta (due to equalized stiffness in adjacent aortic segments), reduced axial wall stress, decreased production of reactive oxygen species (ROS), attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, as well as attenuated apoptosis within the aortic wall. Cyclic pressurization of stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix (ECM) remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening. The present study introduces the novel concept of segmental aortic stiffening (SAS) as an early pathomechanism generating aortic wall stress and thereby triggering AAA growth. Therefore monitoring SAS by ultrasound might help to better identify patients at risk for AAA disease and better predict the susceptibility of small AAA to further growth. Moreover our results suggest that interventional mechanical stiffening of the AAA-adjacent aorta may be further tested as a novel treatment option to limit early AAA growth.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.34.suppl_1.297
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 14
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    Local MicroRNA Modulation Using a Novel Anti-miR-21–Eluting Stent Effectively Prevents Experimental In-Stent Restenosis
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. 9 ( 2015-09), p. 1945-1953
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. 9 ( 2015-09), p. 1945-1953
    Abstract: Despite advances in stent technology for vascular interventions, in-stent restenosis (ISR) because of myointimal hyperplasia remains a major complication. Approach and Results— We investigated the regulatory role of microRNAs in myointimal hyperplasia/ISR, using a humanized animal model in which balloon-injured human internal mammary arteries with or without stenting were transplanted into Rowett nude rats, followed by microRNA profiling. miR-21 was the only significantly upregulated candidate. In addition, miR-21 expression was increased in human tissue samples from patients with ISR compared with coronary artery disease specimen. We systemically repressed miR-21 via intravenous fluorescein-tagged-locked nucleic acid-anti-miR-21 (anti-21) in our humanized myointimal hyperplasia model. As expected, suppression of vascular miR-21 correlated dose dependently with reduced luminal obliteration. Furthermore, anti-21 did not impede reendothelialization. However, systemic anti-miR-21 had substantial off-target effects, lowering miR-21 expression in liver, heart, lung, and kidney with concomitant increase in serum creatinine levels. We therefore assessed the feasibility of local miR-21 suppression using anti-21–coated stents. Compared with bare-metal stents, anti-21–coated stents effectively reduced ISR, whereas no significant off-target effects could be observed. Conclusion— This study demonstrates the efficacy of an anti-miR–coated stent for the reduction of ISR.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.115.305597
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 15
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    Segmental Aortic Stiffening Contributes to Experimental Abdominal Aortic Aneurysm Development
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Vol. 131, No. 20 ( 2015-05-19), p. 1783-1795
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. 20 ( 2015-05-19), p. 1783-1795
    Abstract: Stiffening of the aortic wall is a phenomenon consistently observed in age and in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined. Methods and Results— Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening precedes aneurysm growth. Finite-element analysis reveals that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) wall stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent aortic segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with the reduced segmental stiffness of the AAA-prone aorta (attributable to equalized stiffness in adjacent segments), reduced axial wall stress, decreased production of reactive oxygen species, attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, and attenuated apoptosis within the aortic wall, as well. Cyclic pressurization of segmentally stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening. Conclusions— The present study introduces the novel concept of segmental aortic stiffening as an early pathomechanism generating aortic wall stress and triggering aneurysmal growth, thereby delineating potential underlying molecular mechanisms and therapeutic targets. In addition, monitoring segmental aortic stiffening may aid the identification of patients at risk for AAA.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.114.012377
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 16
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    H19 Induces Abdominal Aortic Aneurysm Development and Progression
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Vol. 138, No. 15 ( 2018-10-09), p. 1551-1568
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 138, No. 15 ( 2018-10-09), p. 1551-1568
    Abstract: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. Methods: We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E–deficient ( ApoE −/− ) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription–polymerase chain reaction and in situ hybridization. Results: Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR −/− (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1α as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1α and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1α via recruiting the transcription factor specificity protein 1 to the promoter region. Conclusions: The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.117.032184
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 17
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    Pathway analysis of coronary atherosclerosis
    American Physiological Society ; 2005
    In:  Physiological Genomics Vol. 23, No. 1 ( 2005-09-21), p. 103-118
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 23, No. 1 ( 2005-09-21), p. 103-118
    Abstract: Large-scale gene expression studies provide significant insight into genes differentially regulated in disease processes such as cancer. However, these investigations offer limited understanding of multisystem, multicellular diseases such as atherosclerosis. A systems biology approach that accounts for gene interactions, incorporates nontranscriptionally regulated genes, and integrates prior knowledge offers many advantages. We performed a comprehensive gene level assessment of coronary atherosclerosis using 51 coronary artery segments isolated from the explanted hearts of 22 cardiac transplant patients. After histological grading of vascular segments according to American Heart Association guidelines, isolated RNA was hybridized onto a customized 22-K oligonucleotide microarray, and significance analysis of microarrays and gene ontology analyses were performed to identify significant gene expression profiles. Our studies revealed that loss of differentiated smooth muscle cell gene expression is the primary expression signature of disease progression in atherosclerosis. Furthermore, we provide insight into the severe form of coronary artery disease associated with diabetes, reporting an overabundance of immune and inflammatory signals in diabetics. We present a novel approach to pathway development based on connectivity, determined by language parsing of the published literature, and ranking, determined by the significance of differentially regulated genes in the network. In doing this, we identify highly connected “nexus” genes that are attractive candidates for therapeutic targeting and followup studies. Our use of pathway techniques to study atherosclerosis as an integrated network of gene interactions expands on traditional microarray analysis methods and emphasizes the significant advantages of a systems-based approach to analyzing complex disease.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00101.2005
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2005
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  • 18
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    Abstract 465: Nicotine Differentially Influences Segmental Aortic Stiffening
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 37, No. suppl_1 ( 2017-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. suppl_1 ( 2017-05)
    Abstract: Background: Arterial stiffness is a major risk factor for various cardiovascular diseases and contributes to the development of abdominal aortic aneurysms (AAA). In this context, differential aortic stiffening of adjacent aortic segments increases aortic wall stress and accelerates the disease. Smoking is a major risk factor for AAA, in part due to nicotine. In this study, we investigated aortic stiffening of the thoracic and abdominal aorta and analyzed stiffness-related gene expression. Methods: 36 WT mice (C57BL/6) mice were infused with nicotine or PBS using osmotic mini pumps for 42 days. Thoracic segment (TS) and abdominal segment (AS) aortic stiffness were analyzed using ultrasound (M-Mode and PW). TS and AS were further investigated by ex vivo myograph measurements. Gene expression for TMIP2, MT1-MMP, MMP2, collagen type I and type III was performed for both segments separately. Results: Myograph measurements revealed increased strain within the AS after 2 weeks (p 〈 .05) in response to nicotine (vs. PBS), but no stiffening of the TS. After 6 weeks, the AS showed additional increases in strain with nicotine (p 〈 .05); however, only minor increases in stiffness could be observed for the TS. Ultrasound M-Mode results confirmed the myograph results. Nicotine treatment also led to increased aortic pulse wave velocity (PWV) after 2 weeks (p 〈 .05) and 6 weeks (p 〈 .05). Gene expression analysis revealed up-regulation in the TS and AS of MT1-MMP and MMP2 after 2 weeks of nicotine, while TIMP2 was downregulated, and collagen type I and type III were up-regulated in both TS and AS (p 〈 .05). After 6 weeks, there were no longer significant differences in either segment for any of these genes. Discussion: Aortic stiffening in response to nicotine varies between the TS and AS segment over a time course of 6 weeks. This leads to an increased stiffness gradient between the TS and AS. Gene expression changes in stiffness-related genes occurred in response to nicotine, although no difference appeared between the segments. We conclude that the difference in stiffness development for TS and AS could be based on a different basic morphological structure involving elastin and collagen load, and that these responses may in part explain nicotine’s role in promoting AAA.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.37.suppl_1.465
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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  • 19
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    Abstract 255: Induction of microRNA-21 Inhibits Abdominal Aortic Aneurysm Development and Nicotine-Augmented Expansion
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 32, No. suppl_1 ( 2012-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. suppl_1 ( 2012-05)
    Abstract: Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRs) are crucial regulators of cardiovascular pathology, and represent possible targets for the inhibition of AAA expansion. We identified miR-21 as a key modulator of proliferation and apoptosis in developing AAA in two established murine models: porcine-pancreatic-elastase, and angiotensin II-infusion. In both models, miR-21 increased with AAA development. Lentiviral overexpression of miR-21 (pre-21) induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion (as shown in Picrosirius Red stained images in the attached Figure below). miR-21 overexpression substantially decreased phosphatase and tensin homolog (PTEN), leading to increased levels of p-AKT, a known pro-proliferative and anti-apoptotic pathway. Systemic injection of a locked-nucleic-acid-modified antagomiR targeting miR-21 (anti-21) diminished the pro-proliferative impact of down-regulated PTEN, leading to significantly increased AAA size as compared to scrambled-control-miR (scr-miR). Importantly, similar results were seen in nicotine-augmented murine AAAs, while parallel findings were observed in human aortic tissue samples from patients undergoing surgical AAA repair (with more pronounced effects in smokers). In vitro studies using human aortic smooth muscle cells, fibroblasts as well as endothelial cells identified NFκB signaling pathways as the key regulator of miR-21 induction. Modulation of miR-21 expression shows great potential as a novel and powerful therapeutic option to limit AAA disease progression.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.32.suppl_1.A255
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 20
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    Abstract 38: Cyclin-Dependent Kinase Inhibitor 2B Regulates Transforming Growth Factor Beta 1 Mediated Smooth Muscle Cell Recruitment to Ischemic Blood Vessels
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Abstract: Peripheral artery disease (PAD) is a highly morbid condition affecting nearly 8.5 million Americans. Genome wide association studies (GWAS) have identified genetic variation at the chromosome 9p21 cardiovascular risk locus as an important source of heritable PAD risk. However, it is unknown whether this association is secondary to an increase in atherosclerosis or is the result of a separate angiogenesis-related mechanism. Quantitative ultrastructural evaluation of human plaque laden vascular samples revealed that carriers of the 9p21 risk allele displayed a significantly increased burden of immature intraplaque microvessels than carriers of the ancestral allele. To determine whether this process occurs under non-atherosclerotic conditions, we performed femoral artery ligation surgery in mice lacking Cdkn2b; a candidate gene we previously identified to have reduced expression in human carriers of the 9p21 risk allele. These animals developed advanced hind-limb ischemia and digital auto-amputation, relative to wild-type controls. Interestingly, in situ and in vitro hypoxic assays identified this defect to be a consequence of pro-angiogenic behavior displayed by CDKN2B deficient endothelial cells (EC) and impaired smooth muscle cell (SMC) recruitment to the developing neovessel. Exploratory microarray studies performed to identify the mechanism involved, revealed that TGFβ1 signaling is significantly induced in cultured CDKN2B -deficient cells; a finding later confirmed in the vasculature of individuals carrying the 9p21 risk allele. Subsequent molecular signaling studies reveal this increase to be a result of impaired expression of the inhibitory factor, SMAD-7. Increased TGFβ1 signaling was ultimately found to manifest the upregulation of a poorly studied effector molecule, TGFβ1-induced-1, which is a TGFβ-‘rheostat’ known to have antagonistic effects on the EC and SMC. Dual knockdown and rescue studies confirmed the reversibility of the proposed mechanism, in vitro. Taken together these findings suggest that loss of CDKN2B may not only promote cardiovascular disease through the development of atherosclerosis, but may also impair TGFβ1 signaling and hypoxic neovessel maturation consequently resulting in PAD.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.38
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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